MULTI-DOSE PHARMACEUTICAL COMPOSITION OF ANALGESIC FOR NASAL

ADMINISTRATION

Field of the Invention The present invention relates to a multi-dose pharmaceutical composition for intranasal administration in the form of a nasal spray comprising lyophilized nasal analgesic and suitable diluent for reconsti nation. The reconstitution of solution just prior to administration avoids degradation of active ingredient. The present invention further relates to a kit for the preparation of multi-dose pharmaceutical composition of nasal analgesic in the form of a nasal spray bottle containing lyophilized nasal analgesic, a tube containing diluent for reconstitution, modified nasal pump, nasal tips and pack insert or a label, which provides directions for assembling the kit and the subsequent use. The present invention still further relates to a device comprising nasal tip with cap, modified nasal pump and delivery tube. The present invention still further relates to method of assembling the kit so as to form a device suitable for administration of multi-dose pharmaceutical composition of nasal analgesic in the form of a nasal spray.

Background of the Invention

Pain is the most common symptom for which patients seek medical advice and treatment. Pain can be acute or chronic. While acute pain is usually self-limited, chronic pain can persist longer and lead to significant changes in a patient's personality, lifestyle, functional ability or overall quality of life.

Pain is experienced when the free nerve endings, which constitute the pain receptors in the skin as well as in certain internal tissues are subjected to mechanical, thermal, chemical or other noxious stimuli. The pain receptors (nociceptors) can transmit signals along afferent neurons into the central nervous system and then to the brain. The causes of pain can include inflammation, injury, disease, muscle spasm and the onset of a neuropathic event or syndrome.

A wide variety of compounds can act as analgesics. Two important classes of analgesics are opioid analgesics and non-steroidal anti-inflammatory drugs (NSAIDs).

Opioid analgesics exhibit morphine-like properties and can be sub-classified on the basis of their receptor specificity. They act as an agonist primarily at mu, kappa and perhaps delta receptors in the central nervous system. By acting on these receptors, they cause analgesia and anesthesia as a result of a receptor-mediated central action on pain perception, together with a receptor- medicated modulatory effect on the central transmission of noxious sensation.

NSAIDs have anti-inflammatory action and are effective on pain associated with the release of prostaglandins and other mediators of inflammation. They act by blocking the action of cyclooxygenase (COX).

As a class, analgesics (both opioids and NSAIDs) depending on the mode of administration are associated with a number of undesirable side effects, including respiratory depression, nausea, vomitting, dizziness, mental clouding, constipation, urinary retention, hypotension, clotting disorders and gastric irritation. The development of tolerance and the risk of chemical dependence and abuse are further problems.

Ideally, in certain clinical emergencies such as bone fractures or bums, pain relief should follow immediately upon administration of an analgesic. The relief should be maintained for an extended period that is at least long enough to permit preliminary medication and avoid complicated dosage regimes. In practice, however, the dynamics of pain relief obtained with current analgesic administration technologies does not meet these ideals. While rapid onset of pain relief can be achieved by intravenous injection, this mode of administration cannot in general be carried out by the patient himself and so is relatively expensive and inconvenient. Moreover, intravenous injection is generally associated with rapid offset of pain relief as the circulating analgesic is cleared from the plasma.

Hence nasal administration, by which a drug is transferred into circulating blood through the nasal mucosa, is being energetically studied as a method for non-injection type administration together with transdermal administration, transocular administration, transrectal administration, transpulmonary administration, etc. Among these non-injection type administration methods, nasal administration has advantages such as 1) rapid uptake of the analgesic across the nasal mucosa into the plasma can be achieved, which results in fast onset of analgesia similar to

injection 2) the residence time of the analgesic in the nasal cavity can be increased, which results in prolonged analgesia. 3) an improved profile of absorption of analgesic into the systemic circulation can be achieved since the blood vessel system in the nasal mucous membrane is more developed compared with the skin, the ocular mucous membrane, the rectal mucous membrane, etc.

WO 2000076477, US 4,464,378, US 6,677,346, US 2006110333, WO 2006016530 disclose morphine and morphine derivatives in the form of lyophilized powder for nasal administration with the aid of nasal insufflator or jet-spray.

US 7,267,827 discloses an aqueous pharmaceutical formulation in the form of a nasal spray comprising an effective amount of ketorolac.

US 6,608,073 discloses codeine optionally in combination with opioid analgesics in the form of solution or gel for nasal administration with the aid of finger or cotton tipped applicator.

US 5,756,483 discloses apomorphine and morphine solution or gel for nasal administration with the aid of nasal tampon or nasal sponge.

US 4973596 discloses meperidine solution with a single dose dispenser.

US patent number 4703864 provides for a unitary molded plastic cover for a container such as medicament bottle, in which removable cap portion is attached by a severable tear strip.

US Patent number 5350116 provides for an actuator for a liquid spray pump provided with a skirt which cooperates with the body of the pump to compress a volume of air during pump actuation.

US Patent number 5509578 provides for pump which has a tubular portion which is arranged to penetrate the mouth of a container having a seal in order to dispense liquid from the container.

US Patent number 6948492 and US application number 2006/0021614 provide for an apparatus and method for the self administration of a plurality of doses of an intranasal liquid pharmaceutical composition including opioid analgesics, that includes a drug delivery device containing a plurality of sealed vials.

The dosage forms and modes of administration of nasal analgesics disclosed in prior art cover solution in the foπn of drops/spray available as pre-filled containers. The mode of application is using a plastic syringe or pumps. The powder or microspheres for direct administration (without reconstitution) administered using nasal insufflators. Further semisolid formulations like gels, ointments and creams are applied using nasal tampon or nasal sponges.

The nasal spray devices are commercially available from many manufacturers and some or all these manufacturers have their own patents which are related to a mechanical system that generates nasal spray comprising the spring, the capillary tube, the nozzle system, dose release button, dosing chamber and the dose indicator. Some of leading the manufacturers are Pfeiffer, Valois, Bespak and Becton-Dickinson.

The present inventors while working on the pharmaceutical compositions of analgesics for nasal administration have surprisingly found that reconstitution of lyophilized analgesic powder in the solution form just prior to administration provides a stable solution that avoids degradation of active ingredient. The solution is stable for at least about two weeks and is suitable for multiple- use in the form of nasal spray for the treatment of paediatric analgesia in an emergency setting.

Further the available nasal pumps are not amenable to fit readily into conventional bottles. These nasal pumps are either screw threaded or can be crimped on only by a machine to external threads of bottle. Hence, it is the purpose of the invention to effect necessary changes in a fitting part of the pump for easier attachment to fit tightly externally onto the mouth of the bottle. Such a tight fit would also help in prevention of leakage.

Detailed Description of the Drawings

The embodiments of the kit of the present invention are with reference to the accompanying figures: Figure 1 - Exploded view of the kit with the components and the method of assembling and the subsequent use.

Figure 2 - A drawing of typical modified nasal pump of 0.05 mL capacity modified to fit tightly into the bottle.

Figure 3 — A drawing of typical bottle of 17 mL capacity that contains lyophilized nasal analgesic.

Detailed Description of the Invention

In one aspect of the invention there is provided a multi-dose pharmaceutical composition for intranasal administration in the form of a nasal spray comprising lyophilized nasal analgesic and suitable diluent for reconstitution.

In another aspect of the invention there is provided a method of forming a multi-dose pharmaceutical composition for intranasal administration in the form of a nasal spray, comprising reconstitution of the lyophilized nasal analgesic with suitable diluent just prior to administration, wherein the said method avoids degradation of active ingredient.

Embodiments of the pharmaceutical composition of the present invention may include one or more of the following features. For example, the term '"multi-dose" referred to in this invention relates to the number of doses delivered by the reconstituted solution of nasal analgesic in the form of a nasal spray.

The term "diluent for reconstitution" includes water or saline solution optionally containing pharmaceutically acceptable additives such as preservatives, chelating agents, pH adjusting agents and the like (Table 2), provided they do not interfere with the action of diamorphine or significantly decrease the absorption of it across the nasal mucosa.

The term "nasal analgesic" includes opioids and NSAIDS that can be used for nasal administration in the form of nasal spray.

Opioid analgesics can be selected from the group comprising of alfentanil, butorphanol, diamorphine, dihydrocodeine, fentanyl, meperidine, metazocine, methadone, morphine, naloxone, naltrexone, oxycodone, pentazocine, tramadol and the like.

NSAIDs include ibuprofen, flurbiprofen, diclofenac, indomethacin, piroxicam, ketoprofen, etodolac, diflusinal, meloxicam, aceclofenac, fenoprofen, naproxen, celecoxib rofecoxib and the like.

In another aspect of the invention there is provided a method of forming a multi-dose pharmaceutical composition of diamorphine for intranasal administration in the form of a nasal spray, wherein the method comprises reconstitution of the lyophilized diamorphine with suitable diluent just prior to administration.

Diamorphine is an opioid synthesized directly from the extracts of the opium poppy, Papaver somniferum. It is the 3,6-diacetyl derivative of morphine. It is a narcotic analgesic, which acts primarily on the central nervous system and smooth muscle. It may be used in the treatment of severe pain associated with surgical procedures, myocardial infarction or pain in the terminally ill and for the relief of dyspnoea in acute pulmonary oedema. Diamorphine in solution form rapidly hydrolyses to 6 acetyl morphine.

Currently, it is available as injection (strengths of 5mg, lOmg, 30mg, lOOmg, 250mg and 500mg), which is a white to off-white, sterile, freeze dried powder for reconstitution for injection.

In the present invention lyophilized diamoiphine, is reconstituted with preserved saline solution just prior to administration. The reconstituted solution is stable for at least about two weeks. The solution is then administered intranasally in the form of a nasal spray with the aid of assembled nasal spray device.

Suitable preservatives that can be added to the diluent for reconstitution to extend shelf life include, for example, benzyl alcohol, parabens, thimerosal, chlorobutanol, benzalkonium and combinations thereof, with benzalkonium chloride being preferred. Typically, the preservative will be present in the formulations in a concentration of from about 0.001% up to about 5% by weight of the total formulation.

Examples of chelating agents that can be added to the diluent for reconstitution include one or more of edetic acid and its salts, disodium edetate and the like. Chelating agents help to stabilize the product during storage.

Examples of pH adjusting agents that can be added to the diluent for reconstitution include one or more of hydrochloric acid and sodium hydroxide solutions.

Stability of diamorphine solution reconstituted with diluent: Reconstituted diamorphine solution alongwith the attached nasal spray device was subjected to stability studies at 25°C/ 60%RH. The samples were assayed initially, one week, two week, and three week intervals after preparation. The results are disclosed in table 3. During stability the compatibility of all the exposed components of the nasal spray device with the diamorphine solution was also checked. It was observed that there is a decrease in the assay over three-week period. The observed decrease in assay is consistent with the deacetylation of diamorphine, which occurs in aqueous solution.

Stability of diluent for reconstitution:

The stability of diluent for reconstitution, when the nasal spray device was attached to the bottle, was studied. The samples were subjected to stability studies at 25 ⁰ C/ 60%RH. The samples were assayed for benzalkonium chloride initially, one week, two week, and three week intervals following reconstitution of diamorphine hydrochloride with 10 mL of diluent. The results are disclosed in table 4. It was observed that there is a small drop in the assay of benzalkonium chloride over three-week period, which is not considered significant.

In another aspect of the invention there is provided a kit for the preparation of multi-dose pharmaceutical composition of nasal analgesic in the form of a nasal spray comprising a bottle containing lyophilized nasal analgesic, a tube containing diluent for reconstitution, modified nasal pump, nasal tips and pack insert or a label, which provides directions for assembling the kit and the subsequent use.

The kit of the present invention is in the form of a rectangular box, comprising 5 closed ends, four of which are on the sides and one in the bottom. The upper part of the rectangular box comprises three fold flaps, two of which arises from shorter edges of equal shape and size as to meet at the center. Folding these two fold flaps ensures safe custody of the package contents. The flap arising from the longer edge of the upper portion of the rectangular box has a small protrusion that fits well into the groove when closed as to form a tight fit. (Figure 1 )

Upper portion of the kit has provision of two depressions that ensures tight fit of the tube and the bottle. The lower portion of the rectangular box has provisions for modified nasal pump and nasal tip and nine number of additional nasal tips for muti-dosing. (Figure 1)

Depending on the type of lyophilized analgesic, intended dosage, and frequency of dosage, capacities of modified nasal pump, nasal tip and bottle may vary.

The pump capacity chosen is such that it would deliver a certain predetermined quantity of the reconstituted liquid nasal analgesic. Some of the analgesics need to be administered in certain predetermined strengths and doses. For example, diamorphine dosage strength would be different for children in the range 12-30 kg and the other 30 - 50 kg. Typical dosage strengths would be 0.1 mg/kg (±20%) over the weight range 12-50 kg.

In another aspect of the present invention there is provided a device of figure 2 comprising a) Nasal tip with cap b) Modified nasal pump c) Delivery tube

007/002850

In an embodiment, a typical modified nasal pump (0.05 mL capacity) employed for attachment to 17 mL bottle is exhibited in Figure 2. The various components of the pump are numbered in Figure 2 such as nasal tip with cap (10), delivery tube (300) and the like. Suitable changes have been effected in the main attachment component (200) of the pump as to make a tight fit into the bottle exhibited in Figure 3. To achieve this, allowable tolerances in variation in diameter of the fitting circular components requires to be as less as possible. It may be noticed that the outer diameter isl9.9 mm (±0.25 mm) at the entry of the bottle. The inner diameter of the component of the modified nasal pump that fits tightly onto the mouth of the bottle by hand is 20.05 mm (±0.1 mm).

The changes effected in the attachment component (200) are such that it is devoid of screw threading or crimping on by machine. The changes effected in the component of the pump are essential as normally threads would be present in a bottle. Further, the changes effected on the pump attachment calls for modification of the existing mould.

The detailed method of assembly and use of nasal spray shown in Figure 1 comprises;

1. removal of "flip off tear off' protective cap from the bottle,

2. removal of the aluminum cover and pulling out the rubber bung,

3. twisting off the seal from the tube containing the diluent for reconstitution, 4. adding the contents of the tube to the bottle. It may not be possible to remove all of the diluent from the tube.

In yet another aspect of the invention there is provided a method of assembling the kit (figure 1 ) so as to form a device suitable for administration of multi-dose pharmaceutical composition of nasal analgesic in the form of a nasal spray, wherein the method comprises a) attaching the modified nasal pump to the bottle by hand so that it fits tightly into a bottle to prevent leakage, b) shaking the assembly of step 1 for reconstitution of the lyophilized nasal analgesic, c) priming the assembly of step 3 to release the intended quantity of the reconstituted nasal analgesic.

d) inserting the nasal tip into the patient's nostril and directing the spray to the sidewall of the nose.

Before the usage of the reconstituted liquid, priming needs to be carried out for adequate number of times. Replacement of nasal tip before use on a new patient is an additional requirement for its effective administration. For example, a typical analgesic such as reconstituted diamorphine in 0.05 mL capacity modified nasal pump and 17 mL bottle, the components assemblage, require priming eight times to ensure that the pump is fully primed and releases 50 μL each time it is used. Normal use by a patient is about 2-4 sprays. Twice priming after new nasal tip replacement is an additional feature. Almost 10 treatments per device can be repeated by employing 0.05 mL modified nasal pump and 17 mL bottle.

The present invention is further illustrated by the following examples which are provided merely to be exemplary of the invention and do not limit the scope of the invention. Certain modifications and equivalents will be apparent to those skilled in the art and are intended to be included within the scope of the present invention.

Examples:

Table 1: Composition of batches of the present invention.

Table 2: Composition of diluent for reconstitution

*Equivalent to 0.02%w/v benzalkonium chloride

Table 3: Stability data: Assay results for diamorphine hydrochloride at one, two, and three weeks after reconstitution with diluent

Table 4: Stability data: Assay results for benzalkonium chloride at one, two, and three weeks after reconstitution of diamorphine hydrochloride with diluent