TECHNICAL FIELD

The present invention relates to a treatment for Allan-Herndon-Dudley syndrome. BACKGROUND

5 In this specification where a document, act or item of knowledge is referred to or

discussed, this reference or discussion is not an admission that the document, act or item of knowledge or any combination thereof was at the priority date, publicly available, known to the public, part of common general knowledge; or known to be relevant to an attempt to solve any problem with which this specification is concerned.

10 The Allan-Herndon-Dudley Syndrome (AHDS) is a well characterised, X-linked mental

retardation syndrome, usually males affected and females being carriers with a normal phenotype. Mutations in the monocarboxylate transporter 8 gene (MCT8) have been found to be the underlying pathology behind this condition. One essential function of the protein encoded by this gene appears to be the transport of triiodothyronine into neurons. Abnormal transporter

15 function is reflected in elevated free triiodothyronine and lowered free thyroxine levels in the

blood.

Infancy and childhood in AHDS are marked by hypotonia, weakness, reduced muscle mass, and delay of developmental milestones. Facial manifestations are not distinctive, but the face tends to be elongated with bifrontal narrowing, and the ears are often simply formed or

20 cupped. Some patients have myopathic faces. Generalized weakness is manifested by

excessive drooling, forward positioning of the head and neck, failure to ambulate independently, or ataxia in those who do ambulate. Speech is dysarthric or absent altogether. Hypotonia gives way in adult life to spasticity. The hands exhibit dystonic and athetoid posturing and fisting.

Cognitive development is severely impaired and in some cases paroxysmal dyskinesia is

25 observed. The latter is often triggered by tactile or emotional stimuli but seizures, although not uncommon, do not dominate. No major malformations occur, intrauterine growth is not impaired, and head circumference and genital development are usually normal. Behaviour tends to be passive, with little evidence of aggressive or disruptive behaviour. Some patients present with a hypermetabolic state, failure to thrive, and inability to gain weight observed.

30 Although clinical signs of thyroid dysfunction are usually absent in affected males, the

disturbances in blood levels of thyroid hormones suggest the possibility of systematic detection through screening of high-risk populations. Characteristic thyroid function test abnormalities are increased serum T3 and decrease of serum rT3 concentrations. T4 is reduced in most cases and TSH is normal or slightly elevated.

35 Despite being a well characterised syndrome, there has, unfortunately, been little to no

progress in the development of a suitable treatment for AHDS. SUMMARY

Accordingly, the present invention provides a treatment for Allan-Herndon-Dudley syndrome.

A first aspect of the present invention provides a pharmaceutical composition comprising DITPA and one or more conventional ingredients.

The pharmaceutical composition may further comprise one or more anti-inflammatory agents.

A second aspect of the present invention provides a combination comprising DITPA and one or more anti-inflammatory agents.

A second aspect of the present invention provides use of the pharmaceutical composition or the combination in the treatment of Allan-Herndon-Dudley syndrome. The present invention also provides a method of treatment for Allan-Herndon-Dudley syndrome comprising administering an effective amount of the pharmaceutical composition or the combination. The present invention further provides use of the pharmaceutical composition or the combination in the manufacture of a medicament for the treatment of Allan-Herndon-Dudley syndrome.

A fourth aspect of the present invention provides a dosage regime for the treatment of a patient with Allan-Herndon-Dudley syndrome, wherein a daily dosage of DITPA is divided into three equal portions and each portion is administered to the patient with about 8 hours apart. DETAILED DESCRIPTION

It has been found that 3,5-diiodothyropropionic acid can provide an effective treatment for Allan-Herndon-Dudley syndrome.

3,5-diiodothyropropionic acid

3,5-diiodothyropropionic acid, which is generally known as DITPA (and hereinafter referred to by this term), is a thyroid hormone analog (CAS Registry No. 1 158-10-07), having the following structure:

The chemical formula is C ₁₅ H ₁₂ l ₂ 0 ₄ , and the molecular weight is 510.06.

Allan-Herndon-Dudley syndrome

Allan-Herndon-Dudley syndrome is a rare disorder of brain development that causes moderate to severe intellectual disability and problems with movement. This condition, which usually occurs in males, disrupts development from before birth and results in impaired speech and a limited ability to communicate.

Most children with Allan-Herndon-Dudley syndrome have weak muscle tone (hypotonia) and underdevelopment of many muscles (muscle hypoplasia). As they get older, they usually develop joint deformities called contractures, which restrict the movement of certain joints. Abnormal muscle stiffness (spasticity), muscle weakness, and involuntary movements of the arms and legs also limit mobility. As a result, many people with Allan-Herndon-Dudley syndrome are unable to walk independently and become wheelchair-bound by adulthood.

It is known that mutations in the SLC16A2 gene cause Allan-Herndon-Dudley syndrome. The SLC16A2 gene, also known as MCT-8, provides instructions for making a protein that plays a critical role in the development of the nervous system. This protein transports a particular hormone into nerve cells in the developing brain. This hormone, called triiodothyronine or T3, is produced by a butterfly-shaped gland in the lower neck called the thyroid. T3 appears to be critical for the normal formation and growth of nerve cells, as well as the development of junctions between nerve cells (synapses) where cell-to-cell communication occurs. T3 and other forms of thyroid hormone also help regulate the development of other organs and control the rate of chemical reactions in the body (metabolism).

Gene mutations alter the structure and function of the SLC16A2 protein. As a result, this protein is unable to transport T3 into nerve cells effectively. A lack of this critical hormone in certain parts of the brain disrupts normal brain development, resulting in intellectual disability and problems with movement. Because T3 is not taken up by nerve cells, excess amounts of this hormone continue to circulate in the bloodstream. I ncreased T3 levels in the blood may be toxic to some organs and contribute to the signs and symptoms of Allan-Herndon-Dudley syndrome.

This condition is inherited in an X-linked recessive pattern. A condition is considered X- linked if the mutated gene that causes the disorder is located on the X chromosome, one of the two sex chromosomes. In males (who have only one X chromosome), one altered copy of the gene in each cell is sufficient to cause the condition. In females (who have two X

chromosomes), a mutation must be present in both copies of the gene to cause the disorder. Males are affected by X-linked recessive disorders much more frequently than females. A characteristic of X-linked inheritance is that fathers cannot pass X-linked traits to their sons.

In X-linked recessive inheritance, a female with one altered copy of the gene in each cell is called a carrier. She can pass on the mutated gene, but usually does not experience signs and symptoms of the disorder. Carriers of SLC16A2 mutations have normal intelligence and do not experience problems with movement. Some carriers have been diagnosed with thyroid disease, a condition which is relatively common in the general population. It is unclear whether thyroid disease is related to SLC16A2 gene mutations in these cases.

Allan-Herndon-Dudley syndrome may also be known as Allan-Herndon syndrome, monocarboxylate transporter-8 (MCT-8) deficiency, MCT8 (SLC16A2)-specific thyroid hormone cell transporter deficiency, and mental retardation X-linked with hypotonia.

Treatment

The present invention provides use of DITPA for the treatment of Allan-Herndon-Dudley syndrome.

The terms "treatment", "treating" and the like, as used herein refers to prevention of the syndrome, i.e. arresting its development and to relieving or ameliorating the effects of the syndrome, i.e. cause regression of the effects of the syndrome including the prevention or elimination of the occurrence of one or more symptoms and/or their underlying cause, the reduction in severity and/or frequency of one or more symptoms, and improvement or remediation of damage. Thus, for example, the present treatment encompasses both prevention of the syndrome in a predisposed individual and treatment of the syndrome in a clinically symptomatic individual.

Patients with Allan-Herndon-Dudley syndrome usually present symptoms such as, but not limited to, truncal hypotonia, spastic quadriplegia, absent or limited speech, severe mental retardation; some patients have a hypermetabolic state, fail to thrive and are unable to gain weight. The characteristic thyroid function abnormalities are increased serum T3 and decreased serum rT3 concentrations, with reduced serum T4 and normal or slightly elevated TSH.

The "individual", or patient, will be a human, male or female. The individual will commonly be a male, but may also be a female. Groups of individuals most likely to benefit from treatment will be neonates, infants and children. A neonate usually refers to be a baby from birth to 4 weeks, an infant usually refers a baby under 12 months old, and a child usually refers to a 1 year old to a 12 year old. Accordingly, treatment is most suitable for individuals up to 12 years of age. However, patients outside this age group are not excluded as they also may benefit from treatment, particularly if they are suffering symptoms of Allan-Herndon-Dudley syndrome, such as for example, exaggerated startle reactions. Accordingly, the treatment of Allan- Herndon-Dudley syndrome may also provide a form of palliative care for older patients including teenage children, young adults and older adults. There is also the possibility that treatment could be provided in utero in an effort to prevent the development of the syndrome. Such treatment would be given to females who are carriers with a normal phenotype, and then become identified in pregnancy as a mother carrying a fetus with the MCT8 deficiency.

Treatment of patients with Allan-Herndon-Dudley syndrome is likely to be ongoing from diagnosis, that is, for a substantial part or the whole of the lifetime of the patient, repeated as needed, e.g. repeated daily, or every other day. The dose and regimen for each patient may need to be adjusted based on, for example, the results of monitoring tests which may be conducted on the patient.

The term "therapeutically effective amount" refers to an amount of DITPA that will elicit the biological or medical response of a patient, tissue or cell that is being sought by the researcher, veterinarian, medical doctor or other clinician. This amount may be within the range of from about 0.1 to about 5 mg/kg body weight/day, from about 0.5 to about 5 mg/kg body weight/day, from about 0.5 to about 3 mg/kg body weight/day, or from about 1 to about 2 mg/kg body weight/day. Preferably, the amount of DITPA is within the range of from about 1 to about 5 mg/kg body weight/day. In some embodiments, the amount of DITPA is about 0.5 mg/kg body weight/day, about 1 mg/kg body weight/day, about 1.5 mg/kg body weight/day, about 2 mg/kg body weight/day, about 2.7 mg/kg body weight/day, about 3 mg/kg body weight/day, about 3.6 mg/kg body weight/day, about 4 mg/kg body weight/day, about 4.5 mg/kg body weight/day, about 4.75 mg/kg body weight/day, or about 5 mg/kg body weight/day. In one embodiment, the daily dose of DITPA is divided into 3 equal portions given 3 times a day, at intervals of about 8 hours.

Generally, diagnosis of Allan-Herndon-Dudley syndrome is based on sequencing of the SLC16A2/MCT8 gene. A presumptive diagnosis of MCT8 deficiency may be made based on elevated fT3, decrease of serum rT3 concentrations, low fT4 in the blood and typical clinical features.

It has been found that as a thyromimetic, DITPA effectively entered tissues without dependence on MCT8 for transport, and may rectify the thyroid hormone deficit that is characteristic of patients with Allan-Herndon-Dudley syndrome, that is, DITPA may suppress elevated TSH levels, normalizes high serum T3, raises low serum rT3 and increases serum T4 . In addition to having these effects, DITPA has not shown to cause signs of potential hypothyroidism or thyrotoxicosis; instead, DITPA may show beneficial angiogenic effects on the cardiovascular system, such as increasing left ventricular systolic performance, improving diastolic function, and decreasing peripheral vascular resistance.

Modes of administration

The present invention also provides a method for treatment of Allan-Herndon-Dudley syndrome, which comprises administration of a therapeutically effective amount of DITPA to a patient in need thereof.

DITPA may be administered via any route that provides a desired therapeutically effective amount and outcome. Generally, DITPA is administered in a pharmaceutical composition comprising DITPA as the therapeutically active ingredient.

Routes of administration can broadly be divided into a three categories by effect, namely, "topical" where the desired effect may be local or non-local, so the substance is applied directly where its action is desired, "enteral" where the desired effect is systemic (which may be local or non-local), so the substance is given via the digestive tract, and "parenteral" where the desired effect is systemic, so the substance is given by routes other than the digestive tract.

The U.S. Food and Drug Administration recognise 1 1 1 distinct routes of administration. The following is a non-limiting list of examples of routes of administration.

Examples of topical routes of administration having a local effect include epicutaneous (onto the skin) and intravitreal (onto the eye).

Examples of enteral routes of administration having a systemic (non-local) effect include any form of administration that involves any part of the gastrointestinal tract, such as oral (into the mouth), intranasal (into the nose), rectal (into the rectum), and vaginal (into the vagina).

Examples of parenteral routes of administration by injection, infusion, implanation or diffusion having a systemic effect include intravenous (into a vein), intraarterial (into an artery), intramuscular (into a muscle), intracardiac (into the heart), subcutaneous (under the skin), percutaneous (via needle-puncture into the skin), intradermal (into the skin itself), intrathecal (into the spinal canal), intraperitoneal (infusion or injection into the peritoneum), intravesical infusion (infusion into the urinary bladder), epidural (injection or infusion into the epidural space), transdermal or transcutaneous (diffusion through the intact skin), transmucosal (diffusion through a mucous membrane), insufflation (diffusion through the nose), inhalational (diffusion through the mouth), sublingual (under the tongue), and buccal (absorbed through cheek near gumline).

Enteral and parenteral routes of administration are preferred. In some embodiments, orally into the mouth is preferred. In some embodiments, injection or infusion is preferred. In these embodiments, intravenous (into a vein), intraarterial (into an artery), intramuscular (into a muscle), subcutaneous (under the skin), percutaneous (via needle-puncture into the skin), intradermal (into the skin itself), transdermal or transcutaneous (diffusion through the intact skin), sublingual (under the tongue), and buccal (absorbed through cheek near gumline) are preferred.

Pharmaceutical composition

Pharmaceutical compositions comprising DITPA can be in any suitable administration form

(see, for example, Pharmaceutics and Pharmacy Practice, J. B. Lippincott Company,

Philadelphia, Pa. , Banker and Chalmers, eds., pages 238-250 (1982)).

Depending on the intended mode of administration, the pharmaceutical composition comprising DITPA may be a solid, semi-solid, or liquid, such as, for example, a tablet, a capsule, a caplet, a liquid, a suspension, an emulsion, a gel, a suppository, granules, pellets, beads, a powder, or the like, preferably in unit dosage form suitable for single administration of a precise dosage. Suitable pharmaceutical compositions and dosage forms may be prepared using conventional methods known to those in the field of pharmaceutical formulation and described in the pertinent texts and literature, e.g. Remington J. P., The Science and Practice of Pharmacy, ed. A. R. Gennaro, 20 ^th edition, Lippincott, Williams and Wilkins Baltimore, Md. (2000). Examples of oral dosage forms include, but are not limited to, tablets, capsules, caplets, solutions, suspensions, and syrups, and may also comprise a plurality of granules, beads, powders, or pellets that may or may not be encapsulated. Preferred oral dosage forms are tablets, capsules, solutions, suspensions, and syrups. Any of these oral dosage forms may be mixed with food or beverages.

Tablets may be manufactured using standard tablet processing procedures and equipment. Direct compression and granulation techniques are preferred. In addition to the active agent, tablets will generally contain inactive, pharmaceutically acceptable carrier materials such as binders, lubricants, disintegrants, fillers, stabilisers, surfactants, colouring agents, and the like. Binders are used to impart cohesive qualities to a tablet, and thus ensure that the tablet remains intact. Suitable binder materials include, but are not limited to, starch (including corn starch and pregelatinized starch), gelatin, sugars (including sucrose, glucose, dextrose, and lactose), polyethylene glycol, waxes, and natural and synthetic gums, e.g., acacia sodium alginate, polyvinylpyrrolidone, cellulosic polymers (including hydroxypropyl cellulose, hydroxypropyl methylcellulose, methyl cellulose, microcrystalline cellulose, ethyl cellulose, hydroxyethyl cellulose, and the like), and Veegum™. Lubricants are used to facilitate tablet manufacture, promoting powder flow and preventing particle capping (i.e. particle breakage) when pressure is relieved. Useful lubricants are magnesium stearate, calcium stearate, and stearic acid. Disintegrants are used to facilitate disintegration of the tablet, and are generally starches, clays, celluloses, algins, gums, or crosslinked polymers. Fillers include, for example, materials such as silicon dioxide, titanium dioxide, alumina, talc, kaolin, powdered cellulose, and microcrystalline cellulose, as well as soluble materials such as mannitol, urea, sucrose, lactose, dextrose, sodium chloride, and sorbitol. Stabilisers, as well known in the art, are used to inhibit or retard drug decomposition reactions that include, by way of example, oxidative reactions.

For manufacturing capsules, the active agent-containing composition may be encapsulated in the form of a liquid or solid (including particulates such as granules, beads, powders, or pellets). Suitable capsules may be either hard or soft, and are generally made of gelatin, starch, or a cellulosic material, with gelatin capsules preferred. Two-piece hard gelatin capsules are preferably sealed, such as with gelatin bands or the like. See, for example, Remington J. P., The Science and Practice of Pharmacy, ed. A. R. Gennaro, 20 ^th edition, Lippincott, Williams and Wilkins Baltimore, Md. (2000), which describes materials and methods for preparing encapsulated pharmaceuticals.

Oral dosage forms, whether tablets, capsules, caplets, or particulates, may, if desired, be formulated so as to provide for gradual, sustained release of the active agent over an extended time period. Generally, as will be appreciated by those of ordinary skill in the art, sustained release dosage forms are usually formulated by dispersing the active agent within a matrix of a gradually hydrolyzable material such as a hydrophilic polymer, or by coating a solid, drug- containing dosage form with such a material. Hydrophilic polymers useful for providing a sustained release coating or matrix include, by way of example: cellulosic polymers such as hydroxypropyl cellulose, hydroxyethyl cellulose, hydroxypropyl methyl cellulose, methyl cellulose, ethyl cellulose, cellulose acetate, and carboxymethylcellulose sodium; acrylic acid polymers and copolymers, preferably formed from acrylic acid, methacrylic acid, acrylic acid alkyl esters, methacrylic acid alkyl esters, and the like, e.g. copolymers of acrylic acid, methacrylic acid, methyl acrylate, ethyl acrylate, methyl methacrylate and/or ethyl methacrylate; and vinyl polymers and copolymers such as polyvinyl pyrrolidone, polyvinyl acetate, and ethylene-vinyl acetate copolymer.

Pharmaceutical compositions for parenteral administration include sterile aqueous and non-aqueous solutions, suspensions, and emulsions. Injectable aqueous solutions contain DITPA in water-soluble form. Examples of non-aqueous solvents or vehicles include fatty oils, such as olive oil and corn oil, synthetic fatty acid esters, such as ethyl oleate or triglycerides, low molecular weight alcohols such as propylene glycol, synthetic hydrophilic polymers such as polyethylene glycol, liposomes, vesicles, nanoparticles, and the like. Vesicle and/or nanoparticle preparations may be prepared with many different conventional ingredients, including, but not limited to, tocopheryl phosphate, lecithin, phospholipids, phospholipon 90G or phospholipon 90NG, volpo, cholesterol, span, tween, pluronic, DPPC, glyercol. Reagents in such preparations may include organic solvents, such as ethanol, isopropanol, ether and/or chloroform. Parenteral formulations may also contain adjuvants such as solubilizers, preservatives, wetting agents, emulsifiers, dispersants, and stabilizers, and aqueous suspensions may contain substances that increase the viscosity of the suspension, such as sodium carboxymethyl cellulose, sorbitol, and dextran. Injectable formulations are rendered sterile by incorporation of a sterilizing agent, filtration through a bacteria-retaining filter, irradiation, or heat. They can also be manufactured using a sterile injectable medium. The active agent may also be in dried, e.g. lyophilized, form that may be rehydrated with a suitable vehicle immediately prior to administration via injection.

In addition, DITPA may also be formulated for transdermal or implant administration. Such long acting implantation administrations include subcutaneous or intramuscular implantation. Thus, for example, DITPA may be formulated with suitable polymeric or hydrophobic materials (for example as an emulsion in an acceptable oil) or ion exchange resins or as sparing soluble derivatives, for example as a sparingly soluble salt.

A transdermal delivery system may include a carrier, such as a liquid, gel, solid matrix, or pressure sensitive adhesive or patch, into which DITPA is incorporated.

Although solutions of DITPA are preferred, emulsions are also effective. Such emulsions may be aqueous, wherein the aqueous phase is the major and continuous phase, or nonaqueous, wherein a water-insoluble solvent system comprises the continuous phase.

Although DITPA will generally be administered enterally or parenterally, other modes of administration are suitable as well. For example, administration may be rectal or vaginal, preferably using a suppository that contains, in addition to DITPA, excipients such as a suppository wax. Formulations for nasal or sublingual administration are also prepared with standard excipients well known in the art. DITPA may also be formulated for inhalation, e.g., as a solution in saline, as a dry powder, or as an aerosol.

Combination therapy

The present invention also provides a combination of DITPA and one or more antiinflammatory agents, and use of the combination in the treatment of Allan-Herndon-Dudley syndrome. Not wishing to be bound by theory, but it is considered that administration of one or more anti-inflammatory agents will have a synergistic effect on the effectiveness of DITPA in the treatment of Allan-Herndon-Dudley syndrome. The neuronal cells in the MCT8 condition are subjected to inflammation. Therefore, the inclusion of one or more anti-inflammatory agents will reduce the inflammation and reduce the levels of pro-inflammatory markers in the body, as may be measured in the blood, and may be measured in the cerebrospinal fluid. Examples of inflammatory markers are TNF-alpha, interleukins (e.g. IL-1 beta, IL-6, IL-8), high sensitivity C- reactive protein, and plasminogen activator inhibitor (PAI-1 ). The combination therapy will reduce any inflammation and contribute to the overall therapeutic effects.

Administration of the one or more anti-inflammatory agents may be concurrent, sequential or separate with respect to administration of DITPA (i.e. co-therapy). For concurrent administration, DITPA and the one or more anti-inflammatory agents may be administered in the same or different formulations. In some embodiments, the one or more anti-inflammatory agents are co-administered with DITPA. Co-administration may be concurrent with different formulations. It may also be sequential, either before or after administration of DITPA. In some embodiments, the one or more anti-inflammatory agents are administered separately, but within a treatment regime that includes administration of DITPA.

The one or more anti-inflammatory agents may be administered via the same or a different route of administration as DITPA, except when present in the same formulation as DITPA in which case the pharmaceutical composition comprising DITPA and the one or more one or more anti-inflammatory agents will be administered by the one route of administration. In this respect, it should be noted that any of the pharmaceutical compositions described herein may be modified to also comprise one or more anti-inflammatory agents.

The combination therapy may involve a dose within a molar ratio of DITPA:anti- inflammatory agent(s) of 1 :50 to 50: 1 , with the dose of DITPA within the range of from about 1 to about 5 mg/kg body weight/day. When DITPA and the one or more anti-inflammatory agents are administered in the same formulation, the pharmaceutical composition comprises DITPA as the therapeutically active agent and the one or more anti-inflammatory agents as secondary active agents. The one or more anti-inflammatory agents may be present in the pharmaceutical composition in amount of from 0 up to about 100 weight percent of the total weight of the amount of DITPA present in the pharmaceutical composition.

The term "anti-inflammatory agent" as used herein relates to any substance capable of preventing and/or reducing and/or treating inflammation.

The anti-inflammatory agent may be selected from the group consisting of steroidal and non-steroidal anti-inflammatory agents, or combinations thereof.

Many steroids, specifically glucocorticoids, reduce inflammation by binding to

glucocorticoid receptors. These drugs are often referred to as corticosteroids. Some examples include but are not limited to, corticosterone, cortisone, hydrocortisone (Cortisol), cortisone acetate, prednisone, prednisolone, methylprednisolone, dexamethasone, betamethasone, triamcinolone, beclometasome, budesonide, fluticasone, mometasone, ciclesonide, fludrocortisone acetate, deoxycorticosterone and aldosterone.

Nonsteroidal anti-inflammatory drugs, usually abbreviated to NSAIDs, are drugs with analgesic and antipyretic (fever-reducing) effects and which have, in higher doses, anti- inflammatory effects. Some examples include but are not limited to, salicylates such as aspirin (acetylsalicylic acid), diflunisal, salsalate; propionic acid derivatives such as ibuprofen, naproxen, fenoprofen, ketoprofen, flurbiprofen, oxaprozin, loxoprofen; acetic acid derivatives such as indomethacin, sulindac, etodolac, ketorolac, diclofenac, nabumetone; enolic acid (oxicam) derivatives such as piroxicam, meloxicam, tenoxicam, droxicam, lornoxicam, isoxicam; fenamic acid derivatives (fenamates) such as mefenamic acid, meclofenamic acid, flufenamic acid, tolfenamic acid; selective COX-2 inhibitors such as celecoxib, rofecoxib, valdecoxib, parecoxib, lumiracoxib, etoricoxib, firocoxib; sulphonanilides such as nimesulide; licofelone. Other examples include, the arylalkanoic acids such as diclofenac, aceclofenac, acemetacin, alclofenac, bromfenac, etodolac, indometacin, indometacin, farnesil, nabumetone, oxametacin, proglumetacin, sulindac and tolmetin; 2-arylpropionic acids (profens) such as alminoprofen, benoxaprofen, carprofen, dexibuprofen, dexketoprofen, fenbufen, fenoprofen, flunoxaprofen, flurbiprofen, ibuprofen, ibuproxam, indoprofen, ketoprofen, ketorolac, loxoprofen, miroprofen, naproxen, oxaprozin, pirprofen, suprofen, tarenflurbil and tiaprofenic acid; W-arylanthranilic acids (fenamic acid) such as flufenamic acid, meclofenamic acid, mefenamic acid and tolfenamic acid; tromethamine, celecoxib, nepafenac, aspirin, rofecoxib, naproxen, sulindac, piroxicam, pheylbutazone, tolmetin, indomethacin, acetominophen (paracetamol), tramadol and propoxyphene.

The anti-inflammatory agent may also be an immune selective anti-inflammatory derivative (or ImSAIDs). ImSAIDs are a class of peptides with anti-inflammatory properties. I mSAIDs work by altering the activation and migration of inflammatory cells, which are immune cells responsible for amplifying the inflammatory response. The ImSAIDs represent a new category of anti-inflammatory agents and are unrelated to steroid hormones or non-steroidal anti- inflammatory agents.

Examples of other anti-inflammatory agents include meoxicam, cromolyn, nedocromil, hydroxychloroquine, montelukast, zileuton, zafirlukast and meloxicam.

Other anti-inflammatory agents include tocopherol and derivatives thereof including salts such as sodium tocopheryl phosphate and di-sodium tocopheryl phosphate.

Pharmaceutical compositions

The pharmaceutical composition comprising DITPA as the therapeutically active ingredient, may optionally further comprise one or more conventional ingredients. Examples of conventional ingredients include, but are not limited to, carriers, gelling agents, stabilizers, solvents, excipients, solubilisers, binders, buffers, preservatives, lubricants, suspending agents, disintegrating agents, flavours, sweeteners, antioxidants, isotonic agents, and combinations thereof. Other conventional ingredients may be discussed below.

Any conventional ingredient included in a pharmaceutical composition must be

"pharmaceutically acceptable" meaning that it is compatible with the other ingredients of the composition and is not deleterious to DITPA or the patient. Accordingly, the present invention further provides a pharmaceutical composition comprising DITPA and one or more pharmaceutically acceptable conventional ingredients.

The conventional ingredients may be present from 0 up to about 50 weight percent of the total weight of the pharmaceutical composition, or in an amount up to 5 times the weight percent of the amount of DITPA.

Examples of suitable stabilizers include albumin, globulin, gelatin, mannitol, glucose, dextran, ethylene glycol and the like. Examples of suitable solvents include water, lower alcohols (C ₂ -C ₆ ) including ethanol, isopropyl alcohol, propyl alcohol, and so on. Other examples of solvents include glycols such as ethylene glycol, propylene glycol, glycerol, and the like. The solvent may also be one or more dialkylsulfoxides and/or dialkylsulfones. The solvent may also comprise one or more ketones, ethers, and esters such as for example acetone,

methylethylketone, dimethylether, diethylether, dibutylether, and alkyl acetates, alkyl proprionates, alkyl butyrates, and the like.

The term "antioxidant" refers to a molecule capable of slowing or preventing the oxidation of other molecules. Oxidation is a chemical reaction that transfers electrons from a substance to an oxidizing agent. Oxidation reactions can produce free radicals, which start chain reactions that damage cells. Antioxidants terminate these chain reactions by removing free radical intermediates, and inhibit other oxidation reactions by being oxidized themselves. As a result, antioxidants are often reducing agents.

Antioxidants are generally classified into two broad divisions, depending on whether they are soluble in water (hydrophilic) or in lipids (hydrophobic). Ascorbic acid (vitamin C) is an example of a water soluble antioxidant. Carotenes, tocopherol (Vitamin E), retinol (Vitamin A), ubiquinol (the reduced form of coenzyme Q) and calciferol (Vitamin D) are examples of lipid soluble antioxidants.

Carotenes are carotenoids containing no oxygen. Carotenoids are based on carotenes with one or more hydrogen atoms substituted by a hydroxyl group and/or some pairs of hydrogen atoms are substituted by oxygen atoms. The term "hydroxy carotenoids" refers to carotenes substituted with one or more hydroxyl groups. Cryptoxanthin is an example of a hydroxy carotenoid: it is closely related to beta-carotene with only the addition of a hydroxyl group.

Vitamin E exists in eight different forms, namely four tocopherols and four tocotrienols. All feature a chroman ring, with a hydroxyl group that can donate a hydrogen atom to reduce free radicals and a hydrophobic side chain which allows for penetration into biological membranes. Such derivatives of Vitamin E may be classified as "hydroxy chromans". Both tocopherols and tocotrienols occur in alpha, beta, gamma and delta forms, determined by the number and location of methyl groups on the chroman ring. The tocotrienols differ from the analogous tocopherols by the presence of three double bonds in the hydrophobic side chain.

Retinol belongs to the family of chemical compounds known as retinoids. There are three generations of retinoids. First generation retinoids include retinol, retinal, tretinoin (retinoic acid, Retin-A), isotretinoin and alitretinoin. Second generation retinoids include etretinate and its metabolite acitretin. Third generation retinoids include tazarotene, bexarotene and adapalene.

Ubiquinol is a benzoquinol and is the reduced form of ubiquinone (coenzyme Q ₁₀ ).

Calciferol (Vitamin D) comes in several forms. The two major forms are vitamin D ₂ (e.g. ergocalciferol) and vitamin D ₃ (e.g. calcitriol, cholecalciferol). The other forms include vitamin (molecular compound of ergocalciferol with lumisterol, 1 : 1 ), vitamin D ₄ (22- dihydroergocalciferol) and vitamin D5 (sitocalciferol, made from 7-dehydrositosterol).

Any antioxidant or derivative thereof described herein would be suitable for the present invention. Preferred antioxidants and derivatives thereof are selected from the group consisting of carotenoids, hydroxy chromans, carotenoids, retinoids, benzoquinols and calcitriols. Hydroxy chromans are preferred. Tocols such as a tocopherol and its derivatives including salts (sodium), in any form, is most preferred.

One example of a gelling agent is sodium carboxymethyl cellulose.

One example of a sweetener is sodium saccharin.

The pharmaceutical composition may also comprise one or more agents known to accelerate the delivery of medicaments through the skin or mucosa (including intestinal mucosa) of animals, including humans, which are sometimes known as penetration enhancers, accelerants, adjuvants, and sorption promoters, and are collectively referred to herein as "enhancers". Some examples of enhancers include polyhydric alcohols such as dipropylene glycol; oils such as olive oil, squalene, and lanolin; polyethylene glycol ethers and fatty ethers such as cetyl ether and oleyl ether; fatty acid esters such as isopropyl myristate; fatty acid alcohols such as oleyl alcohol; urea and urea derivatives such as allantoin; polar solvents such as dimethyldecylphosphoxide, methyloctylsulfoxide, dimethylacetonide, dimethyllaurylamide, dodecylpyrrolidone, isosorbitol, decylmethylsulfoxide, and dimethylformamide; salicylic acid; benzyl nicotinate; bile salts; higher molecular weight aliphatic surfactants such as lauryl sulfate salts. Other agents include oleic acid and linoleic acids, ascorbic acid, panthenol, butylated hydroxytoluene, tocopherol, tocopheryl acetate, tocopheryl linoleate, propyloleate, tocopheryl phosphate, sodium tocopheryl phosphate, di-sodium tocopheryl phosphate, Trolox™ (6- hydroxy-2,5,7,8-tetramethylchroman-2-carboxylic acid, a water-soluble derivative of vitamin E), isopropyl palmitate, oleamide, polyoxyethylene lauryl ether, polyoxyethylene olelyl ether and polyoxyethylene oleyl ether. The one or more enhancers may be present from 0 up to about 10 weight percent of the total weight of the pharmaceutical composition, or in an amount up to 5 times the weight percent of the amount of DITPA.

Preparation of pharmaceutical compositions

The pharmaceutical compositions may be formulated according to techniques such as those well known in the art of pharmaceutical formulation. See, for example, Remington: The Science and Practice of Pharmacy, 21 st Ed., 2005, Lippincott Williams & Wilkins.

A simple method for preparing a pharmaceutical composition comprising DITPA and one or more conventional ingredients involves mixing the DITPA with the one or more optional ingredients to form the the pharmaceutical composition. Preferably, DITPA is provided in powdered form, having >98.0% purity.

When preparing a pharmaceutical composition also comprising one or more antiinflammatory agents, the one or more anti-inflammatory agents may be mixed with the one or more conventional ingredients at the same time as the DITPA.

In one embodiment, the pharmaceutical composition comprises DITPA and a vehicle solution, preferably aqueous and/or able to form a suspension. One example of an aqueous vehicle comprises water, one or more enhancers, a gelling agent, and a sweetener. The one or more enhancers may be tocopheryl phosphate, sodium tocopheryl phosphate, di-sodium tocopheryl phosphate, the gelling agent may be sodium carboxymethyl cellulose, and the sweetener may be sodium saccharin. The sodium tocopheryl phosphate may be present in an amount of 0.25% w/v, sodium carboxymethyl cellulose may be present in an amount of 0.5% w/v, and the sodium saccharin may be present in an amount of 0.02%, with water making the balance to about 12 ml. To prepare such a pharmaceutical composition, 30 mg powdered DITPA is mixed in 12 ml aqueous vehicle. When DITPA is mixed with a vehicle solution, as described, the mixture will form a suspension of 2.5 mg DITPA/ml. The volume of the mixture that is to be administered to achieve the patient's dose may be calculated according to body weight of the patient. The following is an example on how to calculate the volume: For a patient's body weight of 25 kg and the dose of 1 .5 mg/kg then the amount of DITPA to be administered is 37.5 mg per day. Dividing the dose into 3 portions means that 0.5 mg/kg will be given 3 times a day. Each of the 3 daily portions is prepared as follows: 25 kg x 0.5 mg/kg = 12.5 mg DITPA. The amount of mixture at 2.5 mg/ml needed for 12.5 mg is 12.5/2.5 mg/ml, and therefore the volume of the mixture is 5 ml. The unused portion is discarded. Surplus mixture of DITPA in vehicle is discarded.

Any pharmaceutical composition comprising DITPA is preferably prepared immediately before use (or within at least 30 minutes), particularly if a solution or suspension. However, DITPA may be pre-formulated as a ready to use pharmaceutical preparation that has been demonstrated to have stability and a good shelf-life.

Dosages

In the treatment of Allan-Herndon-Dudley syndrome, an appropriate dosage level will generally be about 0.1 to about 5 mg per kg patient body weight per day which can be administered in single or multiple doses. In some embodiments, the dosage level may be within the range of from about 0.1 to about 5 mg/kg body weight/day, from about 0.5 to about 5 mg/kg body weight/day, from about 0.5 to about 3 mg/kg body weight/day, or from about 1 to about 2 mg/kg body weight/day. Preferably, the dosage level of DITPA is within the range of from about 1 to about 5 mg/kg body weight/day. In some embodiments, the dosage level of DITPA is about 0.5 mg/kg body weight/day, about 1 mg/kg body weight/day, about 1.5 mg/kg body weight/day, about 2 mg/kg body weight/day, about 2.7 mg/kg body weight/day, about 3 mg/kg body weight/day, about 3.6 mg/kg body weight/day, about 4 mg/kg body weight/day, about 4.5 mg/kg body weight/day, about 4.75 mg/kg body weight/day, or about 5 mg/kg body weight/day. The dosage may be selected, for example to any dose within any of these ranges, for therapeutic efficacy and/or symptomatic adjustment of the dosage to the patient to be treated.

It will be understood that the specific dose level and frequency of dosage for any particular patient may be varied and will depend upon a variety of factors including the activity of the specific compound employed, the metabolic stability and length of action of that compound, the age, body weight, general health, sex, diet, mode and time of administration, rate of excretion, drug combination, the severity of the particular condition, and the patient undergoing therapy.

In one embodiment, the dose may be given once a day. In an alternate embodiment, the daily dose is divided into 3 equal portions given close to 8 hours apart. Dividing a daily dosage into 3 portions should result in less fluctuation of blood levels of DITPA, and other relevant markers, thereby stabilising blood profiles. Patients are more likely to benefit from the therapy with these results. Accordingly, dividing a daily dosage into 3 portions should provide an advantage over a single dose given once daily.

Effective dosages and schedules for administering DITPA may be determined empirically, and such determinations are within the skill in the art. An administration route of DITPA may also vary depending on the form of pharmaceutical composition.

In this specification, except where the context requires otherwise, the words "comprise", "comprises", and "comprising" mean "include", "includes", and "including" respectively, i.e. when the invention is described or defined as comprising specified features, various embodiments of the same invention may also include additional features.

Although this invention has been described by example and with reference to possible embodiment thereof, it is to be understood that modifications or improvements may be made thereto without departing from the scope of the invention.

FIGURES

The examples will be described with reference to the accompanying figures in which: Figure 1 A is a chart showing body weight and volume of mixture required for the dose of 0.5 mg/kg;

Figure 1 B is a chart showing body weight and volume of mixture required for the dose of 0.67 mg/kg;

Figure 1 C is a chart showing body weight and volume of mixture required for the dose of 0.89 mg/kg;

Figure 1 D is a chart showing body weight & volume of mixture required for the dose of 1.19 mg/kg; and

Figure 1 E is a chart showing body weight & volume of mixture required for the dose of

1.583mg/kg.

EXAMPLES

Various embodiments/aspects of the present invention will now be described with reference to the following non-limiting examples.

Example 1A - Preparation of DITPA for oral administration (1.5mg/kg)

Example for body weight = 25 kg.

Total DITPA to give per oral dosing = 25 kg x 1.5 mg/kg/day = 37.5 mg DITPA. This amount would be divided into 3 equal portions, with each portion to be given approximately 8 hours apart on each day. Each portion amounts to a dose of 0.5 mg/kg/day, and for the 25 kg body weight is 12.5 mg DITPA.

The following describes the preparation of a mixture of DITPA for the 0.5 mg/kg dose.

Prepare 6 ml of the DITPA mixture as follows:

1. 15 mg of DITPA was placed into a glass vial.

2. 6 ml of vehicle solution was then added, and the glass vial was capped and the

composition was mixed thoroughly with gentle shaking.

3. The composition was a syrupy mixture at a strength of 2.5 mg/ml.

4. The volume of the mixture required for administering the 12.5 mg portion for the 25 kg body weight is therefore, 12.5 mg / 2.5 mg.m ¹ = 5 ml.

Figure 1 A is a chart showing body weight and volume of mixture required for the dose of 0.5 mg/kg. This is 1/3 of the daily dose; therefore, it is repeated 3 times a day.

Example 1 B - Preparation of DITPA for oral administration (2 mg/kg)

Example for body weight = 25 kg.

Total DITPA to give per oral dosing = 25 kg x 2 mg/kg/day = 50 mg DITPA. This amount is divided into 3 equal portions, with each portion to be given approx 8 hours apart on each day. Each portion amounts to a dose of 0.67 mg/kg/d, and for the 25 kg body weight is 16.7 mg DITPA. The following describes the preparation of a mixture of DITPA for the 0.67 mg/kg dose. Prepare 12 ml of the DITPA mixture as follows:

1. 30 mg of DITPA was placed into a glass vial.

2. Add 12 ml of vehicle solution that is provided, cap the vial and mix thoroughly with gentle shaking.

3. The mixture results as a syrupy mixture at a strength of 2.5 mg/ml.

4. The volume of the mixture required for administering the 16.7 mg portion for the 25 kg body weight is therefore, 16.7 mg / 2.5 mg.m ¹ = 6.7 ml.

Figure 1 B is a chart showing body weight and volume of mixture required for the dose of 0.67 mg/kg. This is 1/3 of the daily dose; therefore, repeat this 3 times a day.

Example 1 C - Preparation of DITPA for oral administration (2.67 mg/kg)

Example for body weight = 25 kg.

Total DITPA to give per oral dosing = 25 kg x 2.67 mg/kg/day = 66.75 mg DITPA. This amount is divided into 3 equal portions, with each portion to be given approx 8 hours apart on each day. Each portion amounts to a dose of 0.89 mg/kg/d, and for the 25 kg body weight is 22.25 mg DITPA. The following describes the preparation of a mixture of DITPA for the 0.89 mg/kg dose. Prepare 12 ml of the DITPA mixture as follows:

1. 30 mg of DITPA was placed into a glass vial.

2. Add 12 ml of vehicle solution that is provided, cap the vial and mix thoroughly with gentle shaking.

3. The mixture results as a syrupy mixture at a strength of 2.5 mg/ml.

4. The volume of the mixture required for administering the 22.25 mg portion for the 25 kg body weight is therefore, 22.25 mg / 2.5 mg.mr ¹ = 8.9 ml.

Figure 1 C is a chart showing body weight and volume of mixture required for the dose of 0.89 mg/kg. This is 1/3 of the daily dose; therefore, repeat this 3 times a day.

Example 1 D - Preparation of DITPA for oral administration (3.56 mg/kg)

Example for body weight = 25 kg.

Total DITPA to give per oral dosing = 25 kg x 3.56 mg/kg/day = 89 mg DITPA. This amount is divided into 3 equal portions, with each portion to be given approx 8 hours apart on each day. Each portion amounts to a dose of 1.19 mg/kg/d, and for the 25 kg body weight is 29.67 mg DITPA. The following describes the preparation of a mixture of DITPA for the 1.19 mg/kg dose. Prepare 12 ml of the DITPA mixture as follows:

1. 30 mg of DITPA was placed into a glass vial.

2. Add 12 ml of vehicle solution that is provided, cap the vial and mix thoroughly with gentle shaking.

3. The mixture results as a syrupy mixture at a strength of 2.5 mg/ml.

4. The volume of the mixture required for administering the 29.67 mg portion for the 25 kg body weight is therefore, 29.67 mg / 2.5 mg.ml ^"1 = 11.87 ml.

Figure 1 D is a chart showing body weight and volume of mixture required for the dose of 1.19 mg/kg. This is 1/3 of the daily dose; therefore, repeat this 3 times a day.

Example 1 E - Preparation of DITPA for oral administration (4.75 mg/kg)

Example for body weight = 25 kg.

Total DITPA to give per oral dosing = 25 kg x 4.75 mg/kg/day = 1 18.75 mg DITPA. This amount is divided into 3 equal portions, with each portion to be given approx 8 hours apart on each day. Each portion amounts to a dose of 1.583 mg/kg/d, and for the 25 kg body weight is 39.58 mg DITPA. The following describes the preparation of a mixture of DITPA for the 1 .583 mg/kg dose. Prepare 18 ml of the DITPA mixture as follows:

1. 45 mg of DITPA was placed into a glass vial.

2. Add 18 ml of vehicle solution that is provided, cap the vial and mix thoroughly with gentle shaking.

3. The mixture results as a syrupy mixture at a strength of 2.5 mg/ml.

4. The volume of the mixture required for administering the 39.58 mg portion for the 25 kg body weight is therefore, 39.58 mg / 2.5 mg.ml ^"1 = 15.8 ml.

Figure 1 E is a chart showing body weight and volume of mixture required for the dose of 1.583mg/kg. This is 1 /3 of the daily dose; therefore, repeat this 3 times a day.

* 10ml of vehicle solution comprised 0.25% w/v, sodium carboxymethyl cellulose may be present in an amount of 0.5% w/v and the sodium saccharin may be present in an amount of 0.02%, with water making the balance.