NL2009514C2 - Pharmaceutical composition comprising methadone hydrochloride. - Google Patents

Description

Pharmaceutical composition comprising methadone hydrochloride

The present invention relates to a multidose composition containing racemic methadone hydrochloride suitable.

5 Methadone hydrochloride, the structural formula of which is: h3c. ch3

N

_ Jy-CHa

10 / \_v and enantiomer , HCI

^Γ“· 15 is a known active ingredient in human and veterinary medicinal products for anaesthesia and analgesia. In human medicine it is used to treat addiction.

US5578645 discloses a method for treating addiction to narcotic drugs in a mammal comprising administering to the mammal a therapeutically effective amount of a solution comprising racemic methadone and at least one branched chain amino acid 20 wherein the methadone is administered in a dosage amount of from about 10 to 80 mg/kg of body weight/day.

EP 1020183 discloses a preparation orally administered which is regulated in releasing an analgesic from microtablets, permits the dose equal to individually and accurately releasing a drop agent from a storage medical case and can be distributed to 25 the number of base capable of readily and accurately regulating a prescribed amount of an effective substance. The preparation which is regulated in releasing at least one kind of analgesics from microtablets with a diameter not more than 3 mm is disclosed. It is favourable that the analgesic is comprised of at least one kind of opioids (e.g. hydromorphone, oxycodone, morphine, levorphanol, methadone, dihydrocodein or the 30 like), the microtablet contains an analgesic homogeneously dispersed in a sustained-release matrix and the matrix includes at least one kind of polymer (e.g. cellulose ether and the like), waxes, fats, oils, fatty alcohols or their corresponding esters.

2

None of the methadone compositions of the prior art are multi dose formulations.

The present invention provides for a solution to the disadvantage of the prior art compositions.

5 The present inventors have found that a pharmaceutical composition comprising racemic methadone or a salt thereof as an active ingredient, and a preservative provide s for a solution to said problem.

In an embodiment of the present invention the preservative is a none therapeutically active preservative.

10 The composition according to the present invention is a solution comprising racemic methadone hydrochloride and a preservative and is suitable for use in equidae. Preferably the composition according to the present invention is used as a sedative and/or an analgesic in the treatment of pain.

The preservative is preferably chosen from the group consisting of 15 parabens, but not limited to this group. Parabens have the general formula:

O^OR

20

V

OH

25 The advantage of a composition according to the present invention is that it is a multi-dose formulation that can be used in combination with other active substances in horses. As methadone is an opioid it is subject to global narcotic legislation. Veterinarians and doctors must keep track of each use of methadone. Any disposal of the product must be justified and described in a logbook. The use of a multi-dose formulation 30 leads to less disposal of methadone. This allows the user to fulfil narcotic legislation effectively. The multi-dose formulation furthermore contributes to the safe use of this opioid and to the safety of the environment.

3

In a preferred embodiment the preservatives a selected from the group consisting of methyl parahydroxybenzoate and propyl parahydroxybenzoate since the inventors found that these parabens have the best antimicrobial activity in the preferred applicable pH range of 4-8. These parabens have a broad spectrum of antimicrobial 5 activity and these parabens act synergistic. These parabens are widely used in cosmetics, food products and pharmaceutical preparations and are therefore recognized to be safe.

Preferably a pharmaceutical composition according to the present invention comprises racemic methadone hydrochloride as an active ingredient. An embodiment of the invention relates to a combination of racemic methadone hydrochloride, to be used in 10 therapy, and at least one other therapeutically active ingredient. Preferably, said active ingredient are selected from the group consisting of: Benzodiazepine (e.g. midazolam), dissociative (e.g. ketamine), tranquilizer (e.g. acepromazine), NSAID (meloxicam) and sedative ( e.g. a2-agonist).

Moreover, the invention also relates to a use of the present racemic 15 methadone hydrochloride for the manufacture of a medicine for sedation and/or treatment of pain. According to the invention, said medicine can also contain at least one other therapeutically active ingredient. Preferably, said other therapeutically active ingredient is selected from the group consisting of: Benzodiazepine (e.g. midazolam), dissociative (e.g. ketamine), tranquilizer (e.g. acepromazine), NSAID (meloxicam) or a2-agonist (e.g. 20 xylazine, detomidine).

The present pharmaceutical formulation, combination of pharmaceutical composition containing it, is to be administered to a subject in need of a treatment therewith. In an embodiment of the present invention the pharmaceutical composition is a veterinary pharmaceutical composition.

25 In particular, the subject is a patient, human or mammal, such as a horse, suffering from pain, troubles or needing surgery. The amount of the racemic methadone hydrochloride of the invention, also referred to herein as the active ingredient, which is required to achieve a therapeutic effect, that is the therapeutically effective amount, will vary with the severity of the pain, the route of administration and the age and other 30 conditions of the subject.

For a horse, suitable dosages are between 0.05 mg/kg and 0.5 mg/kg body weight of the subject.

4

The desired dose may be presented as one, two, three or more sub-doses administered at appropriate intervals throughout the day.

While it is possible for the active ingredient to be administered as such, it is preferable to present it as a pharmaceutical formulation. Accordingly, the present 5 invention provides a pharmaceutical formulation comprising methadone hydrochloride, together with a pharmaceutically acceptable preservative and optionally another therapeutic agent. The carrier must be “acceptable” in the sense of being compatible with the other ingredients of the formulation and not deleterious to the recipients thereof. Suitable excipients are described in standard manuals, e.g., in the Handbook of 10 Pharmaceutical Excipients, 6th ed. Rowe, Sheskey en Quinn.

The invention further includes a pharmaceutical formulation, as hereinbefore described, in combination with packaging material suitable for the pharmaceutical formulation, said packaging material including instructions for therapeutically using of the pharmaceutical formulation.

15 Formulations are in particular those suitable for but not limited to parenteral administration.

The formulations may be prepared by any method well known in the art of pharmacy, for example, using methods such as those described in Gennaro et al., Remmington: The Science and Practice of Pharmacy, 20th Edition, Lippincott, Williams 20 and Wilkins, 2000; see especially part 5: pharmaceutical manufacturing. Such methods include the step of bringing into association the active ingredient with the carrier which constitutes one or more accessory ingredients. Such accessory ingredients include those conventional in the art, such as Sodium chloride.

Formulations suitable for administration may be presented as a solution, an 25 emulsion or a suspension. The formulation may also be administered as a bolus.

In the context of the present invention, the use of methadone hydrochloride in a therapeutic context does not exclude the use of any other active ingredient for treatment of the condition to be treated. The other active ingredient can be administered before, simultaneously with, or after methadone hydrochloride according to the invention. 30 Methadone hydrochloride can even be combined together with the other active compound into one pharmaceutical composition. The expert will recognise that, in each case of combined use or add - on therapy, the doses and/or formulations may have to be adapted accordingly.

5

The subject-matter of the appended claims are also part of the content of the description. The present invention is further illustrated by the following non-limiting example.

5 EXAMPLE

The following composition is an example of a composition according to the present invention (see Table 1).

Table 1.

10 Amount/ ml

Ingredient Manufacturer composition Function

Macfarlan Smith Active

Methadone hydrochloride' Ltd. 10 mg substance

Methyl . _ parahydroxybenzoate Clariant 1 mg Preservative 1 ο

Propyl parahydroxybenzoate Clariant 0,2 mg Preservative

Sodium chloride Merck 7,2 mg Tonicity agent

Water 1 ml Solvent 20 * 10.0 mg Methadone hydrochloride is equivalent to 8.9mg of methadone.

The pH of the composition can be adjusted with hydrochloric acid and sodium hydroxide.

25 30

Claims (9)

A pharmaceutical composition comprising racemic methadone or a salt thereof and a preservative. A pharmaceutical composition according to claim 1 comprising methadone hydrochloride. The pharmaceutical composition according to claim 1 or 2, wherein the preservative is selected from the group consisting of parabens. Pharmaceutical composition according to one or more of the preceding claims, wherein the composition is a solution and preferably is an aqueous solution, emulsion or suspension. A pharmaceutical composition according to any one of the preceding claims, wherein the pharmaceutical composition is a veterinary pharmaceutical composition. Pharmaceutical composition according to one or more of the preceding claims as a sedative or an analgesic. Pharmaceutical composition according to one or more of the preceding claims as a sedative or analgesic for equidae. Pharmaceutical composition according to one or more of the preceding claims, wherein the composition is a multi-dose composition. Pharmaceutical composition according to one or more of the preceding claims, wherein the pharmaceutical preparation is for parenteral administration. 25 2009514