PHARMACEUTICAL COMPOSITIONS

Provided herein are semi-solid pharmaceutical compositions comprising an unsaturated free fatty acid, a stiffening agent and at least one active pharmaceutical ingredient; methods for their manufacture; and the use of said pharmaceutical compositions as a medicament. In particular, pharmaceutical compositions are provided comprising lopinavir and ritonavir for use in treating and/or inhibiting the progression of diseases and/or disorders such as HPV related dysplasia of the cervix.

BACKGROUND OF THE INVENTION

Semi-solid materials have unique rheological behaviour. Semi-solid systems have a permanent three-dimensional structure which imparts solid-like properties to the system.

When the system is disturbed by some level of strain or applied force, the three-dimensional structure is broken down but subsequently realigns once the strain or force is removed. As such, semi-solids have applications as pharmaceutical compositions, such as compositions for topical application. For example, the semi-solid can be mechanically spread uniformly over a surface, such as skin or a mucus membrane, to yield a film covering said surface.

Semi-solid pharmaceutical compositions include ointments, pastes, oil-in water (o/w) creams (semi-solid emulsions with solid internal phases), semi-solid emulsions with fluid internal phases, gels, and rigid foams.

Ointments typically contain a dissolved or suspended active pharmaceutical ingredient. Typically, ointments are smooth oil compositions and contain a significant proportion of a pharmaceutically acceptable oil or fat. Ointments are often hydrocarbon based. For example, fluid hydrocarbons, such as C ₁₆ -C ₃₀ straight chain and branched, are entrapped in a fine crystalline matrix of C ₃₀ -C ₅₀ hydrocarbons and as such serve to act as the ointment base. The extent and nature of the crystalline matrix determines the stiffness of the ointment, for example the manufacturing process used to produce the ointment can affect the size and number of crystallites of the C ₃₀ -C ₅₀ hydrocarbons. White and yellow petrolatum are examples of hydrocarbon-based ointments.

Other materials can also be used as the base material of an ointment. For example, semi-solid pharmaceutical compositions for topical application frequently contain fixed oils of vegetable origin consisting essentially of mono-, di-, and tri-glycerides of mixtures of saturated and unsaturated fatty acids. The most common oils include peanut, sesame, olive, cotton seed, almond, arachis, maize, and persic oil. Glycerides are esters formed from glycerol and fatty acids. Glycerol has three hydroxyl functional groups, which can be esterified with one, two, or three fatty acids to form mono-, di-, or tri-glycerides respectively.

Fatty acids are carboxylic acids with an aliphatic carbon chain which can be saturated or unsaturated, the length of the chain can vary from five or fewer carbon atoms (short-chain fatty acids, such as butyric acid), to twenty-two or more carbons (very long chain fatty acids). Fatty acids are usually derived from triglycerides or phospholipids. Phospholipid molecules consist of two hydrophobic fatty acid“tails” and a hydrophilic“head” consisting of a phosphate group. These two components are joined together by a glycerol molecule. Both triglyceride and phospholipids comprise fatty acids in a bound state. Conversely, free fatty acids are fatty acids which are not bound, that is they are not esterified.

Particular excipients can be used, primarily in topical compositions, to increase the composition’s viscosity. Examples of such excipients include cetyl alcohol, cetyl esters wax, microcrystalline wax, paraffin, stearyl alcohol, white wax, and yellow wax.

Semi-solid compositions employing the above-mentioned ointment base materials and/or additional excipients are associated with certain drawbacks. For example, vegetable oils may contain low levels of free fatty acids and the free fatty acid component of the vegetable oil can vary from batch to batch and/or over time. In particular, the identity of the free fatty acid and the relative amounts can vary from batch to batch and/or over time. This can be particularly problematic for active ingredient containing pharmaceutical products, which are required to be produced to a consistent and reproducible quality. Indeed, it is imperative that excipients used to manufacture pharmaceutical product are also of a consistent quality, i.e., minimal batch to batch variation.

Another disadvantage is that some excipients used in semi-solid compositions are not ideally suited for use with active pharmaceutical ingredients which are poorly soluble in the excipient. For example, when a composition is required with the active pharmaceutical ingredient dissolved in the composition, heating may be required to achieve solubilisation of the active pharmaceutical ingredient. This can be problematic if the active pharmaceutical ingredients are prone to degradation, such as oxidative and/or hydrolytic degradation, and wherein the rate and/or extent of degradation is increased when the active pharmaceutical ingredient is heated. This could potentially result in a loss of potency of the pharmaceutical composition during the manufacturing process and/or unwanted impurities being generated. Therefore, there is a need for manufacturing processes for producing a pharmaceutical composition which minimises the degradation of the active pharmaceutical ingredient and wherein the pharmaceutical composition is reproducibly manufactured to a pharmaceutically acceptable quality.

In addition, semi-solid compositions, upon topical administration to a site of application, can often leave significant residue, which is disadvantageous to the patient during treatment and/or may affect patient compliance.

The present invention is based on work carried out by the inventors to formulate a semi-solid composition comprising at least one active pharmaceutical ingredient. They have unexpectedly established that when a stiffening agent is combined with an unsaturated free fatty acid, a semi-solid composition is formed at room temperature. Accordingly, the present invention provides a pharmaceutical composition which is semi-solid at room temperature and comprises an unsaturated free fatty acid, a stiffening agent, and at least one active pharmaceutical ingredient. The combination of an unsaturated free fatty acid and stiffening agent has broad applicably in semi-solid dosage forms such as, for example, ointments and creams for topical application, liquid filled hard gel capsules, soft gel capsules, pessaries and suppositories.

The use of a free fatty acid (unsaturated free fatty acid and/or a saturated free fatty acid) in the composition is particularly advantageous as the quality of the free fatty acid in the composition can be controlled, such as identity, amount and purity of the free fatty acid. In contrast, other excipients, such as vegetable oils and polysorbates, may contain low and variable levels of free fatty acids. The free fatty acid composition of vegetable oil and polysorbate, such as the identity of the free fatty acid and the amount, can vary from batch to batch, and over time. Advantageously, in one embodiment, the active pharmaceutical ingredient is soluble in the unsaturated free fatty acid and no heat above room temperature is required to achieve solubilisation. This is particularly advantageous when using an active pharmaceutical ingredient that is prone to degradation especially when the extent and/or rate of degradation, such as degradation by oxidation and/or hydrolysis, is increased when the active pharmaceutical ingredient is exposed to heat.

Additionally and/or alternatively, the weight ratio of the unsaturated free fatty acid: stiffening agent can be varied depending on the exact nature of the composition, for example further excipients may be present in the composition, so that the composition is particularly well suited for a certain type of dosing, for example syringe applicator vaginal dosing. This is particularly useful in providing a topically applied treatment for the prevention or treatment of diseases as the composition can be specifically tailored for the site of application and/or the route of application. Topical treatments also potentially allow a patient to self-administer the treatment and/or the topical treatment can be used as an alternative to other medical treatments, such as surgery. Both of these are particularly beneficial to patients who live in a country with poor access to medical alternatives.

In addition, in certain embodiments the inventors have found that upon topical application of the pharmaceutical composition to a site of application, the pharmaceutical composition leaves minimal or no visible residue. For example, upon topical application of the pharmaceutical composition to the skin, the pharmaceutical composition can be absorbed by the skin leaving no residue. Advantageously, when the pharmaceutical composition only comprises fats in the form of free fatty acids (unsaturated free fatty acids and/or saturated free fatty acids) the composition during and after application to the skin is more silky, less greasy, less oily, less tacky and/or less glossy compared to pharmaceutical compositions comprising fats in which the fatty acid is predominantly present in a bound state (i.e., not a free fatty acid). Fats not in the form of free fatty acids are not easily absorbed by the skin.

In addition, the inventors have found that when the composition further comprises a muco-adhesive, the pharmaceutical composition transforms in-situ into a muco-adhesive composition upon mucosal application of the pharmaceutical composition.

Conveniently, the compositions of the invention are useful in the treatment of cancer. Many different forms of cancer exist, and it is believed that there are many different causes of the disease. The incidence of cancer varies, but it represents the second highest cause of mortality, after heart disease, in most developed countries.

Human tumour viruses are recognised to be a major cause of human cancer, and there is a great deal of evidence which supports the contention that these viruses cause cancer by inducing genetic instability in infected cells. Indeed, both the human T-cell leukemia virus type 1 (HTLV1) Tax and the human papilloma virus type 16 (HPV16) E6 oncoproteins are known to induce genetic instability producing abnormal numbers of centrosomes,

multinucleation and nuclear atypia.

Invasive cervical cancer (ICC) is an example of a cancer associated with viral infection which causes >270,000 deaths per annum with over 85% of these occurring in low resource countries. Infection with high-risk types of HPV has been established as the main aetiological agent for ICC. The development of ICC can take 10-20 years and is preceded by HPV related pre-invasive pathology which is characterised as either low-grade (CIN1) or high-grade cervical intraepithelial neoplasia (CIN2/3). Lesions can be screened for by cervical cytology testing where they are diagnosed (or graded) as either borderline atypical squamous cells of undetermined significance (ASCUS), low-grade squamous intraepithelial lesions (LSIL) or high-grade squamous intraepithelial lesions (HSIL).

The reduction in ICC related mortality in the developed world has been largely dependent on organised cytology screening and similar trends in cervical cancer mortality have been achieved by organised single screen and treatment in the rest of the world. However, in the poorer nations lack of resources and health education means that most pre-invasive cervical disease remains undiagnosed and untreated. Thus, where resources are limited, low-cost screening and treatment options are clearly a high priority.

Current treatment options in clinical practice are either by ablative (destructive) or excisional modalities. Systematic reviews have demonstrated that these treatment modalities have similar success rates but have different morbidities. In the developed world, Large Loop Excision of the Transformation Zone LLETZ (aka loop electrosurgical excision procedure - LEEP) is used in the majority of colposcopy clinics. Over 80% of these procedures are performed under local analgesia and the whole of the transformation zone is available for subsequent histological examination. The procedure is associated with a risk of

primary/secondary haemorrhage, prolonged discharge, infection and a risk of preterm delivery in subsequent pregnancies. The former side effects can be problematic particularly in low resource countries. Ablative treatment in the form of cold coagulation and cryotherapy are often advocated for use in low resource countries since these are low cost, require minimal infrastructure and can be carried out by trained non-medical health professionals. However, some studies have suggested that cryotherapy has a higher failure rate compared to other treatment modalities.

There are a variety of locally-applied, non-surgical approaches which have been evaluated for the treatment of cervical dysplasia including; photodynamic therapy (PDT); off- licence use of the anti-cytomegalovirus (CMV) drug cidofovir; local application of the immune activator Imiquimod and direct application of the cytotoxic drug 5 flurouracil (5FU). Although some of these alternative treatment modalities show promise, their treatment outcomes are inferior to the reported 80-95% success rates obtained in quality assured colposcopy units.

An effective, inexpensive, non-surgical, self-applied treatment for HPV related cervical dysplasia would have great potential particularly in low resource settings. Furthermore, improved compliance with topical treatment would be enhanced, if the side effects are minimised.

A recent advance in the treatment of cancers caused by viruses is disclosed in

WO2015/059485 which describes the protease inhibitors, lopinavir and ritonavir (which had previously been used as orally ingested medicaments for the clinical management of retroviral infections such as HIV) as being clinically useful for topical administration to tissues to prevent or treat malignancies caused by human papilloma virus. The authors were particularly surprised to find that soft capsules of KALETRA ^® (which is marketed by Abbott/ Abbvie for the treatment of HIV infections by oral administration) can be

administered topically (e.g. inserted into the vagina for treatment of the cervix) for the prevention or treatment of cancerous conditions, for the prevention or treatment of oncogenic viral infections and for the prevention or treatment of benign proliferative orders.

KALETRA ^® (or its equivalent LOPIMUNE) is available for oral consumption as a solution comprising 80 mg lopinavir and 20 mg ritonavir per millilitre or as a soft capsule for oral administration that comprises 133.3 mg lopinavir and 33.3 mg ritonavir. The solution additionally contains alcohol (42% w/w), high fructose corn syrup, propylene glycol, purified water, glycerol, povidone, flavourings, polyoxyl 40 hydrogenated castor oil, acesulfame potassium, saccharin sodium, sodium chloride, peppermint oil, sodium citrate, citric acid, and menthol. The soft capsule contents contain, along with lopinavir and ritonavir, oleic acid, propylene glycol, polyoxy 35 castor oil, and purified water. (KALETRA ^® Summary of Product Characteristics, EMA).

The compositions of the invention offer significant benefits when compared to oral soft capsule compositions when a topical formulation is required. Accordingly, in one particular embodiment, when the composition comprises lopinavir and ritonavir is topically applied, for example to the skin or vaginal wall, the composition can be used to treat and prevent cancerous conditions, for the prevention or treatment of oncogenic viral infections, and for the prevention or treatment of benign proliferative orders.

SUMMARY OF INVENTION

Disclosed herein are pharmaceutical compositions comprising an unsaturated free fatty acid, a stiffening agent, and at least one active pharmaceutical ingredient, wherein the pharmaceutical composition is a semi-solid at room temperature.

According to a first aspect of the invention, there is provided a pharmaceutical composition comprising: an unsaturated free fatty acid; a stiffening agent; and at least one active pharmaceutical ingredient; wherein the unsaturated free fatty acid is present at a level of at least 20% by weight of the total pharmaceutical composition weight and wherein the pharmaceutical composition is semi-solid at room temperature. According to a second aspect of the invention, there is provided a process to manufacture a pharmaceutical composition of the first aspect, the process comprising the step of incorporating a stiffening agent, at least one active pharmaceutical ingredient, and an unsaturated free fatty acid together to provide the pharmaceutical composition which is a semi-solid at room temperature, wherein the unsaturated free fatty acid is present at a level of at least 20% by weight of the total composition.

According to a third aspect, there is provided a process to manufacture a

pharmaceutical composition of the first aspect, the process comprising:

a. incorporating at least one active pharmaceutical ingredient in an unsaturated free fatty acid; and

b. incorporating a stiffening agent into the mixture obtained from step a. to provide a semi-solid composition;

wherein the unsaturated free fatty acid is present at a level of at least 20% by weight of the total composition.

According to a fourth aspect of the invention there is provided a pharmaceutical composition according to the first aspect of the invention for use as a medicament. In one embodiment, the pharmaceutical composition is used as a medicament for treating and/or inhibiting the development or progression of diseases and/or disorders. In one embodiment, the pharmaceutical composition is used as a medicament for treating and/or inhibiting the development or progression of cancers and/or benign proliferative disorders. In one embodiment, the pharmaceutical composition comprises an effective amount of the at least one active pharmaceutical ingredient. In one embodiment, the pharmaceutical composition comprises an effective amount of the at least one active pharmaceutical ingredient for treating and/or inhibiting the development or progression of a disease or disorder. In one

embodiment, the pharmaceutical composition comprises an effective amount of the at least one active pharmaceutical ingredient for treating and/or inhibiting the development or progression of cancers and/or benign proliferative disorders. In a further embodiment, the pharmaceutical composition comprises an effective amount of the at least one active pharmaceutical ingredient for treating a Human Papilloma Virus (HPV) infection with or without attendant abnormal pathology. In one embodiment, the pharmaceutical composition is used as a medicament for treating and/or inhibiting the development of early stage neoplasias. In one embodiment, the pharmaceutical composition is used as a medicament for treating or preventing the development of HPV related cervical, vulval, vaginal, penile, anal, oral or laryngeal neoplasias and/or warts. In one embodiment, the pharmaceutical composition is for use as a medicament for treating or preventing the development of cervical neoplasias.

According to a fifth aspect of the invention there is provided a method of treating and/or inhibiting the development or progression of diseases and/or disorders in a subject in need of such treatment or inhibition comprising administering a therapeutically effective amount of a composition according to the first aspect of the invention. In one embodiment, there is provided a method of treating and/or inhibiting the development or progression of cancers and/or benign proliferative disorders in a subject in need of such treatment or inhibition comprising administering a therapeutically effective amount of a composition according to the first aspect of the invention. In one embodiment, the cancer or disorder is caused or induced by a human papilloma virus (HPV). In a further embodiment, there is a provided a method of treating a Human Papilloma Virus (HPV) infection with or without attendant abnormal pathology in a subject in need of such treatment or inhibition comprising administering a therapeutically effective amount of the pharmaceutical composition according to the first aspect of the invention. In one embodiment, there is provided a method of treating and/or inhibiting the development of early stage neoplasias in a subject in need of such treatment or inhibition comprising administering a therapeutically effective amount of the pharmaceutical composition according to the first aspect of the invention. In one embodiment, there is provided a method of treating or preventing the development of HPV related cervical, vulval, vaginal, penile, anal, oral or laryngeal neoplasias and/or warts in a subject in need of such treatment or inhibition comprising administering a therapeutically effective amount of the pharmaceutical composition according to the first aspect of the invention. In one embodiment, there is provided a method of treating or preventing the development of cervical neoplasias in a subject in need of such treatment or inhibition comprising administering a therapeutically effective amount of the pharmaceutical composition according to the first aspect of the invention.

Conveniently, the cancer or benign proliferative disorder is caused by a viral infection, more preferably by an oncogenic virus and in particular human tumour viruses such as HPV.

Conveniently, the invention concerns treating a subject having an HPV related dysplasia of the cervix comprising administering to said subject a therapeutically effective dose of the disclosed pharmaceutical compositions. DETAILED DESCRIPTION

The disclosed compositions, processes of manufacture and methods may be understood more readily by reference to the following detailed description which form a part of this disclosure. It is to be understood that the disclosed compositions, processes of manufacture and methods are not limited to the specific compositions, processes of manufacture and methods described and/or shown herein, and that the terminology used herein is for the purpose of describing particular embodiments by way of example only and is not intended to be limiting of the claimed compositions, processes of manufacture and methods.

Reference to a particular numerical value includes at least that particular value, unless the context clearly dictates otherwise. When a range of values is expressed, another embodiment includes from the one particular value and/or to the other particular value.

Further, reference to values stated in ranges include each and every value within that range. All ranges are inclusive and combinable.

When values are expressed as approximations, by use of the antecedent“about,” it will be understood that the particular value forms another embodiment.

It is to be appreciated that certain features of the disclosed compositions, processes of manufacture and methods which are, for clarity, described herein in the context of separate embodiments, may also be provided in combination in a single embodiment. Conversely, various features of the disclosed compositions, processes of manufacture and methods that are, for brevity, described in the context of a single embodiment, may also be provided separately or in any sub-combination.

As used herein, the singular forms“a,”“an,” and“the” include the plural.

The following abbreviations are used herein: human papilloma virus (HPV); Atypical squamous cells of undetermined significance (ASC-US); Low grade squamous intraepithelial lesion (LSIL); High grade squamous intraepithelial lesion (HSIL); Cervical intraepithelial neoplasia 1 (CIN1); Cervical Intraepithelial neoplasia 2 (CIN2); Cervical intraepithelial neoplasia 3 (CIN3); Carcinoma in situ (CIS); Invasive Cervical Carcinoma (ICC).

The term“about” when used in reference to numerical ranges, cutoffs, or specific values is used to indicate that the recited values may vary by up to as much as 10% from the listed value. As many of the numerical values used herein are experimentally determined, it should be understood by those skilled in the art that such determinations can, and often times will, vary among different experiments. The values used herein should not be considered unduly limiting by virtue of this inherent variation. Thus, the term“about” is used to encompass variations of ± 10% or less, variations of ± 5% or less, variations of ± 1% or less, variations of ± 0.5% or less, or variations of ± 0.1% or less from the specified value.

As used herein,“treating” and like terms refer to reducing the severity and/or frequency of symptoms, eliminating symptoms and/or the underlying cause of said symptoms, reducing the frequency or likelihood of symptoms and/or their underlying cause, delaying, preventing and/or slowing the progression of diseases and/or disorders, such as cancers or benign proliferative disorders, and improving or remediating damage caused, directly or indirectly, by the diseases and/or disorders such as cancers or benign proliferative disorders.

As used herein, the phrase“therapeutically effective dose” refers to an amount of a composition comprising at least one active pharmaceutical ingredient, as described herein, effective to achieve a particular biological or therapeutic result such as, but not limited to, biological or therapeutic results disclosed, described, or exemplified herein. The

therapeutically effective dose may vary according to factors such as the disease state, age, sex, and weight of the individual, and the ability of the composition to cause a desired response in a subject. Such results include, but are not limited to, the reduction, remission, and/or regression of the benign or malignant disease or prevention of the development of the benign or malignant disease, as determined by any means suitable in the art.

As used herein,“subject” includes a vertebrate, mammal, domestic animal or preferably a human being.

PHARMACEUTICAL COMPOSITIONS

According to a first aspect of the invention, there is provided a pharmaceutical composition comprising: an unsaturated free fatty acid; a stiffening agent; and at least one active pharmaceutical ingredient; wherein the unsaturated free fatty acid is present at a level of at least 20% by weight of the total pharmaceutical composition weight and wherein the composition is semi-solid at room temperature.

Contrary to prior art compositions which employ vegetable oils and/or polysorbates as agents to thicken the composition, the inventors have found that an unsaturated free fatty acid and a stiffening agent can be used to prepare a pharmaceutical composition which is a semi solid at room temperature. In the present compositions, a liquid unsaturated free fatty acid has been stiffened by a stiffening agent to yield a semi-solid composition. A semi-solid is any material that can be present in a stationary material state until an external stress is applied resulting in flow of the material. The physical properties of a semi solid are a mixture of a solid and liquid. It will be apparent to the skilled person that the pharmaceutical composition is in a form of a semi-solid, for example by testing the pharmaceutical composition using a rheometer. From rheometric testing of the

pharmaceutical composition the yield stress, the storage modulus, the loss modulus and tan d can be determined. The yield stress is a direct measure for the initiation of material flow (solid state to fluid state) in response to an applied stress. The storage modulus is a direct measure of a fluid’s solid-like behaviour. The loss modulus is a direct measure of a fluid’s fluid-like behaviour. Tan d is the ratio of the loss modulus to the storage modulus and is a unitless measure. A tan d value of <1 defines a material as largely solid like, while a tan d value >1 defines a material as predominantly fluid-like. For example, the rheological behaviour of the semi-solid can be tested according to the methodology described in Example 6

In one embodiment, the pharmaceutical composition has a tan d value of between about 0.5 and about 1.5 at 37°C, such as about 0.8 and about 1.2.

In one embodiment, there is provided a pharmaceutical composition comprising: a) an unsaturated free fatty acid;

b) a stiffening agent; and

c) at least one active pharmaceutical ingredient;

wherein the unsaturated free fatty acid is present at a level of at least 20% by weight of the total pharmaceutical composition weight and wherein the composition has a tan d value of between about 0.5 and about 1.5 at 37°C, such as about 0.8 and about 1.2.

In one embodiment, the pharmaceutical composition is an ointment, a cream, an oral dose liquid filled hard gel capsule, a soft gel capsule, a pessary or a suppository. In one embodiment, the pharmaceutical composition is an ointment. In one embodiment, the pharmaceutical composition is an opaque ointment.

In one embodiment, there is provided a pharmaceutical composition comprising: a) an unsaturated free fatty acid;

b) a stiffening agent; and

c) at least one active pharmaceutical ingredient;

wherein the unsaturated free fatty acid is present at a level of at least 20% by weight of the total pharmaceutical composition weight; and wherein the pharmaceutical composition is an ointment at room temperature.

In one embodiment, the pharmaceutical composition has a complex viscosity of between about 500 and about 20000 cps when measured at 37°C, such as between about 1000 to about 10000 cps, such as between about 3000 and about 9000 cps, such as between about 4000 and about 8000 cps, such as between about 5000 and about 7000 cps, or such as about 6000 cps. In a further embodiment, the pharmaceutical composition has a complex viscosity of between about 500 and about 3000 cps when measured at 37°C, such as between about 800 and about 2500 cps, such as between about 1000 and about 2000 cps, or such as between about 1200 and about 2000 cps. In a further embodiment, the pharmaceutical composition has a complex viscosity of about 1400 cps when measured at 37°C or about 1900 cps when measured at 37°C.

In one embodiment, the pharmaceutical composition is for topical application. In one embodiment, the pharmaceutical composition is for topical application to skin or mucosa. In one embodiment, the pharmaceutical composition is for intravaginal delivery. In one embodiment, the pharmaceutical composition is for intravaginal delivery using a syringe. In one embodiment, the pharmaceutical composition is for dispensing from a tube.

In one embodiment, the pharmaceutical composition is for topical delivery of the at least one active pharmaceutical ingredient to a site of application. In one embodiment, the site of application comprises mucosa. In one embodiment, the mucosa is vaginal mucosa.

In one embodiment, the pharmaceutical composition is for topical delivery of the at least one active pharmaceutical ingredient to the cervix (e.g. as an ointment, a cream, an oral dose liquid filled hard gel capsule, a soft gel capsule, a pessary or a suppository) for preventing the development of, or treating, cervical cancer (e.g. caused by high-risk types of HPV such as HPV16).

When used to treat (or prevent the development of) cervical cancer, the

pharmaceutical compositions can be formulated as creams or ointments that may be applied directly to the cervix by techniques known to the art.

In one embodiment, the pharmaceutical composition is a topical pharmaceutical composition. In a further embodiment, the topical pharmaceutical composition

advantageously provides prolonged retention of the at least one active pharmaceutical ingredient at the site of application. This ensures that the composition remains at the site of application for long enough to allow a significant proportion of the active pharmaceutical ingredient to be released from the composition and have the desired efficacious effect on the disease and/or disorder being treated. The skilled person would be aware that various in-vitro techniques can be employed to measure release of the active pharmaceutical ingredient from the composition. For example, the amount of active pharmaceutical ingredient delivered through a membrane can be determined using, for example, Vertical Diffusion Studies (“Topical and Transdermal Drug Products, Pharmacopeia Forum, Vol. 35(3) [May- June 2009]). The in-vitro release rate can be correlated to how the composition will perform in an in-vivo setting. In one embodiment, at least 50% by weight of the active pharmaceutical ingredient is released from the composition, such as at least 60% by weight, such as at least 70% by weight, such as at least 80% by weight, such as at least 90% by weight, or such as at least 95% by weight within 2 hours, within 3 hours, within 6 hours, or within 8 hours.

In one embodiment, the composition remains at the site of application for at least 30 minutes, such as at least 1 hour, such as at least 2 hours, such as at least 4 hours, such as at least 6 hours, such as at least 8 hours, such as at least 12 hours, or such as at least 24 hours.

In one embodiment, the pharmaceutical composition remains at the site of application for up to 4 hours, for up to 6 hours, for up to 8 hours, or for up to 10 hours.

In one embodiment, the pharmaceutical composition, upon topical application to a site of application, leaves minimal or no visible residue of the pharmaceutical composition at the site of application. In one embodiment, minimal or no visible residue is observed after at least 5 minutes from topical application, such as about 10 minutes. In one embodiment, the pharmaceutical composition upon topical application to skin is absorbed by the skin. In one embodiment, the pharmaceutical composition upon topical application to skin is absorbed by the skin leaving no visible residue.

In one embodiment, there is provided a pharmaceutical composition comprising: a) an unsaturated free fatty acid;

b) a stiffening agent; and

c) at least one active pharmaceutical ingredient;

wherein the unsaturated free fatty acid is present at a level of at least 20% by weight of the total pharmaceutical composition weight; and

wherein upon topical application of the pharmaceutical composition to a site of application the tackiness and/or greasiness of the pharmaceutical composition is reduced, for example no tackiness and/or greasiness is observed after at least 5 minutes from topical application, such as about 10 minutes. In one embodiment, upon topical application of the pharmaceutical composition to a site of application the tackiness and/or greasiness of the pharmaceutical composition is reduced, for example no tackiness and/or greasiness is observed after at least 5 minutes from topical application, such as about 10 minutes.

In one embodiment, the pharmaceutical composition readily thins upon topical application to skin. Advantageously, the thinning of the pharmaceutical composition upon application to the skin enables easy spreading of the pharmaceutical composition on the skin resulting in complete coverage of the dosed site. In one embodiment, the pharmaceutical composition is opaque, and upon topical application to the opacity of the pharmaceutical composition decreases, for example, the administered pharmaceutical composition is transparent. In one embodiment, the pharmaceutical composition does not discolour the skin upon topical application of the pharmaceutical composition to the skin.

In one embodiment, there is provided a pharmaceutical composition comprising: a) an unsaturated free fatty acid;

b) a stiffening agent; and

c) at least one active pharmaceutical ingredient;

wherein the unsaturated free fatty acid is present at a level of at least 20% by weight of the total pharmaceutical composition weight; and

wherein the pharmaceutical composition is opaque, and upon topical application to the skin the opacity of the pharmaceutical composition decreases, for example, the administered pharmaceutical composition is transparent.

In one embodiment, the pharmaceutical composition is an anhydrous pharmaceutical composition. In one embodiment, the pharmaceutical composition comprises less than 5% by weight of water of the total pharmaceutical composition weight, such as less than 1% by weight, such as less than 0.5% by weight, such as less than 0.1% by weight, such as less than 0.05% by weight. In one embodiment, the pharmaceutical composition is substantially free of water. In one embodiment, the pharmaceutical composition is entirely free of water.

In one embodiment, there is provided a pharmaceutical composition comprising: a) an unsaturated free fatty acid;

b) a stiffening agent; and

c) at least one active pharmaceutical ingredient; wherein the unsaturated free fatty acid is present at a level of at least 25% by weight of the total pharmaceutical composition weight.

In one embodiment, there is provided a pharmaceutical composition comprising: a) an unsaturated free fatty acid;

b) a stiffening agent; and

c) at least one active pharmaceutical ingredient;

wherein the unsaturated free fatty acid is present at a level of at least 45% by weight of the total pharmaceutical composition weight.

In one embodiment, the pharmaceutical composition comprises:

a. an unsaturated free fatty acid;

b. a stiffening agent; and

c. at least one active pharmaceutical ingredient;

wherein the sum of the unsaturated free fatty acid and the stiffening agent present in the pharmaceutical composition is at least 50% by weight of the total pharmaceutical composition weight, wherein the unsaturated free fatty acid is present at a level of at least 20% by weight of the total pharmaceutical composition weight, and wherein the composition is semi-solid at room temperature.

In one embodiment, the pharmaceutical composition comprises:

a. an unsaturated free fatty acid;

b. a stiffening agent; and

c. at least one active pharmaceutical ingredient;

wherein the sum of the unsaturated free fatty acid and the stiffening agent present in the pharmaceutical composition is at least 60% by weight of the total pharmaceutical composition weight, wherein the unsaturated free fatty acid is present at a level of at least 20% by weight of the total pharmaceutical composition weight, and wherein the composition is semi-solid at room temperature.

In one embodiment, the pharmaceutical composition comprises:

a. an unsaturated free fatty acid;

b. a stiffening agent; and

c. at least one active pharmaceutical ingredient; wherein the sum of the unsaturated free fatty acid and the stiffening agent present in the pharmaceutical composition is at least 75% by weight of the total pharmaceutical

composition weight, wherein the unsaturated free fatty acid is present at a level of at least 20% by weight of the total pharmaceutical composition weight, and wherein the composition is semi-solid at room temperature.

In one embodiment, the pharmaceutical composition comprises:

a. an unsaturated free fatty acid;

b. a stiffening agent; and

c. at least one active pharmaceutical ingredient;

wherein the sum of the unsaturated free fatty acid and the stiffening agent present in the pharmaceutical composition is at least 80% by weight of the total pharmaceutical

composition weight, wherein the unsaturated free fatty acid is present at a level of at least 20% by weight of the total pharmaceutical composition weight, and wherein the composition is semi-solid at room temperature.

In one embodiment, the pharmaceutical composition comprises:

a. an unsaturated free fatty acid;

b. a stiffening agent; and

c. at least one active pharmaceutical ingredient;

wherein the sum of the unsaturated free fatty acid and the stiffening agent present in the pharmaceutical composition is at least 85% by weight of the total pharmaceutical

composition weight, wherein the unsaturated free fatty acid is present at a level of at least 20% by weight of the total pharmaceutical composition weight, and wherein the composition is semi-solid at room temperature.

In one embodiment, the pharmaceutical composition comprises:

a. an unsaturated free fatty acid;

b. a stiffening agent; and

c. at least one active pharmaceutical ingredient;

wherein the stiffening agent is a saturated free fatty acid, wherein the sum of the unsaturated free fatty acid and the saturated free fatty acid present in the pharmaceutical composition is at least 50% by weight of the total pharmaceutical composition weight, wherein the unsaturated free fatty acid is present at a level of at least 20% by weight of the total pharmaceutical composition weight, and wherein the composition is semi-solid at room temperature. In one embodiment, the pharmaceutical composition comprises:

a. an unsaturated free fatty acid;

b. a stiffening agent; and

c. at least one active pharmaceutical ingredient;

wherein the stiffening agent is a saturated free fatty acid, wherein the sum of the unsaturated free fatty acid and the saturated free fatty acid present in the pharmaceutical composition is at least 60% by weight of the total pharmaceutical composition weight, wherein the unsaturated free fatty acid is present at a level of at least 20% by weight of the total pharmaceutical composition weight, and wherein the composition is semi-solid at room temperature.

In one embodiment, the pharmaceutical composition comprises:

a. an unsaturated free fatty acid;

b. a stiffening agent; and

c. at least one active pharmaceutical ingredient;

wherein the stiffening agent is a saturated free fatty acid, wherein the sum of the unsaturated free fatty acid and the saturated free fatty acid present in the pharmaceutical composition is at least 75% by weight of the total pharmaceutical composition weight, wherein the unsaturated free fatty acid is present at a level of at least 20% by weight of the total pharmaceutical composition weight, and wherein the composition is semi-solid at room temperature.

In one embodiment, the pharmaceutical composition comprises:

a. an unsaturated free fatty acid;

b. a stiffening agent; and

c. at least one active pharmaceutical ingredient;

wherein the stiffening agent is a saturated free fatty acid, wherein the sum of the unsaturated free fatty acid and the saturated free fatty acid present in the pharmaceutical composition is at least 80% by weight of the total pharmaceutical composition weight, wherein the unsaturated free fatty acid is present at a level of at least 20% by weight of the total pharmaceutical composition weight, and wherein the composition is semi-solid at room temperature.

In one embodiment, the pharmaceutical composition comprises:

a. an unsaturated free fatty acid;

b. a stiffening agent; and

c. at least one active pharmaceutical ingredient; wherein the stiffening agent is a saturated free fatty acid, wherein the sum of the unsaturated free fatty acid and the saturated free fatty acid present in the pharmaceutical composition is at least 85% by weight of the total pharmaceutical composition weight, wherein the unsaturated free fatty acid is present at a level of at least 20% by weight of the total pharmaceutical composition weight, and wherein the composition is semi-solid at room temperature.

In one embodiment, the pharmaceutical composition comprises:

a. an unsaturated free fatty acid;

b. a stiffening agent; and

c. at least one active pharmaceutical ingredient;

wherein the unsaturated free fatty acid is present at a level of at least 20% by weight of the total pharmaceutical composition weight, wherein the pharmaceutical composition is semi solid at room temperature, and wherein the pharmaceutical composition comprises at least one part stiffening agent by weight to 0.1 to 20 parts unsaturated free fatty acid by weight.

In one embodiment, the pharmaceutical composition comprises:

a. an unsaturated free fatty acid;

b. a stiffening agent; and

c. at least one active pharmaceutical ingredient;

wherein the unsaturated free fatty acid is present at a level of at least 20% by weight of the total pharmaceutical composition weight, wherein the pharmaceutical composition is semi- solid at room temperature, and wherein the pharmaceutical composition comprises at least one part stiffening agent by weight to 1 to 20 parts unsaturated free fatty acid by weight.

Advantageously, the pharmaceutical composition only comprises or predominantly comprises fats in the form of free fatty acids (unsaturated free fatty acid and/or saturated free fatty acid), for example all fatty acids present in the composition are in the form of a free fatty acid. This allows the pharmaceutical composition to be manufactured at room temperature which is advantageous when the at least one active pharmaceutical is prone to degradation, such as oxidation and/or hydrolysis, and wherein the rate and/or extent of degradation is increased when the active pharmaceutical ingredient is exposed to heat. In one embodiment, at least 60% by weight of the fatty acids in the pharmaceutical composition are in the free form, such as at least 65% by weight, such as at least 70% by weight, such as at least 80% by weight, or such as at least 85% by weight.

In one embodiment, the pharmaceutical composition comprises: a. an unsaturated free fatty acid;

b. a stiffening agent;

c. at least one active pharmaceutical ingredient;

d. a muco-adhesive agent; and

e. an antioxidant;

wherein the unsaturated free fatty acid is present at a level of at least 20% by weight of the total pharmaceutical composition weight and wherein the pharmaceutical composition is semi-solid at room temperature.

In one embodiment, the pharmaceutical composition consists of:

a. an unsaturated free fatty acid;

b. a saturated free fatty acid;

c. an antioxidant; and

d. one active pharmaceutical ingredient;

wherein the unsaturated free fatty acid is present at a level of at least 20% by weight of the total pharmaceutical composition weight and wherein the pharmaceutical composition is semi-solid at room temperature. The one active pharmaceutical ingredient is selected from the same list as for the at least one active pharmaceutical ingredient.

In one embodiment, the pharmaceutical composition consists of:

a. an unsaturated free fatty acid;

b. a stiffening agent;

c. one active pharmaceutical ingredient;

d. a muco-adhesive agent; and

e. an antioxidant; wherein the unsaturated free fatty acid is present at a level of at least 20% by weight of the total pharmaceutical composition weight and wherein the pharmaceutical composition is semi-solid at room temperature. The one active pharmaceutical ingredient is selected from the same list as for the at least one active pharmaceutical ingredient.

In one embodiment, the pharmaceutical composition consists of:

a. an unsaturated free fatty acid;

b. a stiffening agent;

c. two active pharmaceutical ingredients;

d. a muco-adhesive agent; and e. an antioxidant;

wherein the unsaturated free fatty acid is present at a level of at least 20% by weight of the total pharmaceutical composition weight and wherein the pharmaceutical composition is semi-solid at room temperature. The two active pharmaceutical ingredients are selected from the same list as for the at least one active pharmaceutical ingredient.

In one embodiment, the pharmaceutical composition consists of:

a. an unsaturated free fatty acid;

b. a saturated free fatty acid;

c. an antioxidant;

d. two active pharmaceutical ingredients;

wherein the unsaturated free fatty acid is present at a level of at least 20% by weight of the total pharmaceutical composition weight and wherein the pharmaceutical composition is semi-solid at room temperature. The two active pharmaceutical ingredients are selected from the same list as for the at least one active pharmaceutical ingredient.

In one embodiment, the combination of the stiffening agent and the unsaturated free fatty acid causes the pharmaceutical composition to be a semi-solid at room temperature. In one embodiment, wherein the stiffening agent is a saturated free fatty acid, the combination of the saturated free fatty acid and the unsaturated free fatty acid causes the pharmaceutical composition to be a semi-solid at room temperature.

In one embodiment, the pharmaceutical composition comprises:

a. an unsaturated free fatty acid;

b. a stiffening agent;

c. at least one active pharmaceutical ingredient; and

d. a thickener;

wherein the unsaturated free fatty acid is present at a level of at least 20% by weight of the total pharmaceutical composition weight and wherein the pharmaceutical composition is semi-solid at room temperature.

In one embodiment, the pharmaceutical composition comprises:

a. an unsaturated free fatty acid;

b. a stiffening agent;

c. at least one active pharmaceutical ingredient;

d. a muco-adhesive agent; e. a thickener;

f. a blending agent; and

g. an antioxidant; wherein the unsaturated free fatty acid is present at a level of at least 20% by weight of the total pharmaceutical composition weight and wherein the pharmaceutical composition is semi-solid at room temperature.

In one embodiment, the pharmaceutical composition comprises:

a. oleic acid;

b. stearic acid; and

c. at least one active pharmaceutical ingredient;

wherein the oleic acid is present at a level of at least 20% by weight of the total

pharmaceutical composition weight and wherein the pharmaceutical composition is semi solid at room temperature.

In one embodiment, the pharmaceutical composition comprises:

a. oleic acid;

b. stearic acid; and

c. at least one active pharmaceutical ingredient;

wherein the oleic acid is present at a level of at least 20% by weight of the total

pharmaceutical composition weight, wherein the pharmaceutical composition is semi-solid at room temperature, and wherein the pharmaceutical composition comprises at least 1 part stearic acid by weight to 0.1 to 20 parts oleic acid by weight.

In one embodiment, the pharmaceutical composition comprises:

a. oleic acid;

b. stearic acid; and

c. at least one active pharmaceutical ingredient;

wherein the oleic acid is present at a level of at least 20% by weight of the total

pharmaceutical composition weight, wherein the pharmaceutical composition is semi-solid at room temperature, and wherein the pharmaceutical composition comprises at least 1 part stearic acid by weight to 0.5 to 20 parts oleic acid by weight.

In one embodiment, the pharmaceutical composition comprises:

a. oleic acid; b. stearic acid; and

c. at least one active pharmaceutical ingredient;

wherein the oleic acid is present at a level of at least 20% by weight of the total

pharmaceutical composition weight, wherein the pharmaceutical composition is semi-solid at room temperature, and wherein the pharmaceutical composition comprises at least one part stearic acid by weight to 1 to 20 parts oleic acid by weight.

In one embodiment, the pharmaceutical composition comprises:

a. oleic acid;

b. stearic acid;

c. ritonavir; and

d. lopinavir; wherein the oleic acid is present at a level of at least 20% by weight of the total

pharmaceutical composition weight and wherein the pharmaceutical composition is semi solid at room temperature.

In one embodiment, the pharmaceutical composition comprises:

a. oleic acid;

b. stearic acid;

c. ritonavir; and

d. lopinavir; wherein the oleic acid is present at a level of at least 20% by weight of the total

pharmaceutical composition weight, wherein the pharmaceutical composition is semi-solid at room temperature, and wherein the pharmaceutical composition comprises at least one part stearic acid by weight to 1 to 20 parts oleic acid by weight.

In one embodiment, the pharmaceutical composition comprises:

a. oleic acid;

b. stearic acid;

c. ritonavir; and

d. lopinavir;

wherein the oleic acid is present at a level of at least 45% by weight of the total

pharmaceutical composition weight, wherein the pharmaceutical composition is semi-solid at room temperature, and wherein the pharmaceutical composition comprises at least one part stearic acid by weight to 10 to 18 parts oleic acid by weight. In one embodiment, the pharmaceutical composition comprises:

a. oleic acid;

b. stearic acid;

c. ritonavir;

d. lopinavir;

e. hydroxypropylmethylcellulose; and

f. butylated hydroxytoluene

wherein the oleic acid is present at a level of at least 45% by weight of the total

pharmaceutical composition weight, wherein the pharmaceutical composition is semi-solid at room temperature.

In one embodiment, the pharmaceutical composition comprises:

a. about 55 to about 65% by weight of oleic acid;

b. about 28 to about 32% by weight of stearic acid;

c. about 1.2 to about 1.4% by weight of ritonavir;

d. about 9 to about 11% by weight of lopinavir;

e. about 0.5 to 1.5% by weight of hydroxypropylmethylcellulose; and f. about 0.05 to about 0.5% by weight of butylated hydroxytoluene

wherein all % are by weight based upon the total weight of the composition; and wherein the pharmaceutical composition is semi-solid at room temperature.

In one embodiment, the pharmaceutical composition comprises:

a. about 55 to about 65% by weight of oleic acid;

b. about 28 to about 32% by weight of stearic acid;

c. about 0.5 to about 0.7% by weight of ritonavir;

d. about 4 to about 6% by weight of lopinavir;

e. about 0.5 to 1.5% by weight of hydroxypropylmethylcellulose; and f. about 0.05 to about 0.5% by weight of butylated hydroxytoluene

wherein all % are by weight based upon the total weight of the composition; and wherein the pharmaceutical composition is semi-solid at room temperature.

In one embodiment, the pharmaceutical composition comprises:

a. oleic acid;

b. stearic acid;

c. ritonavir; d. lopinavir;

e. hydroxypropylmethylcellulose;

f. butylated hydroxytoluene;

g. mono diglyceride;

h. ceresin wax;

i. hydrogenated vegetable oil;

j. polyoxyl 100 stearate; and

k. glycerol monooleate;

wherein the oleic acid is present at a level of at least 45% by weight of the total

pharmaceutical composition weight, wherein the pharmaceutical composition is semi-solid at room temperature.

In one embodiment, the pharmaceutical composition comprises:

a. about 55 to about 65% by weight of oleic acid;

b. about 4 to about 5% of stearic acid;

c. about 0.9 to about 1.1% by weight of ritonavir;

d. about 9 to about 11% by weight of lopinavir;

e. about 0.5 to about 1.5% by weight of hydroxypropylmethylcellulose; f. about 0.1 to about 0.3% by weight of butylated hydroxytoluene;

g. about 4 to about 6% by weight of mono diglyceride;

h. about 5 to about 7% by weight of ceresin wax;

i. about 9 to about 11% by weight of hydrogenated vegetable oil;

j. about 1 to about 3% by weight of polyoxyl 100 stearate; and

k. about 2 to about 4% by weight of glycerol monooleate;

wherein all % are by weight based upon the total weight of the composition; and wherein the pharmaceutical composition is semi-solid at room temperature.

In one embodiment, the pharmaceutical composition comprises:

a. about 50 to about 60% by weight of oleic acid;

b. about 4 to about 5% of stearic acid;

c. about 0.9 to about 1.1% by weight of ritonavir;

d. about 11 to about 13% by weight of lopinavir;

e. about 0.5 to about 1.5% by weight of hydroxypropylmethylcellulose; f. about 0.1 to about 0.3% by weight of butylated hydroxytoluene; g. about 4 to about 6% by weight of mono diglyceride;

h. about 5 to about 7% by weight of ceresin wax;

i. about 9 to about 11% by weight of hydrogenated vegetable oil;

j. about 1 to about 3% by weight of polyoxyl 100 stearate; and

k. about 2 to about 4% by weight of glycerol monooleate;

wherein all % are by weight based upon the total weight of the composition; and wherein the pharmaceutical composition is semi-solid at room temperature.

In one embodiment, the pharmaceutical composition comprises:

a. about 55 to about 65% by weight of oleic acid;

b. about 4 to about 5% of stearic acid;

c. about 0.4 to about 0.6% by weight of ritonavir;

d. about 4 to about 6% by weight of lopinavir;

e. about 0.5 to about 1.5% by weight of hydroxypropylmethylcellulose;

f. about 0.1 to about 0.3% by weight of butylated hydroxytoluene; g. about 4 to about 6% by weight of mono diglyceride;

h. about 5 to about 7% by weight of ceresin wax;

i. about 9 to about 11% by weight of hydrogenated vegetable oil;

j. about 1 to about 3% by weight of polyoxyl 100 stearate; and

k. about 2 to about 4% by weight of glycerol monooleate;

wherein all % are by weight based upon the total weight of the composition; and wherein the pharmaceutical composition is semi-solid at room temperature.

In one embodiment, the pharmaceutical composition comprises:

a. about 55 to about 65% by weight of oleic acid;

b. about 4 to about 5% of stearic acid;

c. about 0.4 to about 0.6% by weight of ritonavir;

d. about 5 to about 7% by weight of lopinavir;

e. about 0.5 to about 1.5% by weight of hydroxypropylmethylcellulose;

f. about 0.1 to about 0.3% by weight of butylated hydroxytoluene; g. about 4 to about 6% by weight of mono diglyceride;

h. about 5 to about 7% by weight of ceresin wax;

i. about 9 to about 11% by weight of hydrogenated vegetable oil;

j. about 1 to about 3% by weight of polyoxyl 100 stearate; and k. about 2 to about 4% by weight of glycerol monooleate;

wherein all % are by weight based upon the total weight of the composition; and wherein the pharmaceutical composition is semi-solid at room temperature.

In one embodiment, the pharmaceutical composition comprises:

a. about 25 to about 75% by weight of an unsaturated free fatty acid; b. about 0.1 to about 65% by weight of a stiffening agent; and

c. at least one active pharmaceutical ingredient;

wherein all % are by weight based upon the total weight of the composition; and wherein the pharmaceutical composition is a semi-solid at room temperature.

In one embodiment, the pharmaceutical composition comprises:

a. about 55 to about 75% by weight of an unsaturated free fatty acid; b. about 0.1 to about 65% by weight of a stiffening agent; and

c. at least one active pharmaceutical ingredient;

wherein all % are by weight based upon the total weight of the composition; and wherein the pharmaceutical composition is a semi-solid at room temperature.

In one embodiment, the pharmaceutical composition comprises:

a. about 25 to about 75% by weight of an unsaturated free fatty acid; b. about 0.1 to about 65% by weight of a stiffening agent; and

c. at least one active pharmaceutical ingredient; and

d. at least 0.1% by weight of a thickener;

wherein all % are by weight based upon the total weight of the composition; and wherein the pharmaceutical composition is a semi-solid at room temperature.

In one embodiment, the pharmaceutical composition comprises:

a. about 25 to about 75% by weight of an unsaturated free fatty acid; b. about 0.1 to about 65% by weight of a stiffening agent;

c. at least one active pharmaceutical ingredient; and

d. about 0.1 to about 40% by weight of a thickener;

wherein all % are by weight based upon the total weight of the composition; and wherein the pharmaceutical composition is a semi-solid at room temperature.

In one embodiment, the pharmaceutical composition comprises:

a. about 25 to about 75% by weight of an unsaturated free fatty acid; b. about 0.1 to about 65% by weight of a stiffening agent;

c. at least one active pharmaceutical ingredient;

d. about 0.1 to about 10% by weight of a muco-adhesive agent;

e. about 0.1 to about 40% by weight of a thickener;

f. about 0.1 to about 48% by weight of a blending agent; and

g. about 0.05 to about 0.5% of an antioxidant;

wherein all % are by weight based upon the total weight of the composition; and wherein the pharmaceutical composition is a semi-solid at room temperature.

In one embodiment, the pharmaceutical composition comprises:

a. about 25 to about 75% by weight of oleic acid;

b. about 0.1 to about 65% by weight of stearic acid; and

c. at least one active pharmaceutical ingredient;

wherein all % are by weight based upon the total weight of the composition; and wherein the pharmaceutical composition is a semi-solid at room temperature.

In one embodiment, the pharmaceutical composition comprises:

a. about 25 to about 75% by weight of oleic acid;

b. about 0.1 to about 65% by weight of stearic acid;

c. ritonavir;

d. lopinavir;

e. about 0.1 to about 10 by weight of hydroxypropylmethylcellulose; f. about 0.05 to about 0.5% by weight of butylated hydroxytoluene; g. about 0.1 to about 10% by weight of mono diglyceride;

h. about 0.1 to about 10% by weight of ceresin wax;

i. about 0.1 to about 20% by weight of hydrogenated vegetable oil; j. about 0.1 to about 38% by weight of polyoxyl 100 stearate; and

k. about 0.1 to about 10% by weight of glycerol monooleate;

wherein all % are by weight based upon the total weight of the composition; and wherein the pharmaceutical composition is a semi-solid at room temperature.

Unsaturated Free Fatty Acid and Stiffening Agent

Free fatty acids are fatty acids which are not attached to a glycerol backbone, i.e., the fatty acid is not part of a glyceride. One advantage of the pharmaceutical composition comprising a free fatty acid is that the identity, amount and purity of the free fatty acid used to manufacture the pharmaceutical composition can be controlled. An unsaturated free fatty acid is a free fatty acid wherein there is at least one double bond between carbon atoms in the fatty acid.

It is to be understood that free fatty acids products that are commercially available may contain small amounts of other fatty acids. For example, oleic acid typically contains 7- 12% saturated free fatty acids, such as stearic and palmitic acid, together with other unsaturated free fatty acids, such as linoleic acid (Handbook of Pharmaceutical Excipients, 2 ^nd Edition, see entry for Oleic acid). The terms saturated free fatty acid or unsaturated free fatty acid are to be understood as meaning the saturated free fatty acid or the unsaturated free fatty acid are of Pharmacopeia grade, such as the ETS Pharmacopeia and/or the British Pharmacopeia, and that the saturated free fatty acid or unsaturated free fatty acid may contain small amounts of other free fatty acids.

In one embodiment, of the total unsaturated fatty acid (bound and free unsaturated fatty acid) present within the composition, at least 90% by weight, such as at least 95% by weight such as at least 98% by weight, such as at least 99% by weight, or such as at least 99.5% by weight, is in the free form, i.e., not esterified or bound to other components such as glycerol.

In one embodiment, the unsaturated free fatty acid is not in the form of a triglyceride or polysorbate.

In one embodiment, the unsaturated free fatty acid has a melting point below about 25°C. In one embodiment, the unsaturated free fatty acid is selected from oleic acid, linoleic acid, alpha-linoleic acid, palmitoleic acid, gondoic acid, and ricinoleic acid.

In one embodiment, the unsaturated free fatty acid is oleic acid.

The stiffening agent is an excipient used to stiffen the pharmaceutical composition such that the composition is a semi-solid at room temperature. In one embodiment, the stiffening agent is a solid at room temperature. Conveniently, in one embodiment the stiffening agent is a saturated fatty acid, such as a C10-C38 saturated free fatty acid, such as a C16-C22 saturated free fatty acid. A saturated free fatty acid, is a free fatty acid (i.e., the fatty acid is not bound to another molecule, such as glycerol) wherein there are no double bonds between the carbon atoms in the fatty acid.

In one embodiment, the saturated free fatty acid is selected from capric acid, undecylic acid, lauric acid, tridecylic acid, myristic acid, pentadecylic acid, palmitic acid, margaric acid, stearic acid, nonadecylic acid, arachidic acid, heneicosylic acid, behenic acid, tricosylic acid, lignoceric acid, pentacosylic acid, cerotic acid, heptacosylic acid, montanic acid, nonacosylic acid, melissic acid, henatriacontylic acid, lacceroic acid, psyllic acid, geddic acid, ceroplastic acid, hexatriacontylic acid, heptatriacontanoic acid and

octatriacontanoic acid.

In one embodiment, the saturated free fatty acid is stearic acid. Stearic acid is a straight chained saturated fatty acid with an 18-carbon chain.

In one embodiment, the stiffening agent is a solid at room temperature, for example, the stiffening agent has a melting point greater than 35°C, such as greater than 40°C, such as greater than 45°C, such as greater than 50°C, or such as greater than 55°C.

In one embodiment, of the total saturated fatty acid (bound and free saturated fatty acid) present within the composition, at least 90% by weight, such as at least 95% by weight such as at least 98% by weight, such as at least 99% by weight, or such as at least 99.5% by weight, is in the free form, i.e., not esterified or bound to other components such as glycerol.

In one embodiment, the saturated free fatty acid is not in the form of a triglyceride or polysorbate.

In one embodiment, of the total fatty acid (unsaturated and saturated fatty acids in the bound and free states) present within the composition, at least 90% by weight, such as at least 95% by weight such as at least 98% by weight, such as at least 99% by weight, or such as at least 99.5% by weight, is in the free form, i.e., not esterified or bound to other components such as glycerol.

In one embodiment, the saturated free fatty acid and the unsaturated free fatty acid are not in the form of a triglyceride or polysorbate.

The skilled person would be aware of methods used to determine the free fatty acid content versus the total fatty acid content. For example, the free fatty acid content can be measured by reacting the free fatty acid with a chromogeneous compound, thus changing the frequency that the chromogeneous compound absorbs electromagnetic radiation. Thus, the concentration of the chromogeneous compound reacted can be determined by monitoring the chromogeneous compound using a suitable wavelength which in turn can be used to determine the free fatty acid content in the sample.

In one embodiment, the sum of the unsaturated free fatty acid and the saturated free fatty acid present in the pharmaceutical composition is at least 50% by weight of the total pharmaceutical composition weight, such as at least 60% by weight, such as at least 75% by weight, such as at least 80% by weight, or such as at least 85% by weight.

In contrast, other excipients typically used in pharmaceutical compositions, for example vegetable oils such as olive oil and polysorbates, may contain very low levels of free fatty acids (unsaturated and/or saturated free fatty acids), such as <4% w/w, such as <2% w/w, such as <1% w/w, or such as <0.5% w/w. For example, polysorbates have an acid value of circa 2-3, while soybean oil has an acid value of <0.6. In contrast, free fatty acids have much higher acid values, for example oleic acid and stearic acid have acid values of circa 200, which is equivalent to 100% w/w (Handbook of Pharmaceutical Excipients, 2 ^nd Edition, see entries for Oleic acid, Stearic acid, Soybean Oil and Polyoxyethylene Sorbitan Fatty Acid Esters). The acid value is defined as the weight of KOH in mg required to neutralise the organic acids present in 1 g of fat/oil. It is a measure of the free fatty acids present in the fat/oil. In addition, the identity and amount of the free fatty acid in said polysorbate or vegetable oil excipients can vary from batch to batch, and/or over time. For example, prolonged storage of soybean oil at elevated temperatures can result in its free fatty acid content increasing (Handbook of Pharmaceutical Excipients, 2 ^nd Edition, page 481). Vegetable oils and animal fats can be used to thicken pharmaceutical compositions and while the vegetable oil and animal fat may contain low levels of free fatty acids, the vast majority of the free fatty acid is esterified and as such bound to a glycerol molecule within the oil or fat.

In one embodiment, the pharmaceutical composition comprises at least 1 part stiffening agent by weight to 0.1 to 20 parts unsaturated free fatty acid by weight, such as at least one part stiffening agent by weight to 0.5 to 20 parts unsaturated free fatty acid by weight, such as at least one part stiffening agent by weight to 1 to 20 parts unsaturated free fatty acid by weight, such as at least one part stiffening agent by weight to 3.5 to 18 parts unsaturated free fatty acid by weight, such as at least one part stiffening agent by weight to 1 to 5 parts unsaturated free fatty acid by weight, such as at least one part stiffening agent by weight to 1 to 3 parts unsaturated free fatty acid by weight, such as at least one part stiffening agent by weight to 2 to 18 parts unsaturated free fatty acid by weight, such as at least one part stiffening agent by weight to 5 to 18 parts unsaturated free fatty acid by weight, such as at least one part stiffening agent by weight to 10 to 18 parts unsaturated free fatty acid by weight, such as at least one part stiffening agent by weight to 12 to 16 parts unsaturated free fatty acid by weight, such as one part stiffening agent by weight to about 2 parts unsaturated free fatty acid by weight, such as one part stiffening agent by weight to about 13 parts unsaturated free fatty acid by weight, such as one part stiffening agent by weight to about 14 unsaturated free fatty acid by weight, such as one part stiffening agent by weight to 0.1 to 1 parts unsaturated free fatty acid, or such as one part stiffening agent by weight to about 0.5 parts unsaturated free fatty acid by weight. In one embodiment, the unsaturated free fatty acid and the stiffening agent are present in the pharmaceutical composition in a weight ratio of unsaturated free fatty acid: stiffening agent in the range of 1 : 1 to 5 : 1 , such as in the range of 1 : 1 to 3 : 1 , such as about 2 : 1 , or such as 2: 1.

In one embodiment, the unsaturated free fatty acid and the stiffening agent are present in the composition in a weight ratio of unsaturated free fatty acid: stiffening agent in the range of 13 : 1 to 15: 1, such as about 14: 1, or such as 14: 1.

In one embodiment, the unsaturated free fatty acid and the stiffening agent are present in the composition in a weight ratio of unsaturated free fatty acid: stiffening agent in the range of 12: 1 to 14: 1, such as about 13 : 1, or such as 13 : 1.

In one embodiment, the unsaturated free fatty acid is present in the pharmaceutical compositions at a level of at least 25% by weight of the total pharmaceutical composition weight, such as at least 35% by weight, such as at least 45% by weight, such as about 25 to about 75% by weight, such as about 55 to about 75% by weight, such as about 45 to about 75% by weight, such as about 50 to about 70% by weight, such as about 55 to about 70% by weight, such as about 55 to about 65% by weight, such as about 50 to about 60% by weight, such as about 25 to about 60% by weight, or such as about 50 to about 65% by weight.

In one embodiment, the unsaturated free fatty acid is present in the pharmaceutical composition at a level of about 20% by weight of the total pharmaceutical composition weight, such as about 55% by weight, such as about 57% by weight, such as about 58% by weight, such as about 60% by weight, such as about 62% by weight, such as about 63% by weight, such as about 65% by weight, such as about 67% by weight, or such as about 68% by weight..

In one embodiment, the stiffening agent is present in the pharmaceutical composition at about 0.1 to about 65% by weight of the total pharmaceutical composition weight, such as about 3 to about 60% by weight, such as about 3 to about 50% by weight, such as about 3 to about 40% by weight, such as about 3 to about 35% by weight, such as about 3 to about 6% by weight, such as about 4 to about 5% by weight, such as about 4.5% by weight, such as 4.5% by weight, such as about 15 to about 25% by weight, such as about 18 to about 22% by weight, such as about 20% by weight, such as about 20 to about 30% by weight, such as about 24 to about 30% by weight, such as about 26% by weight, such as about 25 to about 35% by weight, such as about 28 to about 32% by weight, such as about 30% by weight, such as 30% by weight, such as about 32% by weight, or such as about 34% by weight.

Active Pharmaceutical Ingredient In one embodiment, the at least one active pharmaceutical ingredient is a solid at room temperature. In one embodiment, the at least one active pharmaceutical ingredient is synthetically prepared. In one embodiment, the at least one active pharmaceutical ingredient is not a fatty acid (free or bound state).

In one embodiment, the at least one active pharmaceutical ingredient is present in a dissolved state in the pharmaceutical composition. In another embodiment, the at least one active pharmaceutical ingredient is present in a dispersed state in the pharmaceutical composition. In another embodiment, an amount of the least one active pharmaceutical ingredient is present in a dispersed state and an amount is present in a dissolved state in the pharmaceutical composition. It will be apparent to the skilled person that the active pharmaceutical ingredient is dissolved or dispersed within the pharmaceutical composition by the use of techniques such as optical microscopy using polarised light filters, differential scanning calorimetry or micro FTIR. For example, a placebo pharmaceutical composition (i.e., a composition containing no active pharmaceutical ingredients) can be spiked with a crystalline active pharmaceutical ingredient. When viewed under an optical microscope using polarised light filters, the crystalline active pharmaceutical ingredient will exhibit

birefringence. Thus, the spiked placebo composition can be used as a comparison standard in order to confirm there is no crystalline active pharmaceutical ingredient in the pharmaceutical composition, and thereby demonstrating the active pharmaceutical ingredient is dissolved within the pharmaceutical composition. Alternatively, and/or additionally, micro FTIR can be used to confirm the active pharmaceutical ingredient is dissolved in the pharmaceutical composition. In this case, spectra obtained for a pharmaceutical composition spiked with the active pharmaceutical ingredient and for the pharmaceutical composition can be compared and used to demonstrate the active pharmaceutical ingredient is dissolved in the

pharmaceutical composition.

In one embodiment, the at least one active pharmaceutical ingredient is stable within the pharmaceutical composition. The compositions of the invention are particularly suitable for active pharmaceutical ingredients used in the composition that are prone to chemical or physical degradation. In one embodiment, the active pharmaceutical ingredient used in the composition is prone to degradation due to hydrolysis. In one embodiment, the active pharmaceutical ingredient used in the composition is prone to degradation due to oxidation.

In one embodiment, the active pharmaceutical ingredient used in the composition is prone to degradation which is accelerated by heat. In one embodiment, the active pharmaceutical ingredient used in the composition is prone to physical form changes, e.g. solid-sate polymorphic transitions.

In one embodiment, the at least one active pharmaceutical ingredient is stable within the pharmaceutical composition for at least 3 months, such as at least 6 months, such as at least 9 months, such as at least 12 months, such as at least 18 months, such as at least 24 months, or such as at least 36 months, at a temperature of 5°C, 25°C, 30°C or at 45°C, and/or at a relative humidity of 60%, 65%, or 75% RH.

In one embodiment, the at least one active pharmaceutical ingredient is stable within the pharmaceutical composition during a process to manufacture the pharmaceutical composition. In one embodiment, the at least one active pharmaceutical ingredient is stable within the pharmaceutical composition during a process to manufacture the pharmaceutical composition wherein the process is performed at room temperature. In one embodiment, the at least one active pharmaceutical ingredient is stable within the pharmaceutical composition during a process to manufacture the pharmaceutical composition wherein the process is performed at elevated temperatures, such as >30°C, such as >40°C, such as >50°C, such as >60°C, such as >65°C, or such as 70°C. In one embodiment, the at least one active pharmaceutical ingredient is stable within the pharmaceutical composition during a process to manufacture the pharmaceutical composition wherein the process is performed under an inert atmosphere, such as a vacuum, such as a vacuum at about -0.5 bar.

In one embodiment, the at least one active pharmaceutical ingredient has a solubility measured at ambient temperature of at least 1% w/v in the unsaturated free fatty acid, such as at least 5% w/v in the unsaturated free fatty acid, such as at least 10% w/v in the unsaturated free fatty acid, such as at least 12% w/v in the unsaturated free fatty acid, such as at least 15% w/v in the unsaturated free fatty acid, or such as at least 18% w/v in the unsaturated free fatty acid.

In one embodiment, the at least one active pharmaceutical ingredient is present in the pharmaceutical composition between about 0.001 and about 50% by weight of the total composition weight, such as between about 0.01 and about 50% by weight, such as between about 0.001 and about 5% by weight, such as between about 0.1 and about 25% by weight, such as between about 0.5 and about 15% by weight, such as between about 0.5 and about 10% by weight, such as between about 0.01 and about 2.5% by weight, such as between about 0.1 and about 2.5% by weight, such as between about 0.2 and about 2% by weight, such as between about 0.2 and about 1.5% by weight, such as between about 0.4 and about 1.5% by weight, such as between about 0.4 and about 0.6% by weight, such as about 0.5% by weight, such as 0.5% by weight, such as between about 0.5 and about 0.7% by weight, such as about 0.6% by weight, such as 0.6% by weight, such as between about 0.9 and about 1.1% by weight, such as about 1% by weight, such as 1% by weight, such as between about 1.2 and about 1.4% by weight, such as about 1.3% by weight, such as 1.3% by weight, such as between about 2 and about 20% by weight, such as between about 2 and about 15% by weight, such as between about 4 and about 12% by weight, such as between about 4 and about 10% by weight, such as between about 4 and about 6% by weight, such as about 5% by weight, such as 5% by weight, such as between about 5 and about 7% by weight, such as about 6% by weight, such as 6% by weight, such as between about 9 and about 11% by weight, such as about 10% by weight, such as 10% by weight, such as between about 11 and about 13% by weight, such as about 12% by weight, or such as 12% by weight.

In one embodiment, the at least one active pharmaceutical ingredient is classified as a Biopharmaceutics Classification System (BCS) Class II or a BCS Class IV active

pharmaceutical ingredient. A BCS class II active pharmaceutical ingredient is classed as an active ingredient having a high permeability and a low solubility. A BCS class IV active pharmaceutical ingredient is classed as an active ingredient having a low permeability and a low solubility. According to ICH guidelines (ICH guideline M9 on biopharmaceutics classification system based biowaivers; 6 ^th August 2018) a drug substance is classified as highly soluble if the highest single therapeutic dose is completely soluble in 250 ml or less of aqueous media over the pH range of 1.2 - 6.8 at 37 ± l°C. The assessment of permeability should preferentially be based on the extent of absorption derived from human

pharmacokinetic studies, e.g., absolute bioavailability or mass balance. High permeability can be concluded when the absolute bioavailability is > 85%.

In one embodiment, the at least one active pharmaceutical ingredient is selected from a protease inhibitor, a retinoid, a vitamin D analog, an antileprosy active pharmaceutical ingredient, a calcineurin inhibitor, a cannabinoid, a 5 alpha-reductase inhibitor, an androgen receptor inhibitor, a peroxisome proliferator activated receptor activator, an antihistamine, a chloride channel activator, a tyrosine kinase inhibitor, a hormone, a protease inhibitor, and a mTOR kinase inhibitor.

In one embodiment, the at least one active pharmaceutical ingredient is selected from abacavir, efavirenz, enfuvirtide, nevirapine, ritonavir, lopinavir, tenofovir, adefovir, entecavir, ribavirin, acyclovir, famciclovir, penciclovir, valacyclovir, cidofovir, ganciclovir, valganciclovir, oseltamivir, zanamivir, amprenavir, bexarotene, calcifediol, calcitriol, clofazimine, cyclosporin A, doxercalciferol, dronabinol, dutasteride, enzalutamide, fenofibrate, isotretinoin, loratadine, lubiprostone, nintedanib, paricalcitol, progesterone, saquinavir, sirolimus, tipranavir, tretinoin, atorvastatin, carvedilol, itraconazole, ketoprofen, and simvastatin.

In one embodiment, the at least one active pharmaceutical ingredient is selected from abacavir, efavirenz, enfuvirtide, nevirapine, ritonavir, lopinavir, tenofovir, adefovir, entecavir, ribavirin, acyclovir, famciclovir, penciclovir, valacyclovir, cidofovir, ganciclovir, valganciclovir, oseltamivir and zanamivir.

In one embodiment, the pharmaceutical composition further comprises an active pharmaceutical ingredient synergist. In one embodiment, the active pharmaceutical ingredient synergist is a HIV protease enzyme inhibitor.

In one embodiment, the at least one active pharmaceutical ingredient is a HIV protease enzyme inhibitor. In one embodiment, the HIV protease enzyme inhibitor is selected from lopinavir and ritonavir.

Lopinavir (CAS# 192725-17-0) is a protease inhibitor chemically designated as [1S- [lR*(R*), 3R*, 4R*]]-N-[4-[(2,6-dimethylphenoxyacetyl]amino]-3-hydroxy-5-ph enyl-l- (phenylmethyl)pentyl]tetrahydro-alpha-(l-methylethyl)-2-oxo- l(2H)-pyrimidineacetamide. It has the molecular formula C37H48N405 and a molecular weight of 628.80.

Ritonavir (CAS# 155214-67-5) is a protease inhibitor chemically designated as 10- Hydroxy-2-methyl-5-(l-methylethl)-l-[2-(l-methylethyl)-4-thi azolyl]-3,6-dioxo-8,

Hbis(phenylmethyl)-2,4,7,l2-tetraazatridecan-l3-oic acid, 5-thiazolylmethylester, [5S- (5R*,8R*,l0R8,l 1R*)]. It has the molecular formula C37H48N605S2 and a molecular weight of 720.95.

In one embodiment, the pharmaceutical composition comprises lopinavir and ritonavir. In one embodiment, the molar ratio of lopinavir to ritonavir present in the composition is between about 1 : 10 and about 18: 1, such as between about 1 : 10 and about 15: 1, such as between about 1 :5 and about 15: 1, such as between about 1 : 1 and about 15: 1, such as between about 2: 1 and about 15: 1, such as between about 4: 1 and about 15: 1, such as between about 8: 1 and about 14: 1, such as between about 9: 1 and about 14: 1, such as between about 10: 1 and about 14: 1, such as between 10.5: 1 and about 18: 1, such as between 10.5: 1 and 18: 1, such as between about 10.5: 1 and about 14: 1, such as between about 11 : 1 to about 13: 1, such as between about 11.5 and about 17: 1, such as between about 11.5: 1 and about 16.0: 1, such as between about 11.5: 1 and about 15: 1, such as about 14.5: 1, such as 14.5: 1, such as about 14: 1, such as 14: 1, such as about 13.8:1, such as 13.8: 1, such as about 13.75: 1, such as 13.75: 1, such as about 13.5: 1, such as 13.5: 1, such as about 13: 1, such as 13: 1, such as about 12.5: 1, such as 12.5: 1, such as about 12:1, such as 12: 1, such as about 11.75: 1, such as 11.75: 1, such as about 9: 1, such as 9: 1, such as about 5: 1, such as 5: 1, such as about 4.6: 1, or such as 4.6: 1.

It will be appreciated that lopinavir has a molecular weight of 628.8 daltons and ritonavir has a molecular weight of 720.95 daltons. Accordingly, molar ratios and w/w ratios will not be the same and a factor of 0.872 should be applied when converting molar ratios to w/w.

In one embodiment, lopinavir is present in the pharmaceutical composition at about 0.01 to about 50% of the total pharmaceutical composition weight, such as about 0.1 to about 25% by weight, such as about 2 to about 20% by weight, such as about 2 to about 15% by weight, such as about 4 to about 12% by weight, such as about 4 to about 10% by weight, such as about 4 to about 6% by weight, such as at about 5% by weight, such as 5% by weight, such as about 5 to about 7% by weight, such as about 6% by weight, such as 6% by weight, such as about 9 to about 11% by weight, such as at about 10% by weight, such as 10% by weight, such as about 11 to about 13% by weight, such as about 12% by weight, or such as 12% by weight.

In one embodiment, ritonavir is present in the pharmaceutical composition at about 0.001 to about 5% by weight of the total pharmaceutical composition weight, such as about 0.01 to about 2.5% by weight, such as about 0.1 to about 2.5% by weight, such as about 0.2 to about 2% by weight, such as about 0.2 to about 1.5% by weight, such as about 0.4 to about 1.5% by weight, such as about 0.4 to about 0.6% by weight, such as at about 0.5% by weight, such as at 0.5% by weight, such as about 0.9 to about 1.1% by weight, such as about 1% by weight, such as 1% by weight, such as about 1.2 to 1.4% by weight, such as about 1.3% by weight, such as 1.3% by weight, such as about 0.5 to about 0.7% by weight, such as about 0.6% by weight, or such as 0.6% by weight.

Additional Excipients

Optionally, additional excipients may be included in the composition according to the present invention providing that inclusion of such excipients does not unacceptably impact the ability of the composition to be a semi-solid at room temperature.

In one embodiment, the pharmaceutical composition further comprises a muco- adhesive. A muco-adhesive is an excipient which adhere to a mucous membrane.

In one embodiment, the muco-adhesive is selected from a non-ionic polymer and an ionic polymer. In one embodiment, the non-ionic polymer is a cellulose ether. In one embodiment, the muco-adhesive is selected from a cellulose ether and an ionic polymer. In one embodiment, the ionic polymer is sodium polyacrylate. In one embodiment, the cellulose ether is selected from methyl cellulose, ethylcellulose and hydroxypropylmethylcellulose. In one embodiment, the cellulose ether is hydroxypropylmethylcellulose. In one embodiment, the hydroxypropylmethylcellulose has a degree of methoxy substitution of between 19 and 24% by weight and a degree of hydroxypropyl substitution of between 4 and 12% by weight.

In one embodiment, the muco-adhesive agent is present in the pharmaceutical composition at about 0.1 to 20% by weight of the total pharmaceutical composition weight, such as about 0.1 to about 10% by weight, such as about 0.5 to 10% by weight, such as about 0.5 to 3% by weight, such as about 0.5 to 1.5% by weight, such as about 1% by weight, or such as 1% by weight.

In one embodiment, the muco-adhesive agent has a viscosity of about 2000 to about 6000 cps, such as about 3000 to about 5000 cps, such as about 3500 to about 4500 cps, such as about 3800 to about 4200 cps, such as about 4000 cps, or such as 4000 cps.

In one embodiment, the pharmaceutical composition upon application to a site of application transform to a muco-adhesive composition wherein the site of application comprises a mucosal membrane and wherein the pharmaceutical composition comprises a muco-adhesive agent.

This in-situ transformation of the pharmaceutical composition to a muco-adhesive composition results in the muco-adhesive composition having a different rheological behaviour and/or an increase in adhesiveness compared to the pharmaceutical composition.

In one embodiment, the muco-adhesive composition is a gel. Advantageously, the resulting gel enables the composition to be retained at the site of application for a prolonged period.

In one embodiment, the pharmaceutical composition further comprises a thickener and/or a blending agent.

A thickener is an excipient which when added to a mixture increases the viscosity of the mixture and for conferring the pharmaceutical composition with greater physical stability and/or control during delivery of the active pharmaceutical ingredient to the site of application. A blending agent is an agent which promotes uniformity within the

pharmaceutical composition, for example it promotes uniformity for organoleptic attributes within the pharmaceutical composition. In one embodiment, the thickener is selected from mono di glyceride, ceresin wax, and hydrogenated vegetable oil. In one embodiment, the pharmaceutical composition comprises mono di glyceride, ceresin wax and hydrogenated vegetable oil.

In one embodiment, the thickener is present within the pharmaceutical composition at a level of at least 0.1% by weight of the total pharmaceutical composition weight, such as at least 1% by weight, such as at least 3% by weight, such as at least 5% by weight, such as about 0.1 to about 40% by weight, such as about 3 to about 40% by weight, such as about 3 to about 35% by weight, such as about 3 to about 30% by weight, such as about 4 to about 25% by weight, such as about 5 to about 21% by weight, such as about 4 to about 12% by weight, such as about 4 to about 7% by weight, such as about 0.1 to about 10% by weight, such as about 0.1 to about 20% by weight, such as about 3% by weight, such as about 5% by weight, such as 5% by weight, such as about 6% by weight, such as 6% by weight, such as about 8 to about 12% by weight, such as about 10% by weight, such as 10% by weight, such as about 10 to about 35% by weight, such as about 15 to about 35% by weight, such as about 20 to about 30% by weight, such as about 21%, or such as 21% by weight.

In one embodiment, the mono di glyceride is present in the pharmaceutical composition at about 0.1 to about 30% by weight of the total pharmaceutical composition weight, such as about 0.1 to about 10% by weight, such as about 1 to about 10% by weight, such as about 3 to about 7% by weight, such as about 4 to about 6% by weight, such as about 5% by weight, or such as 5% by weight.

In one embodiment, the ceresin wax is present in the pharmaceutical composition at about 0.1 to about 30% by weight of the total pharmaceutical composition weight, such as about 0.1 to about 10% by weight, such as about 1 to about 10% by weight, such as about 4 to about 8% by weight, such as about 5 to about 7% by weight, such as about 5% by weight, such as about 6% by weight, or such as 6% by weight.

In one embodiment, the hydrogenated vegetable oil is present in the pharmaceutical composition at about 0.1 to about 30% by weight of the total pharmaceutical composition weight, such as about 0.1 to about 20% by weight, such as about 5 to about 15% by weight, such as about 8 to about 12% by weight, such as about 9 to about 11% by weight, such as about 10% by weight, or such as 10% by weight.

In one embodiment, the blending agent is selected from polyoxy 100 stearate and glycerol monooeleate. In one embodiment, the composition comprises polyoxy 100 stearate and glycerol monooeleate. In one embodiment, the blending agent is present in the pharmaceutical composition at at least 0.1% by weight of the total pharmaceutical composition weight, such as at least 1% by weight, such as at least 1.5% by weight, such as about 0.1 to about 48% by weight, such as about 1 to about 10% by weight, such as about 2 to about 5% by weight, such as about 0.1 to about 38% by weight, such as about 0.1 to about 10% by weight, such as about 2% by weight, such as 2% by weight, such as about 3% by weight, such as 3% by weight, such as about 5% by weight, or such as 5% by weight.

In one embodiment, the polyoxy 100 stearate is present in the pharmaceutical composition at about 0.1 to about 38% by weight of the total pharmaceutical composition weight, such as about 0.1 to about 10% by weight, such as about 0.5 to about 5% by weight, such as about 1 to about 3% by weight, such as about 2% by weight, or such as 2% by weight.

In one embodiment, the glycerol monooleate is present in the pharmaceutical composition at about 0.1 to about 10% by weight of the total pharmaceutical composition weight, such as about 0.5 to about 5% by weight, such as about 2 to about 4% by weight, such as about 3% by weight, or such as 3% by weight.

In one embodiment, the pharmaceutical composition comprises an antioxidant. In one embodiment, the antioxidant is butylated hydroxytoluene. In one embodiment, the antioxidant is present in the pharmaceutical composition at about 0.05 to about 0.5% by weight of the total pharmaceutical composition by weight, such as about 0.05 to about 0.15% by weight, such as about 0.1 to about 0.3% by weight, such as about 0.2% by weight, such as 0.2% by weight, such as about 0.1% by weight, or such as 0.1% by weight.

MEDICAL USES

In one embodiment, the pharmaceutical composition is for use as a medicament.

In one embodiment, the pharmaceutical composition is for use as a medicament wherein the pharmaceutical composition is applied topically. In one embodiment, the pharmaceutical composition is topically applied to skin. In one embodiment, the

pharmaceutical composition is topically applied to mucosa. In one embodiment, the pharmaceutical composition is for use a medicament wherein the pharmaceutical composition is topically applied to the cervix. This is particularly advantageous as the patient can self- administer the pharmaceutical composition and/or treatment with the pharmaceutical composition negates the need of treatment by surgery. In one embodiment, the pharmaceutical compositions are useful in the treatment and/or prevention of diseases and/or disorders. In one embodiment, the pharmaceutical compositions are useful in the treatment of benign proliferative disorders.

In one embodiment, the pharmaceutical compositions are useful in the treatment of cancer and particularly useful for preventing the development of cancers. Accordingly, normal subjects (i.e. subjects with no detectable cancer), subjects with pre-malignant cells or particularly cancer prone subjects may be treated by topical administration of compositions according to the invention with a view to preventing the development of cancer.

Disclosed herein are pharmaceutical compositions comprising lopinavir and ritonavir for use as a medicament in the treatment of cancer or benign proliferative disorders (e.g. warts) or in the prevention of the development of cancer.

The invention, to the extent that it is applicable to the prevention and treatment of cancer, may be applied to a wide range of cancers such as ovarian carcinoma, breast carcinoma, lung carcinoma, uterine carcinoma, cervical carcinoma and thyroid carcinoma. The invention is applicable particularly, but by no means exclusively, to pre-cancerous conditions and cancers caused by oncogenic viruses, e.g. high-risk or even low-risk forms of human papilloma viruses (HPVs).

Conveniently, the compositions may be administered to treat, and particularly prevent, the development of cervical cancer. Conveniently, the inhibitors are used to treat, or prevent the development of cervical cancers caused by HPV (particularly high-risk types of HPV such as HPVl6 or HPV 18).

The compositions may be used to prevent or treat cancer as a monotherapy (i.e. including the use of the pharmaceutical composition comprising two or more active pharmaceutical ingredients) or in combination with other compounds or treatments used in cancer therapy (e.g. chemotherapeutic agents, radiotherapy).

Disclosed herein are pharmaceutical compositions comprising lopinavir and ritonavir for use as a medicament in the treatment of cancer or benign proliferative disorders (e.g. warts) or in the prevention of the development of cancer.

Conveniently, the compositions are used to treat humans. However, it will be appreciated that the compositions may also have some veterinary use.

DOSING

It will be appreciated that the amount of the at least one active pharmaceutical ingredient required is determined by biological activity and bioavailability, which in turn depends, in part, on the precise mode of administration, the physicochemical properties of the pharmaceutical composition employed, and whether the pharmaceutical compositions are being used as a monotherapy or in a combined therapy with other medicines. Indeed it is also possible that the at least one active pharmaceutical ingredient could be topically applied in addition to oral dosing of the same at least one active pharmaceutical ingredient or other active pharmaceutical ingredient(s). The frequency of administration will also be influenced by the abovementioned factors and particularly the half-life of the active pharmaceutical ingredients within the subject being treated.

Daily doses may be given as a single administration (e.g. as a soft gel capsule, a hard gel capsule, a pessary or a suppository). Alternatively, administration may be twice or more times during a day. As an example, the pharmaceutical compositions (e.g. as an ointment or as a cream) may be topically administered at least once a day, such as once a day, or such as twice a day.

Optimal dosages to be administered may be determined by those skilled in the art, and will vary with the strength of the preparation, the mode of administration, and the

advancement of the disease condition. Additional factors depending on the particular subject being treated will result in a need to adjust dosages, including, for example, subject age, weight, gender, diet, and time of administration.

Suitable amounts of the at least one active pharmaceutical ingredient to be given as a daily dose are of about 0.01 mg to about 10 g, such as about 0.1 mg to about 10 g, such as about 1 mg to about 5g, such as about 1 mg to about 1 g, such as about 5 mg to about 2 g, such as about 10 mg to about 1 g, such as about 5 mg to about 500 mg, such as about 10 mg to about 500 mg, such as about 10 mg to about 400 mg, such as about 5 mg to about 200 mg, such as about 5 mg to about 50 mg, such as about 10 mg to about 40 mg, such as about 20 mg to about 40 mg, such as about 25 mg to about 35 mg, such as about 27 mg to about 32 mg, such as about 29 mg, such as 29 mg, such as about 28.7 mg, such as 28.7 mg, such as about 15 mg to about 35 mg, such as about 20 mg to about 30 mg, such as about 23 mg to about 27 mg, such as about 25 mg, such as 25 mg, such as about 5 mg to about 25 mg, such as about 10 mg to about 20 mg, such as about 12 mg to about 16 mg, such as about 14 mg, such as 14 mg, such as about 14.3 mg, such as about 14.3 mg, such as about 11 mg to about 15 mg, such as about 13 mg, such as 13 mg, such as about 12.5 mg, such as 12.5 mg, such as about 100 mg to about 400 mg, such as about 200 mg to about 400 mg, such as about 250 mg to about 350 mg, such as about 280 mg to about 320 mg, such as about 290 mg to about 310 mg, such as about 300 mg, such as 300 mg, such as about 25 mg to about 325 mg, such as about 50 mg to about 250 mg, such as about 125 mg to about 175 mg, such as about 140 mg to about 160 mg, such as about 150 mg, or such as 150 mg.

Suitable amounts of lopinavir to be given as a daily dose of about 0.01 mg to about 10 g, such as about 0.1 mg to about 10 g, such as about 1 mg to about 5 g, such as about 5 mg to about 2 g, such as about 10 mg to about 1 g, such as about 10 mg to about 500 mg, such as about 10 mg to about 400 mg, such as about 100 mg to about 400 mg, such as about 200 mg to about 400 mg, such as about 250 mg to about 350 mg, such as about 280 mg to about 320 mg, such as about 290 mg to about 310 mg, such as about 300 mg, such as 300 mg, such as about 25 mg to about 325 mg, such as about 50 mg to about 250 mg, such as about 125 mg to about 175 mg, such as about 140 mg to about 160 mg, such as about 150 mg, or such as 150 mg.

Suitable amounts of ritonavir to be given as a daily dose of about 0.01 mg to about 10 g, such as about 0.1 mg to about 10 g, such as about 1 mg to about 5 g, such as about 1 mg to about 1 g, such as about 5 mg to about 500 mg, such as about 5 mg to about 200 mg, such as about 5 mg to about 50 mg, such as about 10 mg to about 40 mg, such as about 20 mg to about 40 mg, such as about 25 mg to about 35 mg, such as about 27 mg to about 32 mg, such as about 29 mg, such as 29 mg, such as about 28.7 mg, such as 28.7 mg, such as about 15 mg to about 35 mg, such as about 20 mg to about 30 mg, such as about 23 mg to about 27 mg, such as about 25 mg, such as 25 mg, such as about 5 mg to about 25 mg, such as about 10 mg to about 20 mg, such as about 12 mg to about 16 mg, such as about 14 mg, such as 14 mg, such as about 14.3 mg, such as 14.3 mg, such as about 11 mg to about 15 mg, such as about 13 mg, such as 13 mg, such as about 12.5 mg, or such as 12.5 mg.

In one embodiment, about 300 mg of lopinavir and about 29 mg ritonavir per day may be administered to the cervix of a woman.

In one embodiment, about 300 mg of lopinavir and about 25 mg ritonavir per day may be administered to the cervix of a woman.

In another embodiment, about 150 mg of lopinavir and about 14 mg ritonavir per day may be administered to treat the cervix of a woman.

In another embodiment, about 150 mg of lopinavir and about 13 mg ritonavir per day may be administered to treat the cervix of a woman.

In an embodiment about 3.0 g of the pharmaceutical composition may be

administered to a subject per day. Such dosage forms may comprise about 300 mg of lopinavir and about 29 mg of ritonavir; or about 150 mg of lopinavir and about 14 mg of ritonavir. In another embodiment, about 2.5 g of the pharmaceutical composition may be administered to a subject per day. Such dosage forms may comprise about 300 mg of lopinavir and about 25 mg of ritonavir; or about 150 mg of lopinavir and about 12.5 mg of ritonavir.

In an embodiment about 3.0 g of the pharmaceutical composition disclosed in Table 3 or Table 4 is administered to the cervix by a syringe applicator as a once per day application (preferably in the evening before retiring for the night).

In a most preferred embodiment about 2.5 g of the pharmaceutical composition disclosed in Table 6 or Table 7 is administered to the cervix by a syringe applicator as a once per day application (preferably in the evening before retiring for the night).

TREATMENT REGIMENS

The pharmaceutical composition may be administered to a subject for as long as treatment is required. The length of time for which treatment will be required will depend upon the exact condition being treated or prevented and its severity. A skilled person will appreciate that treatment should be maintained in view of a number of factors which will include any requirement to eradicate the disease and/or disorder.

In one embodiment, a course of treatment may be for 2 - 4 weeks, 7-21 days or for about 14 days. After this time a clinician may assess whether the course of treatment has been successful. A decision may then be made whether or not to continue treatment.

It will be appreciated that a clinician may wish to take into account menstruation when deciding on a treatment regimen for women with conditions relating to the cervix. Conveniently, a treatment regimen may be for about 14 - 21 days and can be administered between menses. A clinician may elect to stop topical treatment of the cervix during menses and recommence a new course of treatment in the next menstrual cycle. By way of example, a treatment regimen can be: (1) 14 - 21 days of administration; (2) followed by 1 - 14 days without treatment (during which menses may occur if treating the cervix); and (3) a further cycle of 14 -21 days of treatment if this is considered medically necessary.

TREATMENT OF HPV RELATED DYSPLASIA

Conveniently, the pharmaceutical compositions may be used to treat female subjects having an HPV related dysplasia of the cervix.

As used herein,“dysplasia” encompasses pre-invasive lesions and cancer. HPV related pre-invasive lesions include high grade squamous intraepithelial lesion (HSIL), atypical squamous cells of undetermined significance (ASCUS), and low grade squamous intraepithelial lesion (LSIL). HPV related cancers include, for example, cervical

intraepithelial neoplasia (CIN) and invasive cervical cancer (ICC).

The disclosed methods and treatment regimens can be used to treat HPV related dysplasia. In some aspects, for example, the disclosed methods and treatment regimens can be used to treat HSIL. In some aspects, the disclosed methods and treatment regimens can be used to treat ASCUS. In other aspects, the disclosed methods and treatment regimens can be used to treat LSIL. In other aspects, the disclosed methods and treatment regimens can be used to treat CIN. In yet other embodiments, the disclosed methods and treatment regimens can be used to treat ICC. Additionally, the disclosed methods and treatment regimens can be used to inhibit the progression of HPV related dysplasia. In some aspects, for example, the disclosed methods and treatment regimens can be used to inhibit the progression of HSIL. In some aspects, the disclosed methods and treatment regimens can be used to inhibit the progression of ASCUS. In other aspects, the disclosed methods and treatment regimens can be used to inhibit the progression of LSIL. In other aspects, the disclosed methods and treatment regimens can be used to inhibit the progression of CIN. In yet other embodiments, the disclosed methods and treatment regimens can be used to inhibit the progression of ICC.

In one embodiment, there is provided a method of treating a patient having an HPV related dysplasia of the cervix comprising administering intravaginally to said patient a therapeutically effective dose of a pharmaceutical composition according to the first aspect.

In one embodiment, the pharmaceutical composition reduces the severity of the HPV related dysplasia. In one embodiment, the severity of the HPV is reduced from CIN3 to CIN2, from CIN3 to CIN1, from CIN3 to HPV negative, from CIN2 to CIN1, from CIN2 to HPV negative, or from CIN1 to HPV negative.

In one embodiment, the patient has a cervical cytology of high grade squamous intraepithelial lesion (HSIL), atypical squamous cells of undetermined significance

(ASCUS), or low grade squamous intraepithelial lesion (LSIL).

In one embodiment, the pharmaceutical composition reduces the cervical cytology from HSIL to a normal cytology, from HSIL to ACSUS, from HSIL to LSIL, from ACSUS to a normal cytology, or from LSIL to a normal cytology.

In some embodiments, the composition induces apoptosis of HPV infected cells. PROCESS OF MANUFACTURE

In a second aspect, there is provided a process to manufacture a pharmaceutical composition of the first aspect, the process comprising the step of incorporating (e.g. by mixing) a stiffening agent, at least one active pharmaceutical ingredient, and an unsaturated free fatty acid together to provide the pharmaceutical composition which is a semi-solid at room temperature, wherein the unsaturated free fatty acid is present at a level of at least 20% by weight of the total composition.

In one embodiment, the process comprises a first step comprising incorporating the at least one active pharmaceutical ingredient into the unsaturated free fatty acid to provide a mixture, followed by a second step comprising incorporating a stiffening agent into the mixture from the first step to provide the pharmaceutical composition. In one embodiment, the first step and/or second step comprises stirring. In one embodiment, the stirring is at performed at a rate of at least 10 rpm, such as at least 30 rpm, such as at least 50 rpm, or such as about 60 rpm. In a further embodiment, the first step and/or second step additionally comprise periodic stirring. In one embodiment, the periodic stirring is performed at a rate of at least 300 rpm, such as at least 400 rpm, such as at least 500 rpm, or such as about 600 rpm. In one embodiment, the stirring is performed at a rate of about 60 rpm and the periodic stirring is performed at a rate of about 600 rpm. In one embodiment, the stirring and the periodic stirring in the first step results in the at least one active pharmaceutical ingredient dissolving in to the unsaturated free fatty acid. In one embodiment, the periodic stirring is performed for 5 minutes after incorporating the at least one active pharmaceutical ingredient with the stiffening agent and the unsaturated free fatty acid together. This advantageously aids with the initial de-clumping of the components of the pharmaceutical composition during this part of the process. In one embodiment, the periodic stirring is repeated every 30 minutes. Advantageously, the periodic stirring results in a homogeneous pharmaceutical composition, for example, aids the solubilisation of the active pharmaceutical ingredient.

In one embodiment, the process is performed at room temperature. In one

embodiment, the process is performed at room temperature, and the unsaturated free fatty acid and the stiffening agent are present in the composition at a weight ratio of at least one part stiffening agent by weight to 1 to 5 parts unsaturated free fatty acid by weight, such as at least one part stiffening agent by weight to 1 to 3 parts unsaturated free fatty acid by weight, such as one part stiffening agent by weight to about 2 parts unsaturated free fatty acid by weight. Advantageously, the process is particularly well suited to active pharmaceutical ingredients which are prone to degradation, and wherein the rate and/or extent of degradation is increased when exposed to temperatures above room temperature, for example >30°C, >40°C, >50°C, and >60°C. In one embodiment, the process is performed at a temperature greater than the melting point of the stiffening agent, such as greater than 40°C, such as greater than 50°C, such as greater than 60°C, such as greater than 65°C, or such as about 70°C. In one embodiment, the process is performed at a temperature greater than the melting point of the stiffening agent, such as greater than 40°C, such as greater than 50°C, such as greater than 60°C, such as greater than 65°C, or such as about 70°C, and the unsaturated free fatty acid and the stiffening agent are present in the composition at a weight ratio of at least 1 part stiffening agent by weight to 0.1 to 20 parts unsaturated free fatty acid by weight, such as at least one part stiffening agent by weight to 0.5 to 20 parts unsaturated free fatty acid by weight , or such as at least one part stiffening agent by weight to 1 to 20 parts unsaturated free fatty acid by weight. For example, such as at least one part stiffening agent by weight to 1 to 5 parts unsaturated free fatty acid by weight, such as at least one part stiffening agent by weight to 1 to 3 parts unsaturated free fatty acid by weight, such as at least one part stiffening agent by weight to 2 to 18 parts unsaturated free fatty acid by weight, such as at least one part stiffening agent by weight to 10 to 18 parts unsaturated free fatty acid by weight, such as at least one part stiffening agent by weight to 12 to 16 parts unsaturated free fatty acid by weight, such as one part stiffening agent by weight to about 2 parts unsaturated free fatty acid by weight, such as one part stiffening agent by weight to about 13 parts unsaturated free fatty acid by weight, or such as one part stiffening agent by weight to about 14 parts unsaturated free fatty acid by weight.

In one embodiment, the process comprises incorporating the stiffening agent, the at least one active pharmaceutical ingredient, and the unsaturated free fatty acid by low shear mixing. In another embodiment, the process comprises incorporating the stiffening agent, the at least one active pharmaceutical ingredient, and the unsaturated free fatty acid by high pressure homogenising.

In a third aspect, there is provided a process to manufacture a pharmaceutical composition of the first aspect, the process comprising:

a. incorporating (e.g. by mixing) at least one active pharmaceutical ingredient in an unsaturated free fatty acid; and

b. incorporating (e.g. by mixing) a stiffening agent into the mixture obtained from step a. to provide a semi-solid composition;

wherein the unsaturated free fatty acid is present at a level of at least 20% by weight of the total composition. In one embodiment, the process is performed at room temperature. In one

embodiment, the process is performed at room temperature, and the unsaturated free fatty acid and the stiffening agent are present in the composition at a weight ratio of at least one part stiffening agent by weight to 1 to 5 parts unsaturated free fatty acid by weight, such as at least one part stiffening agent by weight to 1 to 3 parts unsaturated free fatty acid by weight, or such as one part stiffening agent by weight to about 2 parts unsaturated free fatty acid by weight. This has the advantage of the process being particularly well suited to active pharmaceutical ingredients which are unstable when exposed to temperatures above room temperature, for example >30°C, >40°C, >50°C, and >60°C.

In one embodiment, step a. and/or step b. comprises stirring. In one embodiment, the stirring is at performed at a rate of at least 10 rpm, such as at least 30 rpm, such as at least 50 rpm, or such as about 60 rpm. In a further embodiment, step a. and/or step b. additionally comprise periodic stirring. In one embodiment, the periodic stirring is performed at a rate of at least 300 rpm, such as at least 400 rpm, such as at least 500 rpm, or such as about 600 rpm. In one embodiment, the stirring is performed at a rate of about 60 rpm and the periodic stirring is performed at a rate of about 600 rpm. In one embodiment, the stirring and the periodic stirring in the first step results in the at least one active pharmaceutical ingredient dissolving in the unsaturated free fatty acid.

In one embodiment, the process is performed at a temperature greater than the melting point of the stiffening agent, such as greater than 40°C, such as greater than 50°C, such as greater than 60°C, such as greater than 65°C, or such as about 70°C. In one embodiment, the process is performed at a temperature greater than the melting point of the stiffening agent, such as greater than 40°C, such as greater than 50°C, such as greater than 60°C, such as greater than 65°C, or such as about 70°C, and the unsaturated free fatty acid and the stiffening agent are present in the composition at a weight ratio of at least 1 part stiffening agent by weight to 0.1 to 20 parts unsaturated free fatty acid by weight, such as at least one part stiffening agent by weight to 0.5 to 20 parts unsaturated free fatty acid by weight, such as at least one part stiffening agent by weight to 1 to 20 parts unsaturated free fatty acid by weight. For example, such as at least one part stiffening agent by weight to 1 to 5 parts unsaturated free fatty acid by weight, such as at least one part stiffening agent by weight to 1 to 3 parts unsaturated free fatty acid by weight, such as at least one part stiffening agent by weight to 2 to 18 parts unsaturated free fatty acid by weight, such as at least one part stiffening agent by weight to 10 to 18 parts unsaturated free fatty acid by weight, such as at least one part stiffening agent by weight to 12 to 16 parts unsaturated free fatty acid by weight, such as one part stiffening agent by weight to about 2 parts unsaturated free fatty acid by weight, such as one part stiffening agent by weight to about 13 parts unsaturated free fatty acid by weight, or such as one part stiffening agent by weight to about 14 parts unsaturated free fatty acid by weight.

In one embodiment, the process according to the second or third aspects is performed under an inert atmosphere. In one embodiment, the inert atmosphere is provided by a vacuum. In a further embodiment, the vacuum is about -0.5 bar. Performing the process under an inert atmosphere has the advantage that any components of the pharmaceutical composition, such as the at least one active pharmaceutical ingredient, that are prone to degradation, such as oxidative degradation, are protected from said degradation during the manufacturing process.

In one embodiment, the process according to the second or third aspect uses an unsaturated free fatty acid which has an assay of at least 95% by weight, such as at least 98% by weight, such as at least 99% by weight, or such as at least 99.5% by weight. In one embodiment, the process according to the second or third aspect uses a stiffening agent which has an assay of at least 95% by weight, such as at least 98% by weight, such as at least 99% by weight, or such as at least 99.5% by weight. Advantageously, using an unsaturated free fatty acid of a high assay level ensures that the pharmaceutical composition is controlled in respect to, for example, the identity, amount and purity of the free fatty acid within the composition. Additionally, using a stiffening agent having a high assay level ensures that the pharmaceutical composition is controlled in respect to, for example, the identity, amount and purity of the stiffening agent within the composition.

DOSING APPARATUS

In one aspect, there is provided a syringe comprising the pharmaceutical composition of the first aspect. In one embodiment, the syringe for vaginal dosing of the pharmaceutical composition.

In a further aspect, there is provided a kit of parts, the kit comprising instructions for use and a syringe comprising the pharmaceutical composition of the first aspect. In one embodiment, there is provided a kit of parts, the kit comprising instructions for use and a syringe comprising the pharmaceutical composition, the syringe for vaginal dosing of the pharmaceutical composition.

In a further aspect, there is provided a tube comprising the pharmaceutical composition of the first aspect. In one embodiment, the tube is an aluminium tube. In a further aspect, there is provided a kit of parts, the kit comprising instructions for use and a tube comprising the pharmaceutical composition of the first aspect. In one embodiment, the tube is an aluminium tube.

EXAMPLES

The following abbreviations have been used in the examples:

API - active pharmaceutical ingredient

HPMC - hydroxypropylmethylcellulose

PEG - polyethylene glycol

Example 1: Solubility of Ritonavir and/or Lopinavir

The solubility of Ritonavir and Lopinavir, and Ritonavir alone in a range of pharmaceutically acceptable solvents is presented below. As can be seen, Ritonavir and Lopinavir, and Ritonavir alone have high solubility in oleic acid.

'Empirically determined, by mass weighing, at ambient temperature, using Lopinavir/Ritonavir API blend molar ratio of 9: 1 ² Based on oleic acid specific gravity of 0.9

³ Solubility for Ritonavir only, measured at 37°C, Lei et al. ^“ Development of a novel self-micro-emulsifying drug delivery system (SMEDD S) for reducing HIV protease inhibitor-induced intestinal epithelial barrier dysfunction”, Mol. Pharm. 2010 Jun 7:7(3) 844-853

Example 2: Ritonavir and Lopinavir chemical and physical stability

It is known from the literature that potency loss for Lopinavir and Ritonavir is thermolytically driven and Ritonavir is particularly prone to hydrolysis due to its carbomate functional group (Donato et al,“LC Method for Studies on the Stability of Lopinavir and Ritonavir in Soft Gelatin Capsules”, Chromatographia, April 2006, 63, 437-443). Ritonavir is also known to be oxygen labile. A preferable manufacturing route for compositions comprising

Lopinavir/Ritonavir is thus one that excludes heat, water, and/or oxygen. Example 3: Preparation of formulations

For all formulations present below, all materials used are pharmaceutical grade (either US Pharmacopeia or European Pharmacopeia) except for white ceresin wax, which is Japanese Pharmaceutical Excipient grade. The oleic acid used was super refined grade (Supplier: Croda).

Formulation 3a: i mixture (oleic acid and stearic ; full and half strength- molar ratio of lo to ritonavir 9:1

The manufacture of binary mixture of oleic acid and stearic acid active batch with rheology suitable for topical dosing is described below in accordance with Table 1 :- i. Into main vessel add 1, 4. Stir at 60 rpm and periodically homogenize at 600 rpm to dissolve. -0.5 bar vacuum applied.

ii. Into main vessel add 5, 6. Stir at 60 rpm and periodically homogenize at 600 rpm to dissolve. -0.5 bar vacuum applied.

iii. Into main vessel add 2. Stir at 60 rpm and periodically homogenize at 600 rpm to disperse. -0.5 bar vacuum applied.

iv. Into main vessel add 3. Stir at 60 rpm and periodically homogenize at 600 rpm to combine. -0.5 bar vacuum applied.

v. Discharge the product into well labelled polypail, awaiting packing into aluminium tubes.

Formulation 3b: Binary mixture (oleic acid and stearic acid); placebo

The manufacture of a placebo batch containing a binary mixture of oleic acid and stearic acid with rheology suitable for topical dosing is described below in accordance with Table 2:- i. Into main vessel add 1, 4. Stir at 60 rpm and periodically homogenize at 600 rpm to dissolve. -0.5 bar vacuum applied.

ii. Into main vessel add 2. Stir at 60 rpm and periodically homogenize at 600 rpm to disperse. -0.5 bar vacuum applied.

iii. Into main vessel add 3. Stir at 60 rpm and periodically homogenize at 600 rpm to combine. -0.5 bar vacuum applied.

iv. Discharge the product into well labelled polypail, awaiting packing into aluminium tubes. Formulation 3c: Mixture (oleic acid, stearic acid and thickeners); full strength - molar ratio of lopinavir to ritonavir 12:1

The manufacture of a vaginal dosage form full strength active batch exhibiting rheology suitable for syringe applicator vaginal dosing is described below in accordance with Table 3:-

Add into the mixer the following materials - 3,4,5,6,7,8,9,1,10,11

ii. Exclude air from the interior of the vessel

iii. Heat to 70 °C while low shear mixing, to achieve a clear, transparent melt.

iv. Add into the mixer the following material - 2

v. Exclude air from the interior of the vessel

vi. Mix via low shear, to finely disperse the HPMC within the melt

vii. Reduce the content temperature to 45°C while low shear mixing

viii. Discharge to storage vessel and exclude air during storage.

Formulation 3d: Mixture (oleic acid, stearic acid and thickeners): half strength - molar ratio of lopinavir to ritonavir 12:1

The manufacture of a vaginal dosage form half strength active batch exhibiting rheology suitable for syringe applicator vaginal dosing is described below in accordance with Table 4:- i. Add into the mixer the following materials - 3,4,5,6,7,8,9,1,1041 ii. Exclude air from the interior of the vessel

iii. Heat to 70 °C while low shear mixing, to achieve a clear, transparent melt.

iv. Add into the mixer the following material - 2

v. Exclude air from the interior of the vessel

vi. Mix via low shear, to finely disperse the HPMC within the melt

vii. Reduce the content temperature to 45°C while low shear mixing

viii. Discharge to storage vessel and exclude air during storage.

Formulation 3e: Mixture (oleic acid, stearic acid and thickeners); placebo

The manufacture of a vaginal dosage form placebo batch exhibiting rheology suitable for syringe applicator vaginal dosing is described below in accordance with Table 5:- i. Add into the mixer the following materials - 3, 4, 5, 6, 7, 8, 9,1

ii. Exclude air from the interior of the vessel iii. Heat to 70 °C while low shear mixing, to achieve a clear, transparent melt.

iv. Add into the mixer the following material - 2

v. Exclude air from the interior of the vessel

vi. Mix via low shear, to finely disperse the HPMC within the melt

vii. Reduce the content temperature to 45°C while low shear mixing

viii. Discharge to storage vessel and exclude air during storage.

Formulation 3f: Mixture (oleic acid, stearic acid, HPMC and thickeners); full strength molar ratio of lopinavir to ritonavir 13.8:1

The manufacture of a vaginal dosage form placebo batch exhibiting rheology suitable for syringe applicator vaginal dosing is described below in accordance with Table 6:- i. Add into the mixer the following materials - 3, 4, 5, 6, 7, 8, 9, 1, 10, 11 ii. Exclude air from the interior of the vessel

iii. Heat to 70 °C while low shear mixing, to achieve a clear, transparent melt.

iv. Add into the mixer the following material - 2

v. Exclude air from the interior of the vessel

vi. Mix via low shear, to finely disperse the HPMC within the melt

vii. Reduce the content temperature to 45°C while low shear mixing

viii. Discharge to storage vessel, exclude air during storage.

ix. Pack product into aluminium tubes, suitable for 2.5 g dispensing so as to deliver 300 mg Lopinavir and 25 mg Ritonavir

Formulation 3g: Mixture (oleic acid, stearic acid, HPMC and thickeners); half strength - molar ratio of lopinavir to ritonavir 13.8:1

The manufacture of a vaginal dosage form placebo batch exhibiting rheology suitable for syringe applicator vaginal dosing is described below in accordance with Table 7:- i. Add into the mixer the following materials - 3,4,5,6,7,8,9,1,10,11

ii. Exclude air from the interior of the vessel

iii. Heat to 70 °C while low shear mixing, to achieve a clear, transparent melt. iv. Add into the mixer the following material - 2

v. Exclude air from the interior of the vessel

vi. Mix via low shear, to finely disperse the HPMC within the melt

vii. Reduce the content temperature to 45°C while low shear mixing

viii. Discharge to storage vessel, exclude air during storage.

ix. Pack product into aluminium tubes, suitable for 2.5 g dispensing so as to deliver 150 mg Lopinavir and 12.5 mg Ritonavir.

Formulation 3h: Mixture (oleic acid, stearic acid, HPMC and thickeners); full strength - molar ratio of lopinavir to ritonavir 13.8:1; cold process

The manufacture of a vaginal dosage form exhibiting rheology suitable for syringe applicator vaginal dosing is described below in accordance with Table 8:- i. Into medicine mixer add 1, 9, 10, 11

ii. Lower the lid and purge with nitrogen

iii. Mix without heating for several hours until a clear, transparent solution is achieved iv. Raise the lid and add 7

v. Lower the lid and purge with nitrogen

vi. Mix without heating until a clear, transparent solution is achieved

vii. Raise the lid and add 2, 3, 4, 5, 6, 8

viii. Lower the lid and purge with nitrogen

ix. Mix without heating for several hours

x. Discharge the product into bulk storage vessel, awaiting packing into aluminium tubes

Formulation 3i: Binary mixture (oleic acid and stearic acid); full strength- molar ratio of lopinavir to ritonavir 13.8:1

The manufacture of binary mixture of oleic acid and stearic acid active batch is described below in accordance with Table 9:- i. Into main vessel add 1, 4. Stir to dissolve

ii. Into main vessel add 5, 6. Stir to dissolve

iii. Into main vessel add 2. Stir to disperse

iv. Into main vessel add 3. Stir to blend. Aim for a very smooth consistency.

v. Discharge the product into a well labelled polypail. Formulation 3i: Binary mixture (oleic acid and stearic acid); full strength- molar ratio of lopinavir to ritonavir 9.2:1

The manufacture of binary mixture of oleic acid and stearic acid active batch is described below in accordance with Table 10:- i. Into main vessel add 1, 4. Stir to dissolve

ii. Into main vessel add 5, 6. Stir to dissolve

iii. Into main vessel add 2. Stir to disperse

iv. Into main vessel add 3. Stir to blend. Aim for a very smooth consistency.

v. Discharge the product into a well labelled polypail.

Formulation 3k: Mixture (oleic acid, stearic acid, HPMC and thickeners); full strength - molar ratio of lopinavir to ritonavir 13.8:1: cold process

The manufacture of a vaginal dosage form exhibiting rheology suitable for syringe applicator vaginal dosing is described below in accordance with Table 11 :- i. Into medicine mixer add 1, 9, 10, 11

ii. Lower the lid and purge with nitrogen

iii. Mix without heating for several hours until a clear, transparent solution is achieved iv. Raise the lid and add 7

v. Lower the lid and purge with nitrogen

vi. Mix without heating until a clear, transparent solution is achieved

vii. Raise the lid and add 2, 3, 4, 5, 6, 8

viii. Lower the lid and purge with nitrogen

ix. Mix overnight, without heating

x. Discharge the product and pass through a colloid mill.

xi. Filter the milled product through a 400pm GAF filter into a storage vessel.

xii. Purge the headspace with nitrogen, and seal the lid, awaiting packing into aluminium tubes.

Formulation 31: Cream comprising Lopinavir

The manufacture of a cream comprising Lopinavir is described below in accordance with Table 12:

i. Into main vessel add 1, 2, 3, 4, 5 ii. For active batches, exclude air from the interior via vacuum -80 kPa. Replace with nitrogen. (x3) (N/A for placebo batches)

111 Heat the contents to 75°C, mixing as required until clear solution e.g. 60 rpm,

homogenizer 600 rpm

lv. Reduce the contents to 65°C, with stirring e.g. 60 rpm

v. In a beaker dissolve 6 and 7 into 8 then add to side melter along with 9, 10, 11, 12, heating to 65°C with stirring (fixed speed)

vi. Introduce the side melter content into main vessel stirring at 60 rpm

vii. For active batches, exclude air from the interior via vacuum -80 kPa. Replace with nitrogen (x3) (N/A for placebo batches)

Vlll. Homogenize the emulsion e.g. stirrer 60 rpm, homogenizer 1500 rpm for 10 minutes ix. Cool content to at least below 30°C, mixing as required e.g. 60 rpm

X. Discharge the product into HDPE bag lined polypail, well labelled.

Table 1

Formulation Stearic acid as a stiffening agent,

Rationale no thickeners present - no heat

Batch

number: N/A

Batch size: 2000 g

Active

supplier: Cipla

Table 2

Formulation Stearic acid as a stiffening agent,

Rationale no thickeners present - no heat

Batch

number: N/A

Batch size: 1775 g

Active

supplier: Cipla

*N2 PURGE ANY BULK

SUPPLY AFTER USE

** PROTECT

FROM UV LIGHT

Table 3

* Melt completely/mix source supply prior to dispensing

* *N2 purge source supply after sampling

* * * Protect from UV light

Table 4

* Melt completely/mix source supply prior to dispensing

* *N2 purge source supply after sampling

* * * Protect from UV

light

Table 6

* Melt completely/mix source supply prior to dispensing

* *N2 purge source supply after sampling

* * * Protect from UV light

Table 7

* Melt completely/mix source supply prior to dispensing

* *N2 purge source supply after sampling

* * * Protect from UV light

Table 8

* *N2 purge source supply after sampling

* * * Protect from UV light

Table 9

Formulation Stearic acid as a stiffening agent, no Rationale thickeners present - no heat

Batch

number: N/A

Batch size: 1500 g

*N2 PURGE SOURCE

SUPPLY AFTER SAMPLING

** PROTECT FROM UV

LIGHT

Table 10

Formulation Stearic acid as a stiffening agent, no

Rationale thickeners present - no heat

Batch number: N/A

Batch size: 1500.0 g

Table 11

* *N2 purge source supply after sampling

* * * Protect from UV light

Table 12

* *N2 purge source supply after sampling

Example 4: Organoleptic assessment of the Formulations

The formulations described in Example 3 are suitable for topical dosing and syringe dosing. Organoleptic assessments of formulations 3a, 3b, 3c, 3d, 3e, 3f, 3g, 3i, 3j, 3h and 3k were conducted.

Organoleptic assessment of Formulations 3a and 3b

Dosing Procedure:

1 Remove the cap from the tube

2 Dispense a small amount of the ointment onto a clean fingertip.

3 With the fingertip, apply the ointment to the affected skin area, rubbing gently.

4 Replace the cap on the tube

Observations

The opaque ointment presents as easy to dispense from the tube and is controllable on the skin during rubbing. After a short period of rubbing, the ointment clarifies to leave the skin non-tacky and with minimal greasiness. Approximately 10 minutes after dosing, the skin presents as silky, with negligible greasiness. These attributes denote an ointment as particularly suitable for topical application.

Organoleptic assessment of Formulations 3c, 3d and 3e

Dosing Procedure

1 Remove the cap from the tube

2 Thread the dosing syringe applicator onto the tube orifice

3 Squeeze the tube to force product into the syringe applicator until the plunger rises to the 3 g mark.

4 Discharge the ointment from the syringe applicator onto a petri dish.

5 Add 10 drops of water onto the dispended ointment

6 With the fingertip rub gently to blend in the water.

7 Replace the cap on the tube

Observations

The opaque ointment presents as easy to dispense from the tube into the syringe applicator, after a short period of rubbing the ointment becomes increasingly more opaque, increasing whiteness, embodied, gelatinous, and cream-like. These attributes denote an ointment that is compatible with a water environment, and as such, particularly suitable for topical application to an area of the body where water is present, for example vaginal application.

Organoleptic assessment of Formulations 3c, 3d 3f, 3g, 3i, 3i, 3h and 3k

An organoleptic assessment was performed for formulations 3c, 3d, 3f, 3g, 3i, 3j, 3h and 3k using the following methodology.

Dosing Procedure:

1. Remove the cap from tube.

2. Dispense a small amount of the ointment onto a clean fingertip.

3. With the fingertip, apply the ointment to an area of skin, rubbing gently.

4. Replace the cap on the tube.

5. Record observations for colour, transparency, homogeneity, material state, and

textural attributes.

The organoleptic assessment results for formulations 3c, 3d, 3f, 3g, 3i, 3j, 3h and 3k are presented in Table 13 below:

Table 13

Example 5: Stability studies

The compositions according to Example 3 have been proven to be stable during the process employed to manufacture them (i.e. processes described in Example 3). Additionally, the compositions according to Example 3 have been shown to be stable upon storage.

Formulations 3c, 3d, 3f, 3g, 3i, 3j, and 3h were stored under different time and stability conditions, and subsequently analysed. The stability data is presented in Tables 14 and 15. A stable product is defined as one demonstrating 90-110% w/w assay for both Lopinavir and Ritonavir. Based on the data generated, the hot processed product

(Formulations 3f and 3g) when stored at 5°C (range 2-8°C) affords at least 10 months stability. Formulation 3h (prepared using a cold process) demonstrates greater stability than that for formulations 3c and 3d when stored for 3 months stored at 25°C. This is thought to be due to the absence of thermal exposure of Ritonavir and Lopinavir during the

manufacture. Forward projection of the stability data suggest at least 6 months/25°C is achievable for Formulation 3h. To get stability beyond 6 months for Formulation 3h, cold storage (5°C) may be required.

Table 14

*All batches put to stability are packed in to phenolic epoxy lined aluminium tubes

**Formulation 3j was an early formulation. A stability assessment was not taken at the time of manufacture. For stability trending, formulation 3i (a close variant of formulation 3j) was manufactured.

Table 15

*All batches put to stability are packed in to phenolic epoxy lined aluminium tubes

**Formulation 3j was an early formulation. A stability assessment was not taken at the time of manufacture. For stability trending, formulation 3i (a close variant of formulation 3j) was manufactured. The following analytical methodology was used to analyse the formulations. UHPLC:

Equipment Parameters:

Gradient Elution Program

Example 6: Methodology for rheological characterisation of the pharmaceutical composition.

The following methodology can be used to determine the rheological behaviour of the pharmaceutical compositions, for example using a Discovery Hybrid Rheometer (Model HR- 3, TA instruments). The sample is introduced onto the peltier plate (base) in excess (l-2g), and the spindle lowered to make contact with the sample. The excess sample is cleaned up. The spindle is then rotated in a predetermined fashion to exert a series of shear forces on the sample. The various sample shear force response parameters (complex viscosity, storage and loss moduli, tan 5) are captured and then plotted in order to make conclusions regarding inherent sample attributes. Instalment parameters for the purpose of capturing complex viscosity, storage modus and loss modulus are as follows :- Peltier temperature: 37 °C

Sample size: Approximately 1 g

Oscillation frequency method parameters:

Speed range 0.1 to 1 rad/s

Strain 0.5 %

Spindle 40 mm parallel plate

Gap setting 1000 pm

Example 7: Preparation of a 2 parts stearic acid by weight and

1 part oleic acid by weight.

20 g of stearic acid was added to 10 g of oleic acid at room temperature. Due to the high solids loading, a powdery clump formed. Heating to 65 °C followed by passive cooling yielding an opaque, waxy solid.

Potential applications: Pelletized dissolved state API for solid state dosing.

Example 8: Excipient One Factor At A Time (OF AT) analysis

One-Factor- At-a-Time (OF AT) excipient level variation analysis of centre-point full- strength (Formulation 8a) /half- strength (Formulation 8b) formulations, sometimes referred to as Design-Of-Experiments (DOE) has been conducted for each of the materials as per the below table, via seventeen additional Formulations 8c to 8s.

The impact for each change was assessed by rheological response, specifically the recording of the maximum complex viscosity (q) observed across a frequency sweep 0.1-1 radians/second at 0.5 % strain via TA Instruments DHR Rheometer fitted with 40mm parallel plate, a gap setting of 1000 pm, and a temperature of 37 °C.

Aside from the API solvent, which attracts its own set of selection criteria (namely the minimum amount required to achieve dissolved state for Lopinavir and Ritonavir), and antioxidant (with and without), the lower levels for other excipients were selected based on being, in essence, just above zero. The upper level of each excipient was based on

understanding of the likelihood for the anomaly to exert an effect, while still maintaining a doseable semisolid. The centre-point full-strength (Formulation 8a) /half- strength (Formulation 8b) formulations yield viscosities of approximately 2000-l500cps. The half strength contains a higher solvent level than the full-strength, which translates to a somewhat lower viscosity (note: It is the full-strength formulation, with 13 % total drug substance, that dictates the minimum amount of solvent i.e. 55.3 %. The half strength formulation, with only 6.5 % total drug substance, thus contains the balance of the material added to the solvent, which commensurately rises to 61.8 %).

Formulation 8d (r) = 288cps) is too runny for dosing, while Formulation 8s (r) = 9l5cps) is easily stiff enough for dosing. Formulation 8c (r) = l8085cps) is so stiff as to be barely dose-able via the intended 6 mm tube orifice. A larger tube orifice (8-10 mm), or even use of pre-charged dosing applicators would facilitate easier dosing of product at this upper viscosity.

A summary table of the rheological viscosity outputs for the range finding formulations, incorporating a Material Risk Assessment (MRA) is presented in Table 16.

Table 16

3 o

O

4-

-4

h3 n H

N5 w

O

O C/I 4

* thinning effect O

Formulation 8a: Full strength ointment

The manufacture of Formulation 8a is described below in accordance with Table 17:- i. Into main vessel add all materials except for 2

ii. Heat the contents to 75°C, mixing as required until clear solution e.g. 60 rpm, homogenizer 600 rpm

iii. Into the main vessel add 2 to disperse, mixing for e.g. 10 minutes, 60 rpm,

homogenizer 600 rpm

iv. Cool contents to 45°C, mixing as required e.g. 60 rpm, homogenizer 600 rpm v. Discharge the product into HDPE bag lined polypail, well labelled

Formulation 8b: Half strength ointment

The manufacture of Formulation 8b is described below in accordance with Table 18:- i. Into main vessel add all materials except for 2

ii. Exclude air from the interior via vacuum -80kPa. Replace with nitrogen iii. Repeat step ii two more times

iv. Heat the contents to 75°C, mixing as required until clear solution e.g. 60 rpm, homogenizer 600 rpm

v. Into the main vessel add 2

vi. Repeat step ii three times

vii. Mix for e.g. 10 minutes, 60 rpm, homogenizer 600 rpm to disperse

viii. Cool contents to 45°C, mixing as required e.g. 60 rpm, homogenizer 600 rpm ix. Discharge the product into HDPE bag lined polypail, well labelled

x. Pack 75 g into each of 30 tubes with Darex seal

Formulations 8c, 8d, 8e, 8f, 8g, 8h, 8i, 8i, 8k, 81, 8m, 8h, 8o, 8p, 8q, 8r, 8s and 8t

The manufacture of Formulations 8c, 8d, 8e, 8f, 8g, 8h, 8j, 8k, 81, 8m, 8n, 8o, 8p, 8q, 8r, 8s and 8t are described below in accordance with Table 19:- i. Into main vessel add all materials except for 2

ii. Exclude air from the interior via vacuum -80kPa. Replace with nitrogen iii. Repeat step ii two more times

iv. Heat the contents to 75°C, mixing as required until clear solution e.g. 60 rpm, homogenizer 600 rpm

v. Into the main vessel add 2

vi. Repeat step ii three times vii. Mix for e.g. 10 minutes, 60 rpm, homogenizer 600 rpm to disperse viii. Cool content to 45°C, mixing as required e.g. 60 rpm, homogenizer 600 rpm ix. Discharge the product into HDPE bag lined polypail, well labelled

x. Pack 75 g into each of 3 tubes with Latex seal, keep the rest as bulk, well sealed.

Table 17

* *N2 purge source supply after sampling

* * * Protect from UV light Table 18

* *N2 purge source supply after sampling

* * * Protect from UV light

Example 9: A Phase 1, single centre, double blind, randomised, parallel group, ascending single and multiple dose, safety and tolerability, pharmacokinetic (PK) and

pharmacodynamic (PD) study of Formulations 3c, 3d and 3e in healthy women volunteers.

The compositions according to Example 3 (Formulations 3c, 3d, and 3e) were investigated according to the clinical trial described below.

Study Obiectives

1. To evaluate the safety, PK and PD of compositions in healthy women volunteers after

multiple doses of Formulations 3c and 3d.

2. To observe the rates of side effects reported by women using the compositions compared to placebo.

Investigational Plan/Studv Design

This study comprised two cohorts, both in healthy volunteers with no cervical pathology. There were 9 participants per Cohort, of whom 6 received active and 3 received placebo. For all formulations tested, the amount of the composition administered per dose was 3 g. For

Formulation 3c this equates to 300 mg of lopinavir and 28.7 mg of ritonavir being administered to the patients per dose. For Formulation 3d this equates to 150 mg of lopinavir and 14.3 mg of ritonavir administered per dose.

Cohort 1:

Period 1 : Single dose of Formulation 3d or placebo Formulation 3e followed by confinement. PK blood sampling during confinement.

Period 2: 21 daily doses of Formulation 3d or placebo Formulation 3e followed by PK blood sampling.

Cohort 2:

Period 1 : Single dose of Formulation 3c or placebo Formulation 3e followed by confinement. PK blood sampling during confinement.

Period 2: 21 daily doses of Formulation 3c or placebo Formulation 3e followed by PK blood sampling.

Participation Criteria

Inclusion Criteria:

a. Women, 20 to 45 years old, with an intact uterus and vagina. b. Generally, in good health with no clinically significant pulmonary, cardiac,

gastroenterological, pancreatic, neurologic, renal, musculoskeletal, rheumatologic, metabolic, neoplastic, or endocrine disease.

c. BMI of =>l9 and <= 30.0

d. ECG and vital signs within normal ranges

e. Agree to no Alcohol from 48 hours prior to dosing in period 1 until 7 days after receiving the final dose in period 2.

f. Abstain from food or beverages containing grapefruit, starfruit, pomegranate, pineapple, or pomelo for the entire study

g. Able and willing to abstain from sexual intercourse +/- 6 hours around dosing within Periods 1 and 2

h. Able and willing to use stringent methods of contraception after required abstinence period through to Day 29 (7 days after receiving the final dose in period 2), including the use of a non-latex condom (for partner protection) and a second acceptable contraception method; vasectomy, contraceptive pill, contraceptive implants or IUDs are allowed (note: IUDs should have been inserted at least 1 month prior to enrolment and not because of the involvement in this study)

i. Agree to abstain from activities such as vaginal douching or insertion of any vaginal

products other than the study drug for at least 48 hours prior to enrolment and throughout the study.

j. Negative Pap test at screening or within 3 years of enrolment and no history of cervical

intraepithelial lesions within the previous 3 years

k. Able and willing to return to the clinic for all study procedures.

l. Able and willing to provide informed consent.

Exclusion Criteria:

a. Women who are pregnant, plan to become pregnant in the next 3 months, or lactating

females.

b. History of genital herpes with >3 outbreaks per year, or active non-HPV vaginal infection c. Positive result for Hep B, Hep C or HIV.

d. Have an active pelvic infection (positive urine screen for gonorrhoea or chlamydial infection, positive test and symptoms for bacterial vaginosis, Candida vaginitis or trichomonal vaginitis) e. Current or recent abnormal vaginal discharge and /or abnormal vaginal bleeding, within the 3 months prior to randomization as accessed by Investigator.

f. Had an abortion or miscarriage within the 3 months prior to randomization

g. Currently taking any of the following medications: oral corticosteroids, inhaled salmeterol and fluticasone; immunomodulatory treatments, over the counter (OTC) intra-vaginal preparation, or any prescription that in the opinion of the Investigator could interfere with the interpretation of the results.

h. Currently taking any of the medications listed here - Alfuzosin, Amiodarone, dronedarone, Ranolazine, Fusidic Acid, Colchicine, Astemizole, terfenadine, Lurasidone, Pimozide, Quetiapine, Dihydroergotamine, ergonovine, ergotamine, methylergonovine, Cisapride, Lovastatin, simvastatin, Avanafil, Sildenafil, Vardenafil, Oral midazolam, triazolam, St. John's wort.

i. Recent history (within previous 3 months) of Stevens- Johnson syndrome, erythema

multiforme, urticaria, angioedema, deep vein thrombosis, tinnitus, vertigo, blood glucose disorders, pancreatitis, haemophilia.

j. Hypersensitivity to any component of R131 vaginal ointment excipients

k. Participation in any clinical study with an experimental medication or device within 30 days or 5 half-lives (whichever is longer) of enrolment.

l. Current alcohol or substance abuse as assessed by the Investigator.

m. An employee or first-degree family member of an employee, the Sponsor, the CRO or study site.

n. Not having a GP

Screening Evaluations:

The screening evaluations must have been made within 3 months of randomization into the study. Screening consisted of the following components:

Demographic/Medical History

A complete medical history was taken from each participant.

Physical Examination

The physical examination consisted of a review of body systems with height and weight (in indoor clothing).

Blood Tests The following laboratory blood tests were performed:

• Electrolytes (sodium and potassium), ALT, GGT, ALP, albumin, total protein, total bilirubin, urea, uric acid, serum creatinine, TFT, fasting lipids, amylase, glucose, and HbAlc

· Haemoglobin, red cell count, PCV, MCV, MCH, platelet count, white cell count,

neutrophils, lymphocytes, monocytes, eosinophils and basophils. CD4/CD8 counts

• HIV and hepatitis B and C.

The measurement at screening serve as a baseline to monitor any abnormalities that may manifest as a result of dosing

Other Tests

Drugs of abuse testing were carried out on all participants as part of the screening procedures. A urine sample was required to test for cannabinoids (marijuana), amphetamines, benzodiazepines and opiates (i.e. morphine, heroin and codeine).

Urinalysis dipstick to check for protein, leucocytes, nitrites, pH, specific gravity, glucose, ketones, and blood.

Vaginal swabs for microbiology (gonorrhoea, Chlamydia, bacterial vaginosis, Candida) and HPV genotyping

Alcohol breath testing was carried out at the Clinical Site on the first night of each confinement period.

Serum HCG testing was carried out on all participants as part of the screening procedures and within 3 days before the lst dose.

Vital Signs

Vital signs were recorded and consisted of blood pressure (supine and sitting), heart rate, temperature and respiratory rate. Participants’ vital signs should be within the following limits: Heart rate > 60 or < 99 beats/minute

Supine:

Systolic Blood Pressure > 90 or < 160 mm Hg; Diastolic Blood Pressure > 50 or < 90 mm Hg

Sitting: Systolic Blood Pressure > 90 or < 160 mm Hg; Diastolic Blood Pressure > 50 or < 90 mm Hg

Temperature > 36°C or < 37.7°C

Respiratory Rate > 12 or < 20 breaths/minute

Summary of Study Activities/Schedule of Events

Informed consent was needed from each participant. Participants were screened to confirm study eligibility.

Randomisation

Participants were randomized following the Principal Investigator or their delegates documented acceptance of participants following review of completed screening procedures.

Study Confinement

Participants arrived at approximately 5pm on Day 1 and Day 22. The duration of study confinement was approximately 27 hours. Participants were released from the clinical site once the 24-hour post dose assessments had been completed.

Dosing

Dosing began at approximately 8pm on each day dosing was scheduled. Participants were instructed to insert the medication in private. Dosing applicators were returned to study staff and examined to ensure the full dose has been applied and for reconciliation of study drug.

Sample collection Vaginal swabs were self-administered by the participants.

PK Blood samples: blood samples (8 mL) were drawn through venous catheters and transferred into vacutainers containing sodium heparin as the anti-coagulant. The time of collection is recorded as the time the full 8 mL of blood was collected. The venous catheters were kept patent by flushing with 1.5 mL-2.0 mL of heparinized saline following each sample (0-24 hours). The sampling intervals were at: Day 1-2: 0, 1, 2, 4, 8, 12, 24 hours; Day 22-23: 0, 1, 2, 4, 8, 12, 24 hours. Samples were collected at their due time. Any deviation was noted.

Sample processing and storage Plasma: Plasma was separated by centrifugation at 3500 rpm for 5 minutes at about 4°C. No aids for separation of plasma from red cells was used. The plasma sample was transferred with clean pipettes. The assay was determined using a validated Analytical method.

Each plasma sample was placed into a polypropylene storage tube with a screw cap. The plasma was stored frozen at -60°C or colder at the clinical site pending transfer to a Laboratory for assay.

End of Study

Within one week after the last study day, each participant was required to provide a blood sample for analysis. Any abnormalities as compared to initial screening were monitored and followed up until they return to normal.

Participants were assessed for the occurrence of adverse events from consent until the last study day in each cohort.

Vital signs (blood pressure, heart rate, respiratory rate and temperature) at last study visit.

• Laboratory tests (haematology (CBC, CD4+/CD8+ peripheral lymphocyte count,

biochemistry (RFT, LFT, electrolytes, TFT, fasting lipids, HbAlc, amylase), Serum

HCG Pregnancy and urinalysis (dipstick), at last study visit.

• A follow-up phone call to each participant was made within 7 days (+ 2 days) of the end of the study to record any possible Adverse Events (AE) post study. Any events were recorded in source documentation.

All AE’s were followed-up until resolution, or until the Investigator was of the opinion that follow-up was no longer required, or until 30 days from the last dose (as long as the Investigator is satisfied that follow-up was no longer required), whichever is earlier.

Adverse Events

During confinement the designated Supervisor for the study or a delegated representative must have been present at the study site throughout the study. Principal Investigator or at least one delegated Trial Physician was on call throughout the studies. On all study visits each participant was asked how they felt. This occured at each sampling point throughout the study. AE’s were recorded in source documentation.

Each AE was classified by the Principal Investigator as serious adverse event (SAE) or non- serious. Non- serious adverse events were assessed as being mild, moderate, or severe to describe the maximum intensity of the AE. The Principal Investigator also provided the possible relationship between the AE and the study medication as highly probable, probable, possible, remotely or not ("no") related to the study medication.

The Principal Investigator should have stated if the cause of the AE is related to the concurrent non-investigational medication(s) if any are being taken, an underlying disease, a combination of these factors or is unknown.

Safety Results:

• 109 adverse events in total reported by 18 participants, see Table 20.

• 1 event‘related’ to study medication

• 6 events‘probably related’ to study medication

· 82 events‘possibly related’ to study medication

• 6 events‘probably not related’ to study medication

• 14 events‘not related’ to study medication

• No SAEs

Conclusion:

Formulations 3c and 3d are deemed to be well-tolerated since all AEs were either minor or not related to administration of study medication

Table 20: Adverse event summary:

Pharmacokinetic Analyses:

Pharmacokinetic parameters:

The area under the plasma drug concentration time curve (AUC), the peak plasma drug concentration (Cmax) and the time to maximum drug concentration (Tmax) were determined for lopinavir and ritonavir for each subject receiving active treatment.

The plasma drug concentration (C) versus the real sampling time (t) data were analysed by a "noncompartmental" method to obtain the pharmacokinetic parameters. Initially the plasma data in the post distribution phase of the plasma concentration - time plot were fitted using linear regression to: ·

In C = In Co - t.Kel

where Co is the zero-time intercept of the extrapolated terminal phase and Kel is the terminal elimination rate constant. The area (AUCo- _t ) from time zero to the last determined concentration-time point (t) in the post distribution phase was calculated using the trapezoidal rule.

Lopinavir and ritonavir concentration and pharmacokinetic parameters

The mean lopinavir and ritonavir plasma concentration-time data for each sampling time is listed in Tables 21 and 22. The pharmacokinetic parameters for lopinavir and ritonavir are

summarised in Tables 23 and 24.

Table 21: Mean (±SD) Plasma Lopinavir and Ritonavir Concentration Data vs Sampling Times (Formulation 3d) Vaginal Ointment)

Table 22: Mean (±SD) Plasma Lopinavir and Ritonavir Concentration Data vs Sampling Times (Formulation 3c) Vaginal Ointment)

Table 23: Pharmacokinetic Parameters for Lopinavir

Table 24: Pharmacokinetic Parameters for Ritonavir

Discussion of results:

Cmax:

Following an oral dose of 400 mg lopinavir (as Kaletra 400 mg/lOO mg tablets)* twice daily for 2 weeks, the mean Cmax for lopinavir was 12.3 ± 5.4 pg/mL (SPMC Kaletra). Adjusting for dose comparison with a 300 mg dose administered topically in ointment form, the mean Cmax would be 9.23 ± 4.1 pg/mL.

Following a topical dose of 300 mg lopinavir daily for 21 days as 2.5 g ointment containing 12% w/w lopinavir, the mean Cmax was 396.3 ± 297.3 pg/mL.

The ratio of Cmax oral/Cmax topical is >23,000 indicating that less than 0.004% of the topical dose is available systemically.

AUC O-t:

Following an oral dose of 400 mg lopinavir (as Kaletra 400 mg/lOO mg tablets)* twice daily for 2 weeks, the AUCO-t for lopinavir was 113.2 ± 60.5 pg h/mL (SPMC Kaletra). Adjusting for dose comparison with a 300 mg dose administered topically in ointment form, the AUCO-t would be 84.9 ± 45.4 pg h/mL.

Following a topical dose of 300 mg lopinavir daily for 21 days as 2.5 g ointment containing 12% w/w lopinavir, the AUCO-t was 7368.1 ± 4973.1 pg/mL.

The ratio of AUC oral/AUC topical is >11,500 indicating that less than 0.009% of the topical dose is available systemically.

Conclusion:

The combined Cmax and AUC data indicate that systemic absorption of lopinavir from topical administration of the ointment is negligible. Example 10: A Phase lb. Multicentre, Open Label, Study of the Efficacy, Safety and Tolerability of Formulation 3h in Women with Cvtological Abnormalities of the Uterine Cervix.

The composition according to Example 3 (Formulations 3h) is investigated according to the clinical trial described below.

Study Objectives

Efficacy Objectives

• Demonstrate histological clearance of cytological abnormalities following application of Formulation 3h in women with high-grade or low-grade CIN (Cervical intra-epithelial neoplasia).

• Demonstrate changes to colposcopic appearance of the uterine cervix following application of Formulation 3h;

• Assess changes in HPV status following application of Formulation 3h ointment.

Safety Objective · Assess the incidence of AEs following the application of Formulation 3h ointment.

Tolerability Objective

• Assess the tolerability of Formulation 3h, measured by compliance with dosing schedule of Formulation 3h during 21 consecutive days of treatment for up to 3 treatment cycles.

Study Design:

This study is designed as a Phase lb multicentre, open label study investigating the efficacy, safety and tolerability of Formulation 3h ointment in women with cytological abnormalities of the uterine cervix.

In this single arm study, participants are stratified according to their grade of cytological abnormality:

· Biopsy proven high-grade cytological abnormalities of the uterine cervix defined as CIN

2 and above;

• Low-grade cytological abnormalities of the uterine cervix defined as CIN l/LSIL.

Formulation 3h ointment is self-applied to the vagina once a day for 21 consecutive days in up to

3 treatment cycles. Participants attend a clinic visit 7 days after administration of the final dose of investigational product. Participants complete a daily diary card and Vaginal Irritation Questionnaire to capture compliance with investigational product administration, AEs and changes to concomitant medication.

Participation in this study includes a screening visit, up to 3 treatment cycles and an end of study visit as follows:

• Screening Visit: Day -28 to Day 0.

• Treatment Cycle 1 :

Day 1* to Day 21 : Treatment Cycle 1 - investigational product applied once daily for 21 days;

Day 8, 15, 22: telephone follow up; check AEs, conmeds, compliance, dosing issues;

Day 28: visual assessment of disease, if no disease detected#, treatment is stopped, and a biopsy is performed 6 weeks later (Day 70).

• Treatment Cycle 2:

Day 29** to Day 49: Treatment Cycle 2 - non-responders, identified at Day 28, will continue investigational application once daily for 21 days;

Day 36, 43, 50: telephone follow up; check AEs, conmeds, compliance, dosing issues;

Day 56: visual assessment of disease, if no disease detected#, treatment is stopped, and a biopsy is performed 6 weeks later (Day 98).

• Treatment Cycle 3 :

Day 57** to Day 77: Treatment Cycle 3 non-responders, identified at Day 56, can continue investigational application once daily for 21 days OR be referred to their primary physician;

Day 64, 71, 78: telephone follow up; check AEs, conmeds, compliance, dosing issues;

Day 84: visual assessment of disease and biopsy performed 6 weeks later (Day 126)

• Post-treatment assessment visit (PTAV) / Early termination visit (ETV): Day 70, Day 98 or Day 126 depending on response.

*Day 1 commences at the end of a participant’s menstrual cycle.

** Day 29 and 57 may be delayed to the end of the participants’ menstrual cycle if required. #If absence of disease, defined as no colposcopic evidence of CIN, participants are considered responders. If disease is detected, defined as ongoing colposcopic evidence of CIN, participants are considered non-responders.

Participation Criteria

Inclusion Criteria:

To be eligible for study entry participants must satisfy all of the following criteria:

1. Provision of written informed consent prior to any study specific procedures;

2. Female participants aged 25-45 years inclusive at the time of screening visit;

3. Positive result for cervical high-risk HPV (types 16, 18 or‘other’);

4. High-grade cytological abnormality of the uterine cervix defined as CIN 2 as proven by colposcopic biopsy collected at screening

OR

low-grade cytological abnormality of the uterine cervix defined as CIN l/LSIL, as demonstrated by colposcopic biopsy within 6 months prior to screening.

Participants will be stratified according to their grade of cytological abnormality;

5. Transformation zone needs to be fully visible;

6. Generally, in good health with no clinically significant disease as determined by the investigator;

7. Regular menstrual cycle with an approximate 28-day cycle

OR

women who are amenorrhoeic due to effective contraception (such as Mirena, Jadelle, or continuous COC)

8. Agree to abstain from activities such as vaginal douching or insertion of any vaginal products other than the study drug for at least 48 hours prior to enrolment and throughout the study. Tampons may be used during the menstrual cycle only.

9. Women of childbearing potential (WOCBP) must use a highly effective form of birth control (confirmed by the Investigator). Rhythm methods will not be considered as highly effective methods of birth control. Highly effective forms of birth control include: • True sexual abstinence (defined as refraining from heterosexual intercourse for the duration of the study and a minimum of 30 days following the last dose of study drug);

• Vasectomised partner (provided that the partner is the sole sexual partner of the female participant with childbearing potential and that the vasectomised partner has received medical assessment of the surgical success);

• Oral or transdermal combined (oestrogen and progestogen containing) hormonal contraception associated with inhibition of ovulation;

• Oral, injectable or implantable progestogen-only hormone contraception associated with inhibition of ovulation (Depo-Provera™, Implanon);

• Any effective intrauterine device/levonorgestrel intrauterine system;

• Female sterilisation by tubal occlusion;

• Evra Patch™.

WOCBP must agree to use a highly effective method of birth control, as defined above, from enrolment, and at least 14 days prior to Day 1, throughout the study duration and within 30 days after the last dose of IMP.

WOCBP are defined as women who are neither permanently sterilised (hysterectomy, bilateral oophorectomy, or bilateral salpingectomy), nor who are postmenopausal. Women will be considered post-menopausal if they have been amenorrhoeic for 12 months or more without an alternative biological or medical cause e.g. contraceptive method such as Mirena.

10. Male partners of female participants must agree to use condoms during sexual intercourse from the first dose of investigational product until 30 days after the participants last dose to avoid potential transfer of investigational product.

11. Able and willing to abstain from sexual intercourse from 6 hours prior to dosing until 6 hours after dosing;

12. Ability and willingness to attend the necessary visits to the study centre;

13. Ability to comprehend all study related documentation, including written informed consent form, and complete all study-related tasks including daily diary;

14. Be willing and able to adhere to the prohibitions and restrictions specified in the protocol. Exclusion Criteria:

Participants are excluded from the study if one or more of the following criteria are applicable:

1. Any significant disease or disorder (e.g. cardiovascular, pulmonary, gastrointestinal, hepatic, renal, neurological, musculoskeletal, endocrine, metabolic, malignant, psychiatric, major physical impairment) which, in the opinion of the investigator, may either put the participant at risk because of participation in the study, or may influence the results of the study, or the participant’s ability to participate in the study;

2. Any clinically significant abnormal findings in physical examination, vital signs, haematology, clinical chemistry, or urinalysis during screening and at baseline, which in the opinion of the investigator, may put the participant at risk because of her participation in the study, or may influence the results of the study, or the participant’s ability to complete entire duration of the study;

3. Pregnant, breastfeeding, or lactating women (WOCBP must have a negative serum pregnancy test at screening and a negative urine pregnancy test at the start of each treatment period [i.e. Day 1, Day 28, Day 56]);

4. Women who plan to become pregnant in the next 6 months;

5. History of genital herpes with >3 outbreaks per year, or active non-HP V vaginal infection;

6. Active pelvic infection (positive for gonorrhoea or chlamydial infection, positive test for bacterial vaginosis, Candida vaginitis or trichomonal vaginitis). Participants with positive results can be re tested once during screening;

7. Positive bimanual exam consistent with pelvic inflammatory disease;

8. Positive result for hepatitis B, hepatitis C or human immunodeficiency virus;

9. Current or recent abnormal vaginal discharge and /or abnormal vaginal bleeding, within the 3 months prior to Day 1 as assessed by the investigator;

10. Had an abortion or miscarriage or taken the morning-after pill within the 3 months prior to enrolment;

11. Currently taking immunosuppressants, intra-vaginal preparations, or any prescription that in the opinion of the investigator could be a potential safety issue or interfere with the interpretation of the results; 12. Previous exposure to lopinavir/ritonavir (within 3 months prior to screening), contraindication to the use of lopinavir/ritonavir or known allergy, hypersensitivity, or intolerance to any component of lopinavir/ritonavir ointment excipients;

13. Previous HPV vaccination;

14. Recent history (within 3 months prior to screening) of Stevens- Johnson syndrome, erythema multiforme, urticaria, angioedema, deep vein thrombosis, tinnitus, vertigo, blood glucose disorders, pancreatitis, haemophilia;

15. Receipt of any investigational product within 30 days or 5 half-lives prior to dosing;

16. Employees of the clinical study team or family members (first-degree relatives) of such individuals or anyone involved in the planning and/or conduct of the study. Clinical study team refers to employees directly involved in the study who have been delegated study-related tasks accordingly;

17. Participants who, in the opinion of the Investigator, do not understand the information and procedures of the study, or would not be compliant with them (in particular the study restrictions and risks involved).

Dosing Schedule:

Investigational product is administered every day for 21 days for up to 3 cycles as follows:

• Cycle 1 (daily at 8pm from Day 1 to Day 21);

• Cycle 2 (daily at 8pm from Day 29 to Day 49);

· Cycle 3 (daily at 8pm from Day 57 to Day 77).

There is a 7-day treatment cessation in between cycles to allow for menstruation.

Investigational product is self-administered by participants at approximately 8pm (±1 hour) each evening. Participants are provided dosing instructions and important application instructions.

Participants record details of investigational product application in a diary card each day to monitor compliance. Participants are also asked to note in their diary card if there is any waste/spillage.

Participants are required to bring their investigational product and diary card to each study site visit. The tubes are to be weighed prior to dispensing to the participant and again at each clinic visit to assess compliance. There are no fasting requirements associated with the timing of application of investigational product.

Safety Assessments

The following safety assessments are performed at timepoints outlined in the Schedule of Events, see Table 25.

• Medical History

• Physical Examination

• Vital Signs

• Body Weight and Height

• 12-lead Electrocardiogram

• Clinical Laboratory Safety Tests (Haematology, Biochemistry, ETrinalysis, Vaginal Microbiology, Viral Serology, Drugs of Abuse Screen, Alcohol Screen, Pregnancy Screen)

Efficacy Assessments

The efficacy of the investigational product are assessed by improvements in the cytological abnormalities of the uterine cervix. Efficacy assessments are performed at timepoints outlined in the Schedule of Events, see Table 25.

• Colposcopic visual assessment

• Colposcopic Biopsy

• Cytological Sampling

• HPV Genotyping