IE940446A1 - Controlled release formulation - Google Patents

Abstract

A controlled release formulation in solid unit dosage form comprises a multiplicity of microcapsules, each of which contains an active ingredient in a liquid phase and has a predetermined release rate of active ingredient in the gastrointestinal tract following administration. The microcapsules collectively have one or more rates of release of active ingredient dependent on a predetermined permeability of the respective microcapsules. The walls of the microcapsules can be formed of soft gelatine or other soft gel material. Once the wall of the microcapsule has the requisite permeability, the active ingredient in its liquid carrier passes into the gastrointestinal tract for immediate absorption.

Description

Controlled release formulation This invention relates to a controlled release formulation for oral administration, more particularly a controlled release formulation in solid unit dosage form containing a multiplicity of microcapsules.

Drugs for use in therapy and prophylaxis of various medical conditions have varying solubility ranging from insoluble to lipid soluble and pH sensitive solubility characteristics. This variation in solubility can affect the therapeutic effectiveness of drugs. Thus, drugs that are poorly soluble and/or sensitive to pH must be formulated in a way that improves their solubility and ultimately their bioavailability.

In general, a drug that is in solution or suspension when administered by the oral route is rapidly, indeed, frequently instantaneously, absorbed from the stomach and thus a fast effect may be achieved with that drug.

If a drug is already in solution at the time of administration it will be fast acting. By fast acting is meant an instantaneous effect or instantaneous bioavailability which is characterised by significant blood levels within about 10 to 60 minutes after administration. Except in very special cases drugs cannot be absorbed until they are solubilised. However, it may be desired to delay absorption following oral administration because otherwise administration of that drug in solution or suspension does not achieve the desired bioavailability or prolongation of action.

There is a need for an oral formulation which can be used to administer one or more active ingredients which are released in a predetermined manner to target sights in the gastrointestinal tract so as to achieve maximum absorption at the site of release of active ingredient.

There is also a need for an oral formulation which allows for release of active ingredient in the gastrointestinal tract in a manner which minimises high local concentrations of solid active ingredient.

There is also a need to improve absorption of drugs by administering them in a solution or suspension while retaining the controlled release properties of said drugs.

The invention provides a controlled release formulation in solid 5 unit dosage form, said formulation comprising a multiplicity of microcapsules, each of which microcapsules contains an active ingredient in a liquid phase and having a predetermined release rate of active ingredient in the gastrointestinal tract following administration, the microcapsules collectively having one or more rates of release of active ingredient dependent on a predetermined permeability of the respective microcapsules.

The microcapsules of the formulation according to the invention effectively allow one to administer solutions or suspensions of active ingredients as if they were multi-particulate solid oral dosage forms.

The microcapsules release their contents to the gastrointestinal tract in a manner which minimises high local concentrations of active ingredient which might otherwise result in irritation and other undesirable side effects, but additionally the drug is released in an already solubilised form which aids absorption.

The individual microcapsules suitably have an average diameter in the range 100-5,000 pm, more particularly in the range 250-2,000 pm and especially in the range 500-1,000 pm.

The walls of the microcapsules will suitably have a thickness in the range 30-1,000 pm, more especially 200-500 pm.

The walls of the microcapsules have a predetermined permeability by which is meant they either dissolve or have a natural permeability to gastrointestinal fluid so that active ingredient is released therefrom as desired in the gastrointestinal tract.

Microcapsules with naturally permeable walls can be soluble, porous or, alternatively, the solubility or porosity can develop as a result of the change in environmental conditions as the formulation passes through the gastrointestinal tract.

Thus, the wall of each microcapsule can be formed of a pharmaceutically acceptable, film-forming polymer or mixture of polymers which is soluble in the gastrointestinal tract.

In a preferred embodiment, the wall of the microcapsule is formed of soft gelatine or other soft gel materials made from suitable polymers. Examples of other soft gel materials include starches that form a soft gel or high molecular weight polyethylene glycols. However, in practice any material that can dissolve in the gastrointestinal fluid can be used. Such a material can be a material which is incorporated in the wall and which dissolves in the gastrointestinal fluid, namely a porosigen.

The wall of the microcapsule will have a polymeric composition and/or structure which allows for fast release and thus fast absorption of active ingredient once the wall is partially or wholly permeable.

Once the wall of the microcapsule has the requisite permeability, the active ingredient in its liquid carrier passes into the gastrointestinal tract for immediate absorption. The liquid carrier can include one or more auxiliary agents with bioavailability and/or cytoprotective, especially gastroprotective, enhancing properties.

The formulation according to the invention can comprise a blend of microcapsules having walls of variable, but predetermined, permeability so as to achieve immediate, intermediate or sustained release of active ingredient over a given time period in the gastrointestinal tract.

Accordingly, it will be appreciated that the formulation according to the invention has advantages over conventional solid microparticles in which the release of active ingredient is dependent on progressive solubilisation in the gastrointestinal tract.

The permeability of the walls of the microcapsules can be dependent on pH, temperature and other physical conditions prevailing within the gastrointestinal tract.

The controlled release properties of the microcapsules according to the invention will principally be a function of the thickness of the walls of the microcapsules, or by including pH dependent substances such as polymers or shellac.

The microcapsules can contain two or more active ingredients having different solubilities in the aqueous environment of the gastrointestinal tract, but with compatible solubility or suspending capability in the liquid medium of the microcapsule. Alternatively, the microcapsules can contain single active ingredients solubilised in different media but which can be released for simultaneous absorption from microcapsules having walls of diffemt materials but with similar or diffemt permeability characteristics.

The microcapsules can also contain two or more active ingredients having different half lives following absorption from the gastrointestinal tract.

The solubility of the or each active ingredient can be dependent on the pH of a given region of the gastrointestinal tract.

The microcapsules can be manufactured so that they release their contents in the gastrointestinal tract at a point at which the drug is most soluble. This feature enables one to maximise absorption because the microcapsules release their contents when the pH conditions are optimal.

The pH internally of the microcapsules can be optimised by the use of an acid or an alkaline solution, as required to maximise the absorption of active ingredients that are pH sensitive.

An example of a formulation with microcapsules capable of achieving immediate, intermediate and sustained release of active ingredient over a given time period in the gastrointestinal tract might be a formulation for use in the treatment of the common cold and influenza. Such formulations are conventionally multiple active ingredient formulations. The common cold and influenza are each characterised by a variety of symptoms which cannot generally be alleviated by a single active ingredient. For example, it might be desired to administer an antihistamine, a decongestent and one or more cough suppressants.

The formulation according to the present invention is ideally suited for use as a multiple active ingredient formulation.

The walls of the microcapsules can have inherently a mucoadhesive properties and thus bind to the wall of the gastrointestinal tract during release of active ingredient therefrom.

The walls of the microcapsules can also have inherent enteric coating properties.

Some or all of the microcapsules in the formulation can have an enteric coating, for example, an outer membrane of shellac or other enteric coating.

It will be appreciated that one can achieve selective absorption of active ingredients using a formulation in accordance with the invention.

Essentially the solution in which the drug is dissolved or suspended is any pharmaceutically acceptable solvent or liquid phase as long as the solvent or liquid phase does not dissolve the wall of microcapsules.

The liquid phase can suitably be an oil. When the oil is soya bean oil or mineral oil, the active agent would typically form a suspension in such oils. The liquid phase can also be an aqueous phase.

Such aqueous phases include, for example, high molecular weight liquid polyethylene glycols and coconut glycerides.

Suitably the or each active ingredient can be dissolved in a polyol in the core of the microcapsules. Examples of polyols are polyethylene glycols and cellulose derivatives.

The core can also contain one or more auxiliary agents selected from a pH controlling agent, an anti-oxidant, a humectant, a surfactant and a vasodilator.

Suitable pH controlling agents include, for example, citric acid, fumaric acid, sodium citrate and the like.

Examples of anti-oxidants are sodium metabisulphite, butylated hydroxyanisole and butylated hydroxytoluene or a mixture thereof.

A suitable humectant is glycerol.

Examples of suitable surfactants include sodium lauryl sulphate, diethylene glycol monostearate, propylene glycol monosteareate, polyethylene glycol, polysorbates and polyvinyl alcohol or mixtures thereof.

The microcapsules can contain up to 90% by weight of active ingredient. However, in general, the microcapsules will contain between 25 and 75% by weight of active ingredient.

Each formulation will suitably contain between 10 and 300 microcapsules, preferably between 100 and 250 microcapsules.

The microcapsules will suitably be administered by loading them into a hard gelatine capsule which will be swallowed in the normal way or by loading them into another container such as a sachet, the contents of which can then be swallowed. In certain special circumstances the microcapsules may be incorporated into a tablet in a way which maintains their integrity.

A formulation in accordance with the invention can be designed so as to achieve fast, medium and slow release of one or more active ingredients. Thus, it will be appreciated that the formulation in accordance with the invention can be used to achieve maximum bioavailability resulting from maximum absorption of one or more active ingredients from the gastrointestinal tract.

The formulation according to the invention is suitable for the administration of a wide range of active ingredients.

For example the formulation can be used in the case of insoluble active ingredients such as nifedipine, lipid soluble active ingredients such as gemfibrizol, and pH sensitive active ingredients such as captopril.

The formulation according to the invention is also suitable for the administration of active ingredients which are sensitive to the pH environment in the stomach, such as omeprazole and other proton pump inhibitors used in anti-ulcer treatment.

The formulation according to the invention can also be used to improve the bioavailability of active ingredients such as terfenadine which have a low oral bioavailability.

The formulation according to the invention can also be used to dramatically increase the absorption of active ingredients which are poorly absorbed from or destroyed in the gastrointestinal tract such as captopril.

An example of a formulation of an insoluble drug providing both immediate and sustained release in accordance with the invention comprises a capsule containing a mixture of immediate and sustained release seamless microcapsules of varying sizes, for example, 1mm940446 8mm. The active ingredient, for example, nifedipine, nicardipine or nimodipine is dissolved or suspended, as appropriate, for example, in a polyethylene glycol, an oil-base, a suspension of a polyethylene gylcol and a mineral oil or polyoxethylene sorbitan fatty acid esters. An outer membrane liquid, for example, gelatin and an inner active ingredient liquid are combined to form droplets i.e. microcapsules. The microcapsules are passed through a cooling system, for example, oil.

The seamless microcapsules containing the active ingredient are removed from the cooling system and cleaned and dried in separate facilities.

The sustained action of the microcapsules is determined by the thickness of the outer membrane or by the addition of a variety of sustained release polymers to the inner liquid or the outer membrane liquid, for example, polymethacrylates, cellulose derivatives, polyvinylpyrrolidones. As indicated above, the microcapsules can be formulated to release the active liquid ingredient at a specific absorption site, for example, by the use of pH dependent polymethacrylates.

The invention will be further illustrated by the following Examples.

Example 1 Nifedipine is dissolved in soy bean oil, and formed into seamless microcapsules with an outer gelatin coating as hereinbefore described. These microcapsules have a size distribution of l-3mm.

These microcapsules are then coated in a conventional manner with a cellulose polymer coating to provide a controlled release dissolution rate.

The coated microcapsules are finally encapsulated into a hard gelatin capsule shell.

Example 2 Nifedipine seamless microcapsules are formulated as described in Example 1, however, the inherent release characteristics of the pellets was varied from Example 1, by increasing the wall thickness of the microcapsules.

These microcapsules, when coated with the same polymer coating as in Example 1, provide a longer controlled release action.

Example 3 Gemfibrozil (a liquid soluble drug) was formulated along with various surfactants and gelatin into seamless microcapsules of varying thickness.

A portion of these pellets was coated with a methacrylate polymer system and combined in a ratio of 4:1 with uncoated microcapsules, then filled into hard gelatin capsule shells, thereby providing a drug formulation having both immediate and sustained release dissolution characteristics.

Example 4 Captopril is dissolved in soy bean oil, and formed into seamless microcapsules with an outer gelatin coating. These microcapsules have a size distribution of l-3mm.

The microcapsules are then coated in a conventional manner with a cellulose polymer coating to provide a controlled release dissolution rate.

The coated microcapsules are finally encapsulated into a hard gelatin capsule shell. ίο Example 5 Captopril seamless microcapsules are formulated as described in Example 4, however, the inherent release characteristics of the microcapsules was varied from Example 4, by increasing the wall thickness of the microcapsules.

These microcapsules, when coated with the same polymer coating as in Example 4, provide a longer controlled release action.

Claims (23)

1. Claims: 1. A controlled release formulation in solid unit dosage form, said formulation comprising a multiplicity of microcapsules, each of which microcapsules contains an active ingredient in a liquid phase and having a predetermined release rate of active ingredient in the gastrointestinal tract following administration, the microcapsules collectively having one or more rates of release of active ingredient dependent on a predetermined permeability of the respective microcapsules.

2. A formulation according to Claim 1, wherein the individual microcapsules have an average diameter in the range 1005,000 pm.

3. A formulation according to Claim 1 or 2, wherein the individual microcapsules have an average diameter in the range 2502,000 pm.

4. A formulation according to any one of Claims 1-3, wherein the individual microcapsules have an average diameter in the range 500-1,000 pm.

5. A formulation according to any preceding claim, wherein the walls of the microcapsules have a thickness in the range 30-1,000 pm.

6. A formulation according to Claim 5, wherein the walls of the microcapsules have a thickness in the range 200-500 pm.

7. A formulation according to any preceding claim, wherein the wall of each microcapsule is formed of a pharmaceutically acceptable, film-forming polymer or mixture of polymers which is soluble in the gastrointestinal tract.

8. A formulation according to Claim 7, wherein the wall of the microcapsule is formed of soft gelatine or other soft gel material,

9. A formulation according to any preceding claim, which is in the form of a blend of microcapsules having walls of variable, but predetermined, permeability so as to achieve immediate, intermediate or sustained release of active ingredient over a given time period in the gastrointestinal tract.

10. A formulation according to any preceding claim, wherein the microcapsules contain two or more active ingredients having different solubilities in the aqueous environment of the gastrointestinal tract.

11. A formulation according to Claim 10, wherein the solubility of the or each drug is dependent on the pH of a given region of the gastrointestinal tract.

12. A formulation according to any preceding claim, wherein the microcapsules contain two or more active ingredients having different half lives following absorption from the gastrointestinal tract.

13. A formulation according to any preceding claim, wherein the walls of the microcapsules have inherently mucoadhesive properties and bind to the wall of the gastrointestinal tract during release of active ingredient therefrom.

14. A formulation according to any preceding claim, wherein the walls of the microcapsules have inherent enteric coating properties.

15. A formulation according to any preceding claim, wherein some or all of the microcapsules in the formulation have an enteric coating.

16. A formulation according to any preceding claim, wherein the liquid phase is an oil.

17. A formulation according to any one of Claims 10-15, wherein the or each active ingredient is dissolved in a polyol in the core of the microcapsules.

18. A formulation according to Claim 17, wherein the polyol is a cellulose derivative.

19. A formulation according to any preceding claim, wherein the core contains one or more auxiliary agents selected from a pH controlling agent, an anti-oxidant, a humectant, a surfactant and a vasodilator.

20. A formulation according to any preceding claim, wherein the microcapsules contain up to 90% by weight of active ingredient.

21. A formulation according to any preceding claim, wherein the microcapsules contain between 25 and 75% by weight of active ingredient.

22. A formulation according to any preceding claim, wherein each formulation contains between 10 and 300 microcapsules.

23. A formulation according to any preceding claim, wherein the microcapsules are contained in a hard gelatine capsule.