GB2293099A

GB2293099A - Drug formulation

Info

Publication number: GB2293099A
Application number: GB9418550A
Authority: GB
Inventors: Willliam John Bowtle
Original assignee: MAILWAY PACKAGING GROUP Ltd
Current assignee: MAILWAY PACKAGING GROUP Ltd
Priority date: 1994-09-15
Filing date: 1994-09-15
Publication date: 1996-03-20
Also published as: GB9418550D0

Abstract

A drug formulation is prepared by melting a first active ingredient (e.g. ibuprofen) and adding a second active ingredient (e.g. dextropropoxyphene hydrochloride) and any other desired ingredients to the melt to produce a homogenous mixture which can be directed into containers (e.g. blister pockets) of a predetermined volume to define a dosage unit.

Description

DRUG FORMULATION This invention relates to a drug formulation and provides a method of preparing a drug formulation and a drug formulation ner se. Particularly, although not exclusively, the invention relates to a drug formulation which includes ibuprofen i.e. 2-(4-iso-butylphenyl propionic acid) as an active ingredient.

Ibuprofen is a known analgesic drug which has a relatively low melting point of 75 - 770C. This low melting point, together with other physico-chemical characteristics such as the crystallinity, flow characteristics, compressibility and bulk density, make it difficult to manufacture dosage units of the drug which are suitable for administration in tablet or capsule form.

Attempts to manufacture acceptable dosage units have adopted special processes for raw materials control, formulation and manufacture which processes have tended to be expensive. Furthermore, the processes often use nonactive carriers and excipients which may increase the bulk of the dosage unit and exacerbate product instability.

It is an object of the present invention to address problems associated with the manufacture of dosage units which include an active ingredient, for example ibuprofen, that has a relatively low melting point.

According to the invention, there is provided a method of preparing a drug formulation, the method comprising contacting a fluid which comprises a first active ingredient having a melting point of less than 100"C with a second active ingredient.

The melting points described herein are suitably melting points as measured on substantially pure compound.

Melting of compounds may take place at a precise temperature or over a broad temperature range depending upon the nature of the compound.

Preferably, in the method, said second active ingredient is contacted with said first active ingredient when the first active ingredient is in a molten state.

Thus, preferably, contact of said first and second active ingredients takes place at a temperature at or above the melting point of the first active ingredient. In the method, therefore, the first active ingredient suitably acts as a carrier for said second active ingredient.

The first and/or second active ingredients and/or any additional active ingredients and/or any excipients may be solid crystalline, amorphous or semi-solid materials at ambient temperature. They may be delivered in the method in powder, solid-bulk or semi-solid-bulk form. The particle size distribution of the first and/or second active ingredients and/or any additional active ingredient and/or any excipients may be controlled for the raw materials and/or in the method, in order to adjust the dissolution rate of the formulation. The second active ingredient and/or any additional active ingredients and/or said excipients are preferably dissoluble or suspendible in the first active ingredient at a temperature at which the first active ingredient is in a molten state.

In the method, the first active ingredient, suitably in powder form, is heated to melt it. Preferably, the first active ingredient is heated to and maintained at about the minimum temperature at which it is molten such that other ingredients may be added thereto.

Said second active ingredient is preferably added to the molten first active ingredient and mixed therewith, suitably to homogeneity. This step may be carried out under an inert, for example a nitrogen atmosphere.

Downstream steps may also be carried out under an inert atmosphere. One cr more additional active ingredients and/or excipients may be added to, and mixed with, the melt at this stage.

The fluidic mixture of ingredients may be directed into containers, for example capsules, blister pockets or suppository moulds suitably using a temperature-controlled volumetric pump. Said containers are preferably of a predetermined size in order to provide a dosage unit of predetermined size.

The filled containers may be allowed to cool under ambient conditions or may be cooled under controlled temperature gradient conditions. Preferably, the preparation of the formulation and its arrangement in containers is carried out in areas of controlled humidity and/or temperature.

Where blister pockets are used, suitable amounts of the fluidic mixture are preferably filled on-line into thermoformed or cold-formed blister pockets which are subsequently finished as blister packs. Blister-form packs are preferably thermoformed-film/aluminium foil or other appropriate lidding material or cold-formed aluminium foil/aluminium foil. Special grades of film or foil may be selected as appropriate for the product. The dimensions and shape of the pocket containing the drug formulation are preferably matched to those required for the dosage unit. The formed film or foil may include features designed to form special markings such as Trade Marks or product identifiers on the dosage unit. Lidding material may be printed or unprinted.

A drug formulation filled into blister packs may be used for a) direct administration or b) as preparations for rapid dissolution or dispersion in water. This final preparation is free of other packaging components such as capsules shells.

In the production of blister packs, processing conditions, including process temperatures and holding times, may be sufficient to produce sterile products.

Dosage units for non-oral administration may be prepared by directing suitable amounts of the fluidic mixture into moulds suitable for the preparation of, for example, suppositories, pessaries or implants. The moulds may be intermediate processing moulds.

When capsules are used in a dosage unit, the capsules are preferably two-piece capsules but may be one-piece.

Capsules (so-called 'hard' or 'two-piece' or 'soft' or 'one-piece' capsules) are the commercial items of the pharmaceuticals and food supplements industries. They are made commonly from gelatin (with or without glycerol) and may be made from methylcellulose derivatives or starch derivatives or alginate/alginate derivative or any other available materials. They include capsules of varying sizes, shapes, colour(s) and imprint. They may be manufactured to include special closing and/or locking mechanisms and/or anti-leak characteristics.

Finished capsules are preferably unbanded. Where applied, bands are preferably composed of material similar to that of the main shell, e.g. gelatin. Such band(s) may be coloured. They may be applied for technical purposes e.g. to prevent leakage or for commercial purposes, e.g.

product identification or for tamper-evidence purposes.

Bands may be applied in a single or in multiple-step(s).

They may be applied immediately or shortly after filing or at a later time. Capsule products are preferably but not necessarily uncoated. Capsules may be coated to provide the desired controlled release, for example by means of enteric coating or other coating to give targeted release or timed release.

The method described suitably reduces the process complexity and costs involved in preparing a drug formulation. It should be appreciated that, in a preferred embodiment, the method of preparing dosage units of drug formulations simply comprises a melting stage, a mixing stage and a filling stage. This contrasts with known methods of preparing tablets which may comprise mixing, granulation, drying, screening and mixing lubricant, compression and coating stages.

The first active ingredient preferably has a melting point of less than 90"C and, nore preferably, of less than 8 OOC.

The first active ingredient preferably has a melting point of greater than 25 C and, more preferably, of greater than 40 C.

The melting point of the first active ingredient is preferably in the range 25C to 1000C and, more preferably, in the range 40 C to 80 < C.

The second active ingredient may be a liquid at ambient temperature. The second active ingredient preferably has a melting point of greater than 50 C and, more preferably, of greater than 70 C.

The second active ingredient preferably has a melting point which is greater than that of said first active ingredient.

Said first active ingredient is preferably a drug adapted for oral administration to humans or animals. Said first active ingredient may be an analgesic, an antihistamine or a decongestant. Preferably, said first active ingredient is an analgesic.

Said second active ingredient is preferably a drug adapted for oral administration to humans or animals. Said second active ingredient may be an analgesic, an antihistamine or a decongestant. Preferably, said first active ingredient is an analgesic.

Said first and/or said second active ingredients and, if included, any additional active ingredients may be acids, bases, salts or ester forms. They may be anhydrate or hydrated forms. Derivatives of the active ingredients may be selected according to the desired dissipation rate of the formulation. For example, rapid dissolution may be achieved using a highly water-soluble salt or slow release may be achieved using a less water-soluble form, for example a base. Said active ingredients may be specific polymorphs. They may be specific enantiomers or racemic mixtures. They may be the most stable thermodynamic form.

They may convert from one polymorphic form to another during preparation of the drug formulation.

Said first active ingredient is preferably ibuprofen or a pharmaceutically acceptable derivative thereof.

Preferably, said first active ingredient is ibuprofen.

Said second active ingredient may comprise any other active ingredient which is pharmaceutically and/or physically compatible with said first active ingredient.

Said second active ingredient is preferably selected from dextropropoxyphene hydrochloride, codeine phosphate, dihydrocodeine, aspirin or any pharmaceutically acceptable derivative thereof. Where said second active ingredient is a decongestant, it may be pseudoephedrine.

Additional active ingredients may be anti-histamine or, preferably, decongestants.

Where said drug formulation includes one or more pharmaceutically acceptable excipients, said excipients may include diluents, for example glyceryl monostearate, polyethylene glycol and/or microcrystalline cellulose; suspending agents, for example carboxypolymethylene; emulsifying agents, for example polyoxyethylene sorbitan tristearate and/or sorbitan monolaurate; disintegrants, for example modified starch; antioxidants, for example tocopherol and/or butylated hydroxy anisole; preservatives, for example sodium metabisulphite; release rate controlling materials, for example saturated polyglycol glycerides; taste maskers; flavouring agents; and effervescing agents.

Said drug formulation, preferably includes a major amount of said first active ingredients. For example, said drug formulation may include up to 99 wt% of said first active ingredient.

Said drug formulation may include 25 - 98 wt% of said first active ingredient, 0.0001 to 75 wt% of said second active ingredient, with the balance comprising other compounds, suitably other active ingredients and/or excipients. Preferably, said drug formulation includes at least 35 wt% of said first active ingredient. Preferably, said drug formulation includes less than 97 wt% of said first active ingredient. In some embodiments, said drug formulation may comprise greater than 60 wt% of said first active ingredient. Preferably, the drug formulation includes 0.001 to 35 wt%, nore preferably 0.01 to 10 wt% of said second active ingredient. Especially preferred is the case wherein the formulation includes 0.01 to 2 wt% of said second active ingredient.

Said drug formulation may comprise naturallyoccurring, semi-synthetic or synthetic active ingredients or excipients.

Said drug formulation is preferably of a uniform release rate in use. Said formulation may comprise a rapid dissolving product. Alternatively, by selection of appropriate excipients, for example low-HLB saturated polyglycol glycerides, the release profile of the formulation may be selected to provide a prolonged release of active ingredients.

Said formulation may be arranged to have a plurality of release phases, for example fast and slow release phases. In this event, the first and second active ingredients may be distributed in selected release phases according to requirements.

Said drug formulation is preferably provided in a dosage unit which is preferably a solid form. In said dosage unit, said second active ingredient is preferably in intimate contact with said first active ingredient.

Said first and second active ingredients are preferably each in a finely divided form and are arranged to define a substantially homogenous mixture.

Said dosage unit may include 50 to 600 mg of said first active ingredient. Preferably, said dosage unit comprises 100 to 400 mg of said first active ingredient.

Said dosage unit is preferably contained in a container. For example, said dosage unit may be contained in a capsule, blister pocket or suppository mould.

The invention extends to a drug formulation comprising a first active ingredient having a melting point of less than 100"C and a second active ingredient Der se.

The drug formulation may be as described in any statement herein.

This invention will be described further with reference to the following examples.

EXAMPLE 1 Ibuprofen (200 mg), a low melting (circa 75"C) active ingredient, was melted in a suitable vessel. Then, a second active ingredient, dextropropoxyphene hydrochloride (32.5 mg) and an excipient, modified starch (5 mg) were added with stirring to produce a homogenous mixture. The mixture was kept in a fluid state by maintaining its temperature at about 750C. Two-piece size 2 gelatin capsules were then filled with the fluid using a Hibar pump fitted with temperature control. The capsules were then allowed to cool.

EXAMPLES 2 TO 5 By a process similar to the process of Example 1, the formulations described in Table 1 were prepared and arranged in gelatin capsules of the size stated.

RESULTS The stability of the capsules of Examples 1 to 5 was assessed by storing the capsules under ambient and accelerated temperature conditions for 10 weeks, during which there was no evidence of physical or chemical instability.

The reader's attention is directed to all papers and documents which are filed concurrently with or previous to this specification in connection with this application and which are open to public inspection with this specification, and the contents of all such papers and documents are incorporated herein by reference.

All of the features disclosed in this specification (including any accompanying claims, abstract and drawings), and/or all of the steps of any method or process so disclosed, may be combined in any combination, except combinations where at least some of such features and/or steps are mutually exclusive.

Each feature disclosed in this specification (including any accompanying claims, abstract and drawings), may be replaced by alternative features serving the same, equivalent or similar purpose, unless expressly stated otherwise. Thus, unless expressly stated otherwise, each feature disclosed is one example only of a generic series of equivalent or similar features.

The invention is not restricted to the details of the foregoing embodiment(s). The invention extends to any novel one, or any novel combination, of the features disclosed in this specification (including any accompanying claims, abstract and drawings), or to any novel one, or any novel combination, of the steps of any method or process so disclosed.

TABLE 1

EXAMPLE Low melting active Second active ingredient Excipient Capsule ingredient mg Size mg 1 Ibuprofen (200 mg) Dextropropoxyphene Modified Starch (5 mg) 2 hydrochloride (32.5 mg) 2 Ibuprofen (200 mg) Codeine Phosphate (4 mg) Modified Starch (5 mg) 2 3 Ibuprofen (200 mg) Dihydrocodeine (5 mg) Modified Starch (5 mg) 2 4 Ibuprofen (200 mg) Aspirin (300 mg) Modified Starch (5 mg) 0 5 Ibuprofen (200 mg) Dextropropoxyphene Gelucire 50-02 (50 mg) 1 hydrochloride (32.5 mg)

Claims

CLAIMS 1. A method of preparing a drug formulation, the method comprising contacting a fluid which comprises a first active ingredient having a melting point of less than a 100"C with a second active ingredient.
2. A method according to Claim 1, wherein said second active ingredient is contacted with said first active ingredient when the first active ingredient is in a molten state.
3. A method according to Claim 1 or Claim 2, wherein the first active ingredient acts as a carrier for said second active ingredient.
4. A method according to any preceding claim, wherein the second active ingredient is dissoluble or suspendible in the first active ingredient at a temperature at which the first active ingredient is in a molten state.
5. A method according to any preceding claim, wherein, in the method, said first and second active ingredients in a fluidic state are directed into containers.
6. A method according to Claim 5, wherein said containers are selected from capsules, blister pockets and suppository moulds.
7. A method according to Claim 5 or Claim 6, wherein said containers are of a predetermined size in order to provide a dosage unit of predetermined size.
8. A method according to any preceding claim, which solely comprises a melting stage, a mixing stage and a filling stage.
9. A method according to any preceding claim, wherein said first active ingredient has a melting point of less than 900C.
10. A method according to any preceding claim, wherein said first active ingredient has a melting point of greater than 25"C.
11. A method according to any preceding claim, wherein said second active ingredient is a liquid at ambient temperature.
12. A method according to any preceding claim, wherein said second active ingredient has a melting point of greater than 50"C.
13. A method according to any preceding claim, wherein said second active ingredient has a melting point which is greater than that of said first active ingredient.
14. A method according to any preceding claim, wherein said first active ingredient is a drug adapted for oral administration to humans or animals.
15. A method according to any preceding claim, wherein said first active ingredient is an analgesic.
16. A method according to any preceding claim, wherein said second active ingredient is a drug adapted for oral administration to humans or animals.
17. A method according to any preceding claim, wherein said second active ingredient is an analgesic.
18. A method according to any preceding claim, wherein said first active ingredient is ibuprofen or a pharmaceutically acceptable derivative thereof.
19. A method according to any preceding claim, wherein said second active ingredient is selected from dextropropoxyphene hydrochloride, codeine phosphate, dihydrocodeine, aspirin, pseudoephedrine or any pharmaceutically acceptable derivative thereof.
20. A method according to any preceding claim, wherein said drug formulation includes a major amount of said first active ingredient.
21. A method according to any preceding claim, wherein said drug formulation includes 25 - 98 wt% of said first active ingredient and 0.0001 - 75 wt% of said second active ingredient.
22. A method according to any preceding claim, wherein said drug formulation includes 0.01 - 2 wt % of said second active ingredient.
23. A drug formulation comprising a first active ingredient having a melting point of less than 100"C and a second active ingredient.
24. A method substantially as hereinbefore described with reference to the examples.
25. A drug formulation substantially as hereinbefore described with reference to the examples.