WO2010072398A2

WO2010072398A2 - Veterinary formulations

Info

Publication number: WO2010072398A2
Application number: PCT/EP2009/009196
Authority: WO
Inventors: Philip Watson; Claire Fowler
Original assignee: Boehringer Ingelheim Ltd
Current assignee: Boehringer Ingelheim Ltd
Priority date: 2008-12-22
Filing date: 2009-12-21
Publication date: 2010-07-01
Anticipated expiration: 2011-06-22
Also published as: WO2010072398A3

Abstract

The present invention relates to a pharmaceutical formulation comprising buprenorphine or a pharmaceutically acceptable salt thereof and an alcohol, said formulation containing ≤1% w/v of buprenorphine or said salt thereof and a pharmaceutical formulation comprising buprenorphine or a pharmaceutically acceptable salt thereof and an alcohol, said formulation containing ≤3% w/v of alcohol and their uses as analgesics or sedatives. The invention also relates to a product comprising a vessel with a re-sealable closure containing 5 to 50 ml, preferably 10 to 20 ml, of a pharmaceutical formulation comprising buprenorphine or a pharmaceutically acceptable salt thereof and an alcohol, preferably benzyl alcohol.

Description

Veterinary Formulations The present invention relates to pharmaceutical formulations and uses thereof, in particular to pharmaceutical formulations which contain buprenorphine or a salt thereof.

Buprenorphine and pharmaceutically acceptable salts thereof, such as buprenorphine hydrochloride, are used in veterinary practice as an analgesic, for example as a post-operative analgesic and as a sedative. Buprenorphine acts on opiate receptors in the central nervous system. One such product is Vetergesic® (Reckitt-Benckiser) , a solution for injection presented in a 'use-once' ampoule. However under current veterinary practice this product may be misused, with the liquid remaining in the ampoule not discarded but retained for subsequent use, possibly in the next day's surgery.

To reduce waste and avoid the problems of re-use of a product which is not designed to provide multiple doses over a period of time, the present inventors decided to investigate the possibility of a multi-dose formulation containing buprenorphine. As shown in the accompanying Examples, having decided to include a preservative in the formulation, selection of a suitable preservative was not straightforward. However, a suitable formulation was eventually made using an alcohol as preservative.

Thus, in a first aspect, the present invention provides a pharmaceutical formulation comprising buprenorphine or a pharmaceutically acceptable salt thereof and an alcohol, said formulation containing ≤1% w/v of buprenorphine or said salt thereof. In a further aspect the invention provides a pharmaceutical formulation comprising buprenorphine or a pharmaceutically acceptable salt thereof and an alcohol, said formulation containing ≤3% w/v of alcohol. The alcohol is present in an amount effective to act as a preservative of said formulation, typically the formulation will contain at least 0.5% w/v of alcohol, more usually at least 1%, e.g. 1-2%, most preferably about 1.5%. Thus the formulation will typically contain 5 to 50 mg/ml of alcohol, preferably 10 to 25 mg/ml, most preferably about 15 mg/ml. The preserving alcohol component may be made up of more than one type of alcohol, e.g. part benzyl alcohol and part ethanol , but preferably a single alcohol species will be used. 'Alcohol' as used herein incorporates those molecules in which an OH group is covalently attached to a carbon atom which is itself not part of an aromatic group, thus phenols are excluded. The alcohol may be polyhydric but is preferably monohydric. Suitable alcohols include benzyl alcohol, ethanol, isopropanol and phenoxy-ethanol . Benzyl alcohol and ethanol are preferred and benzyl alcohol is especially preferred. Thus the alcohol component preferably comprises, more preferably consists essentially of or consists of benzyl alcohol (i.e. the alcohol component is at least 90%, preferably at least 95%, more preferably at least 98 or 99% benzyl alcohol) . Preferably the alcohol is not a glycol .

Preferably the formulations of the invention contain 1 to 3% w/v of benzyl alcohol. Most preferably they contain around 1.5% w/v benzyl alcohol.

Suitable pharmaceutically acceptable salts are well known in the art and may be formed with an inorganic or organic acid, such as hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, nitric acid, acetic acid, glycolic acid, lactic acid, pyruvic acid, malonic acid, succinic acid, glutaric acid, fumaric acid, malic acid, mandelic acid, tartaric acid, citric acid, ascorbic acid, palmitic acid, raaleic acid, hydroxyraaleic acid, benzoic acid, hydroxybenzoic acid, phenylacetic acid, cinnamic acid, salicylic acid, methanesulfonic acid, benzeneεulfonic acid and toluenesulfonic acid. Buprenorphine hydrochloride is especially preferred and in the formulations of the present invention is preferred even to buprenorphine itself.

Formulations comprising buprenorphine hydrochloride and benzyl alcohol have been described in the art, in WO 2007/061739. These formulations are specifically for otic or transdermal use and are intended to be in single dosage form, in contrast to the present invention which is able to provide a multi-dose formulation, preferably for administration by injection. In WO 2007/061739 the benzyl alcohol is not included to act as a preservative. Instead, the benzyl alcohol is included to act as a solubilizer and hence it is present at levels appropriate for that function, specifically at 5% or 10% w/w.

The level of buprenorphine present in the formulations of WO 2007/061739 reflects the specific route of administration. Otic (administered via the ear) or transdermal routes are less efficient methods of drug delivery than most other routes, e.g. via injection. Hence the buprenorphine is present at higher levels than those typically contemplated by the present invention. A reduction in the amount of buprenorphine or benzyl alcohol in these formulations is not compatible with the role these ingredients perform or the route of administration taught in WO 2007/061739. The formulations of the present invention contain sufficient buprenorphine (unless otherwise clear from the context, reference herein to buprenorphine also encompasses pharmaceutically acceptable salts thereof) for the formulation to function as an analgesic or sedative The formulations are preferably for administration to non-human animals and the appropriate dosage can be determined according to the animal species, the weight of the animal and other clinical factors. Specifically, the present multi-dose formulation is suitable for use in accordance with the guidelines proposed for the existing single dose Vetergesic® product, as exemplified below:

The formulations typically contain ≤1% buprenorphme, e.g. 0.01 to 1%, preferably 0 02 to < 0 1%, more preferably 0.02 to 0.06%, still more preferably 0.03 to 0.04%, most preferably 0.03 to 0 035%. All percentages are given on a w/v basis. Thus formulations preferably contain 0.3 to 0.4 mg buprenorphme per ml of formulation, more preferably 0.30 to 0.35 mg/ml, e.g. about 0.32 mg/ml .

The formulations of the invention may be present in single-dosage form but are particularly suitable as multi-dose formulations. Thus the amount of the formulation present in a single packaged unit, e.g m a glass vial, will typically be 5-50 ml, preferably 10-20 ml, most preferably about 10 ml, which is sufficient to supply an average veterinary surgery for about 3 days, although the formulations are usable after opening for longer than this. Stored correctly, i.e. not above 25⁰C and protected from light, the formulations of the invention should have a 'shelf life¹ of at least 5 days, preferably at least 7 days.

The formulations of the invention will preferably have a pH between 4 and 7, more preferably between 4.5 and 5.5, most preferably between 4.8 and 5.2, e.g. around 5.0.

The formulations of the invention will contain other solvents, buffers, pH adjustorε and/or diluents. Preferred buffers include acetic acid and citric acid and phosphate buffers. Various physiologically acceptable inorganic acids and ackalis which may be used to adjust pH are known in the art and include hydrochloric acid and sodium hydroxide. Agents such as glucose monohydrate have electrolytic properties to aid isotonicity of the injection solution. Other tonicity adjusters include sodium chloride and mannitol. Water is the preferred diluent, acting as solvent and vehicle allowing the concentration of active to be optimised.

The formulations of the invention may optionally contain additional active agents or be combined with other active agents in a therapeutic regime where the other active or actives is not coformulated with buprenorphine. The additional ingredient is preferably a non-opioid analgesic. Suitable additional active agents include acepromazine, alphaxalone/alphadalone, atropine, halothane, isoflurane, ketamine, medetomidine, propofol, sevoflurane, thiopentone and xylazine.

The formulations of the invention are preferably administered by injection. Most preferably the formulations are administered by intramuscular or intravenous injection. Administration should be in accordance with guidelines and standard practice for the Vetergesic^® single-dose ampoule. Thus, sedative affects should be present by 15 minutes after administration and analgesic activity after about 30 minutes. The present invention is not proposing a new use of buprenorphine, rather a new way of formulating it to facilitate safe and convenient use thereof .

Because the formulations may be used over several days and the preservative itself may interact with the container, it is advised that the formulation is stored in a glass vial, preferably Type 1 glass.

The stopper will preferably be suitable for multiple needle insertions, e.g. at least 10 needle insertions, more preferably at least 20 needle insertions, and also resistant to release of extractables and/or reaction with the active agents.

Preferably the stopper will be a composite of synthetic rubber, such as blends of chlorobutyl and synthetic isoprene, e.g. 4588/40 grey (supplied by West Pharma) and preferably this will have an inert coating such as FluroTec or B2-40 (West Pharma) . Most preferably the stopper has a B2-40 coat and a FluroTec film. Other coatings and films may be used which minimise the transfer of silicone oil or other extractables into the formulation and preferably improve lubricity which enhances machinability. Suitable coatings are cross-linkable polydimethylsiloxane-silicone based organic polymers and suitable films are fluorocarbon films, e.g. a modified ethylene-tetrafluoroethylene copolymer . In a further aspect the present invention provides a product comprising a vessel with a re-sealable closure containing 5 to 50 ml, preferably 10 to 20 ml, of a pharmaceutical formulation comprising buprenorphine or a pharmaceutically acceptable salt thereof and an alcohol, preferably benzyl alcohol.

The formulations of the present invention are preferably manufactured using coated tubing, i.e. an inert coating should be applied to any standard rubber or rubber-like tubing. Teflon® is a suitable coating material .

In a further aspect the present invention provides a method of making a pharmaceutical formulation as defined herein which comprises bringing into admixture buprenorphine or a pharmaceutically acceptable salt thereof and an alcohol, preferably benzyl alcohol, at the amounts indicated above.

As with Vetergesic^®, the present formulations are suitable for use as a sedative or analgesic for many animals, including domestic and livestock animals, the formulations are particularly suitable for use with domestic animals such as cats, dogs, rabbits and guinea pigs and other rodents.

Thus, in a further aspect, the present invention provides a formulation as defined herein for use as an analgesic or sedative. Such formulations are preferably for use as an injectable analgesic or sedative.

In a yet further aspect, the present invention provides a formulation comprising buprenorphine or a pharmaceutically acceptable salt thereof and an alcohol for use as an injectable analgesic or sedative. In a preferred embodiment the invention provides a formulation comprising buprenorphine or a pharmaceutically acceptable salt thereof and benzyl alcohol for use as an injectable analgesic or sedative.

Preferred features of these formulations are discussed above. Alternatively viewed, the present invention provides a method for inducing analgesia in an animal or sedating an animal which comprises injecting said animal with a formulation comprising buprenorphine or a pharmaceutically acceptable salt thereof and an alcohol. Preferably the formulation comprises benzyl alcohol as said alcohol .

The formulations of the invention may also be used for the treatment of chronic pain, e.g. pain associated with neoplasia, osteoarthritis or pruritis.

The invention will be further described in the following non-limiting Examples.

Example 1 - Preservative Testing

The selection of possible preservatives and their concentrations was made from a list of those substances in other veterinary products. An initial screen of those in marketed products was carried out, from which the following candidate formulations were prepared and stored at 2 - 8°C or 50⁰C, i.e. at temperature extremes to "stress" the candidate formulations.

Candidate Preservatives

Benzethonium choride

Benzalkoniom chloride

Methyl parabens and propyl parabens Ascorbic acid

Bulk solutions were prepared by dissolving the Buprenorphine Hydrochloride (Macfarlan Smith) and Dextrose 5% in Water for Irrigation, using a magnetic stirrer. Additional excipients were added as listed in Table 1. The pH of the solution was measured and adjusted as appropriate with dilute sodium hydroxide and dilute hydrochloric acid solutions if required. The solutions were made to volume with further Water for Irrigation and the pH re-checked. Aliquots of 10ml were filled into 10ml clear Type 1 glass ampoules and sealed. No oxygen control measures were employed throughout the manufacture of the solution and filling of the ampoules, except for the batch 621-010-Olb.

Table 1

(*) as judged against criteria A and B in the Ph Eur

From the initial development work either benzalkonium chloride or methyl /propyl parabens appeared equivalent candidates .

The candidate formulation chosen to move to pilot batch manufacture was methyl parabens 0.21 mg/ml with propyl parabens 0.02 mg/ml . A manufacturing site was identified and the manufacturing process was determined - aseptic filling and mixing with no terminal sterilisation.

Initial pilot batch manufacture (three batches at approx 1/10 foreseen size) demonstrated unexpected and unpredictable results across all three batches. In addition, particulate matter was seen in some vials.

Summary of pilot batch results

Target : Buprenorphine 0.323 mg/ml Methyl parabens 2.10 mg/ml Propyl parabens 0.180 mg/ml

Table 2

Outcome

It was thought that the methyl parabens and propyl parabens was precipitating out of the formulation and causing the unpredictable results. The particulate matter was thought to be crystals of buprenorphine. The levels of the parabens were reviewed and a series of further assessments carried out on potential alternative candidate formulations, see Example 2 below. Exam^ple 2 - Preservative Testing

Further candidate formulations (level of buprenorphine constant at 0.3mg/inl) were prepared.

Batches of Buprenorphine injections (SP05059/1- SP05059/6) were prepared with the compositions as detailed in Table 3. All formulations contained 5% glucose and hydrochloric acid/sodium hydroxide solutions were used to adjust the solutions to approximately pH 5.3.

Bulk solutions were prepared by dissolving the buprenorphine hydrochloride and dextrose 5% in water for irrigation, using a magnetic stirrer. Additional excipients were added as listed in Table 3. The pH of the solutions were measured and adjusted as appropriate with dilute sodium hydroxide and dilute hydrochloric acid solutions if required. The solutions were made to volume with further water for irrigation and the pH adjusted if necessary. For the solutions containing parabens the water for irrigation was heated before adding the parabens. This solution was allowed to cool before the dextrose was added. For the parabens solution containing propylene glycol, the parabens was dissolved in propylene glycol before adding to the water. The buprenorphine hydrochloride (0.3 mg/ml as buprenorphine) was added and mixed until dissoved. Aliquots of 10 ml were filtered through 0.22 μm filters into 10 ml clear Type 1 glass vials and sealed with stoppers and aluminium crimps and stored at 2.8°C and 5O⁰C. Table 3

In addition, the physical stability was monitored in the following formulations which contain an overage of 10% buprenorphine . Buprenorphine is soluble in these formulations in the region of 15.6 - 16.9 mg/ml.

All formulations were adjusted to pH 5.3. Formulations SP05059/7-SP05059/14 all contain 5% dextrose monohydrate. Formulation SP05059/15 an ampoule formulation which contains 54.25 mg/ml dextrose monohydrate .

Table 4

Crystalline material was observed in all candidate formulations using preservative systems with the exception of benzyl alcohol (m-Cresol was rejected at an early stage as particulate matter was found at four weeks) . Initial preservative efficacy results indicate that the level of benzyl alcohol would have to be raised to 15 - 20 mg/ml (levels of 0.72 mg/ml and 0.9 mg/ml failed the test) .

The solubility studies (SPO5059/7 - SPO5059/15) demonstrated that buprenorphine is soluble at 15.6 - 16.9 mg/ml in all formulations tested.

The decision was taken to change the preservative system to benzyl alcohol as this would have the added benefit of enhancing the solubility of buprenorphine. The level selected was 15mg/ml at pH 5.3, based on the results of preservative efficacy testing which demonstrated as pass at levels of 12, 16 and 20 mg/ml.

Example 3

A preferred formulation according to the invention is

(*) potency adjusted based on raw 504.1 and 476.6

Claims

1. A pharmaceutical formulation comprising buprenorphine or a pharmaceutically acceptable salt thereof and an alcohol, said formulation containing ≤1% w/v of buprenorphine or said salt thereof.

2. A pharmaceutical formulation comprising buprenorphine or a pharmaceutically acceptable salt thereof and an alcohol, said formulation containing ≤3% w/v of alcohol.

3. A formulation as claimed in claim 1 or claim 2 which contains 0.02 to 0.06% w/v of buprenorphine or a pharmaceutically acceptable salt thereof.

4. A formulation as claimed in any preceding claim which comprises 5 to 50 mg/ml of alcohol .

5, A formulation as claimed in claim 4 which comprises 10 to 25 mg/ml of alcohol.

6. A formulation as claimed in any preceding claim wherein the alcohol component comprises one or more of benzyl alcohol, ethanol, isopropanol and phenoxy- ethanol .

7, A formulation as claimed in claim 6 wherein the alcohol component comprises benzyl alcohol.

8. A formulation as claimed in any preceding claim which contains about 1.5% w/v of benzyl alcohol.

9 , A formulation as claimed in any preceding claim wherein the salt is buprenorphine hydrochloride.

10. A product comprising a vessel with a re-sealable closure containing 5 to 50 ml of a pharmaceutical formulation comprising buprenorphine or a pharmaceutically acceptable salt thereof and an alcohol.

11. A product as claimed in claim 10 wherein the alcohol is benzyl alcohol,

12. A product as claimed in claim 10 or 11 wherein the re-sealable closure is a stopper.

13. A product as claimed in claim 12 wherein the stopper has an inert coating,

14. A formulation comprising buprenorphine or a pharmaceutically acceptable salt thereof and an alcohol for use as an injectable analgesic or sedative.

15. A formulation as claimed in any one of claims 1 to 9 for use as an analgesic or sedative.