Title:  Aqueous dispersion suitable for the production of coatings and binders for solid oral drugs

United States Patent:  6,656,507

Issued:  December 2, 2003

Inventors:  Petereit; Hans-Ulrich (Darmstadt, DE); Goelz; Silke (Bensheim, DE); Weisbrod; Wolfgang (Weiterstadt, DE)

Assignee:  Roehm GmbH & Co. KG (Darmstadt, DE)

Appl. No.:  263878

Filed:  March 8, 1999

Abstract

An aqueous dispersion for the production of binders or coatings for solid oral drugs having a water content of 90-40 wt. % and a solids portion of 10-60 wt. %, whereby said solids portion is composed of: (A) 10-99 wt. % of a polymer mixture consisting of: (a) 75-99 wt. % of a polymethacrylate copolymer consisting of up to 98-85 wt. % of alkyl (meth)acrylate monomers with C₁ -C₄ alkyl residues and up to 2-15 wt. % of alkyl (meth)acrylate monomers with a quaternary ammonium group in the alkyl residue, and (b) 25-1 wt. % of an alkali salt of carboxymethylcellulose having a weight average molecular weight of less than 150,000, and (B) 90-1 wt. % of at least one substance normally added to pharmaceutical formulations.

SUMMARY OF THE INVENTION

Accordingly, one object of the invention is to provide a coating and binder for solid oral drugs that, on one hand releases active ingredients for drugs quickly and without affecting the pH value, and on the other hand, which makes possible a good insulating effect in thin coatings, as well as high pigment binding ability and reliable protection of flavor.

Another object of the invention is to provide an aqueous polymer dispersion for drug formulations which, as an applied coating, is not impeded by swelling and adhesion.

Briefly, these objects and other objects of the invention as hereinafter will become more readily apparent can be attained by an aqueous dispersion for the production of binders or coatings for solid oral drugs having a water content of 90-40 wt. % and a solids portion of 10-60 wt. %, whereby said solids portion is composed of:

(A) 10-99 wt. % of a polymer mixture consisting of:

(a) 75-99 wt. % of a polymethacrylate copolymer consisting of 98-85 wt. % of alkyl (meth)acrylate monomers with C₁ -C₄ alkyl residues and 2-15 wt. % of alkyl (meth)acrylate monomers with a quaternary ammonium group in the alkyl residue, and (b) 25-1 wt. % of an alkali salt of carboxymethylcellulose having a weight average molecular weight of less than 150,000, and

(B) 90-1 wt. % of at least one substance normally added to pharmaceutical formulations.

DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

The polymer mixture A consisting of components (a) and (b) in the stated quantity ratio is decisive for the properties of the coatings and binders for solid oral drugs which are produced from the dispersion. In the process, it is indispensable for the two components to be present in an aqueous medium, because the advantageous effects cannot be achieved when an organic solution is used.  It is presumed that polymers (a) and (b) aggregate with one another in an advantageous manner in the aqueous phase either first in the dispersion itself or during the application of the dispersion, or during the evaporation of the water. Surprisingly, by increasing the quantity of component (b), there is an increase in tensile strength of the coated product, but a reduction of elongation at break. The binders or coatings that can be produced from the dispersion have a good mechanical strength, but disintegrate, as desired, very quickly in artificial gastric juice. The release of the active ingredients is practically constant and independent of the pH. In fact, disintegration of the prepared pharmaceutical coatings occurs in less than 30 min for a polymer coating of 2 mg/cm² in artificial gastric juice. The protection of flavor is very reliable, and the pigment binding ability is high.

Water Content and Particle Size

The water content of the dispersion is in the customary range of 90-40 wt. %, preferably 80-50 wt. %. The average particle size of the particulate matter in the dispersion is in the range of 50-500 nm.

Polymer Mixtures A

Component (a)

A portion of polymer mixture A consisting of components (a) and (b), to a large extent insoluble in water, is formed by a (meth)acrylate copolymer (a) that consist of up to 98-85 wt. %, preferably up to 96-88 wt. %, of alkyl (meth)acrylate monomers with C₁ -C₄ alkyl residues, and up to 2-15 wt. %, preferably up to 4-12 wt. % of alkyl (meth)acrylate monomers having a quaternary ammonium group in the alkyl residue.

Suitable alkyl (meth)acrylate monomers having C₁ -C₄ alkyl residues include methyl acrylate, ethyl acrylate, butyl acrylate, butyl methacrylate, and methyl methacrylate. The copolymer contains 20-40 wt. %, especially 25-35 wt % ethyl acrylate and 50-70 wt. %, especially 55-70 wt. % methyl methacrylate.

Suitable alkyl (meth)acrylate monomers having quaternary ammonium groups can be found, for example, in EP 0 181 515. Disclosed Examples include acryl and methacryloxytrimethylammonium chloride or the methosulfate, benzyldimethylammonium methyl methacrylate chloride, diethylmethylammonium ethyl acrylate and methacrylate methosulfate, N-trimethylammonium propyl methacrylamide chloride and N-trimethylammonium 2,2-dimethylpropyl-1-methacrylate chloride. 2-Trimethyl ammonium methyl methacrylate chloride is specially preferred.

Preferably, the (meth)acrylate copolymer having quaternary ammonium groups corresponding to component (a), can be composed of 65 or 60 wt. % methyl methacrylate, 30 wt. % ethyl acrylate and 5 or 10 wt. % 2-trimethylammonium methyl methacrylate chloride (EUDRAGIT.RTM. RS or RL).

The copolymers (a) are obtained by known techniques such as radical, solution, bead, or emulsion polymerization. They can be present as an extruded granulate, ground or spray-dried powder, or as a dispersion, for example, with 30 wt. % solid material.

Component (b)

The water-soluble component (b) of polymer mixture A consisting of components (a) and (b) is formed by alkali salts of carboxymethylcellulose having a molecular weight (weight average) of less than 150,000, preferably 5,000-100,000, especially preferably, 7,000-70,000. If the molecular weight of component (b) is 150,000 or more, there may be a thickening of the batch may occur, so that it can practically no longer be processed. Suitable alkali salts include lithium, sodium and potassium, as well as ammonium salts. Preferably, sodium salts are used. The viscosity of a 2% solution in water at 20^oC. is usually in the range of 1-200 mPas, preferably 2-60 mPas. Preferably such types are used which, because of their method of production, contain only small portions of native fiber.

Mixture Ratio of Components (a) and (b)

The amount of component (b) employed is 1-25 wt. %, preferably 5-15%, especially preferably 5-10 wt. %, relative to the amount of polymethacrylate that is insoluble in water.

The dispersions of the invention can be produced by mixing components (a) and (b) in powder form, or in the molten state, and in each case, subsequent absorption in water. The two components may also be present already as a dispersion or aqueous solution, and can be mixed directly. An extrusion of the powder mixture with subsequent comminution to ensure an even distribution of the two components and then absorption in water is also a practical technique.

Processing into a film is done by drying, preferably during application of the spray. The energy required for evaporation of the water can be obtained by the heated process air generated, by microwaves, or by other radiation, optionally in a vacuum as well.

Fundamentally, the polymers used must be nontoxic and they must present no risk to patients when used in pharmaceutical agents.

B) Customary Additional Ingredients

The dispersion of the invention contains the usual additional ingredients in quantities of 90-1 wt. % relative to polymer mixture A consisting of components (a) and (b). Quantities used and application of the customary additional ingredients in drug coatings are familiar to one of skill in the art. Customary additional ingredients include, for example, softeners, antiblocking agents, pigments, stabilizers, antioxidants, wetting agents, expanding agents, brighteners, aromatic substances or flavorings. They serve primarily as processing aids, and should ensure a safe and reproducible production method, as well as good long-term storage stability. They are added to the liquid polymer formulations before processing and can influence the permeability of the coatings, a characteristic that can be exploited, if desired, as an additional control parameter.

Softeners

Substances suitable as softeners generally have a molecular weight ranging from 100-2,000, and contain one or more hydrophilic groups in the molecule, for example, hydroxyl, ester, or amino groups. Suitable examples of softeners include citric acid alkyl ester, glycerin ester, phthalic acid alkyl ester, sebacic acid alkyl ester, sucrose ester, sorbitan ester, dibutyl sebacate, and polyethylene glycols 200-2,000. Preferred softeners include triethyl citrate and acetyl triethyl citrate. Esters that generally are liquid at room temperature, such as citrates, phthalates, sebacates, or castor oil, may also be mentioned.

Customary quantities of softeners used in the coatings and binders of the invention range from 5-30 wt. % relative to the polymer.

Antiblocking Agents

These substances, which generally have lipophilic properties are added to the spray suspensions and prevent an agglomeration of the cores during the film coating process. Preferred are talc, Mg or Ca stearate, powdered silicic acid, kaolin and nonionic emulsifiers having an HLB value ranging from 3-8. The usual quantities used for antiblocking agents in the coatings and binders of the invention range from 0-50 wt. % relative to the polymer.

Pigments

The addition is only rarely made in the form of a soluble dye. Generally, aluminum or iron oxide pigments are dispersed in a medium. Titanium dioxide is used as a white pigment. Quantities normally used in the coatings and binders of the invention range from 20-60 wt. % relative to the polymer mixture. Because of the high pigment binding ability, however, quantities of up to 80 wt. % can also be processed.

Aside from whiteners, antiblocking agents and pigments, stabilizers, antioxidants, wetting agents, expanding agents, brighteners, aromas and flavoring agents can be named as other substances that are customarily added and known to one of skill in the art.

Application as a Binder

Application as a binder is made by spraying the dispersion onto cores that have no active ingredients (nonpareils) with the simultaneous addition of powdered active ingredients or their mixtures. Furthermore, a dispersion that contains active ingredients can also be processed into a film so that a sheet-like pharmaceutical form is produced.

Another embodiment is the spraying of the dispersion together with the active ingredients dissolved or suspended in it.

Application as Coating

Core

Carriers for coatings include capsules, tablets, granulates, pellets and crystals of regular or irregular shape. The size of granulates, pellets, or crystals ranges from 0.01-2.5 mm, that of tablets from 2.5-30.0 mm. Capsules consist of gelatins, starches and cellulose derivatives.

They generally contain the biologically active substance (active ingredient) in an amount of up to 95%, as well as other inactive pharmaceutical ingredients up to 99.9 wt. %.

Customary production methods include direct pressing, pressing of dry, wet, or sintered granulates, extrusion and subsequent rounding, wet or dry granulation and direct pelletizing (for example, on plates), or by binding of powders (powder layering) to spheres (nonpareils) or particles that contain an active ingredient.

Aside from the active ingredient, they may contain other inactive pharmaceutical ingredients including binders such as cellulose and its derivatives, polyvinylpyrrolidone (PVP), humectants, disintegration accelerators, lubricants, disintigrants, (meth)acrylates, starch and its derivatives, sugar solubilizing agents and the like.

Of particular significance is the disintegration time of the core, which influences the release of the active ingredient. Today, short disintegration times of less than 5 or less than 10 min in the disintegration test according to the European Pharmacopoeia are desirable. Longer disintegration times are problematic because additional coatings further delay the release of the active ingredient and can jeopardize the therapeutic effect. At present, a disintegration time of 30 min is regarded as the limiting value. A small effect on the pH of the disintegration medium is advantageous. Therefore, tests are done in water and artificial gastric juice (0.1N HCl).

Incorporated pharmaceutical substances can elicit an uneven coloring or unpleasant, bitter taste. In order to improve the patient acceptance of such products, taste insulation for at least 30 sec is targeted.

The cores employed are homogeneous or have a layered construction. If engravings are made in the surface, they should as much as possible be only lightly covered by coatings.

Coatings

The layer thickness of the applied polymer mixtures of the invention varies greatly and depends on the processing method or the quantity of additional substances. The thickness ranges from 1-100 .mu.m, preferably from 10-50 .mu.m. On customary tablets, this corresponds to a polymer application of 0.5-5 wt. %.

The function of the polymer mixture in the final pharmaceutical product can be multifaceted:

protection from harmful environmental effects of moisture, gases, light, and the like.

odor or taste insulation

identification by color

mechanical stabilization

insulation from intolerable ingredients

avoidance of adhesion to the mucous membranes.

The low viscosity of the polymer mixture in the aqueous dispersion, even with high portions of solid substances up to 30%, is also advantageous, because engravings on the surface of tablets can be reproduced in detail.

Especially advantageous is the good protective and insulating effect of the polymer mixture of the invention with a simultaneously small effect on the disintegration of the tablets. Especially in comparison to simple coatings with HPMC, taste insulation of more than 30 sec can be achieved even with minimal polymer applications of 1 wt. %. Although thicker coatings improve disguising of the taste, they extend the disintegration time.

Also advantageous is the reliable covering of dye cores by coatings with a high pigment content. A special embodiment shape is the encapsulation of a second active ingredient into the coating on a core that contains active ingredient.

Application of the Film Coating

The method of application of the dispersion is by casting, painting, or spray application from an aqueous dispersion, by suspension, by liquification, or by direct application of powder. In the process, it is critical to the embodiment that regular, closed coatings are produced.

For the method of application by state of the state of the art procedures see, for example, Bauer, Lehmann, Osterwald, Rothgang, "Coated drugs," Wissenschaftliche Verlagsgesellschaft mbH, Stuttgart, Chapter 7, pp. 165-196.

For the properties relevant to the application, required tests and specifications are listed in pharmacopoeia.

Details can be found in the current textbooks, for example:

R. Voigt (1984): Lehrbuch der pharmazeutischen Technologie [Textbook of pharmaceutical technology]; Verlag Chemie, Weinheim Beerfield Beach/Fla.--Basel.

H. Sucker, P. Fuchs, P. Speiser: Pharmazeutische Technologie [Pharmaceutical technology], Georg Thieme Verlag Stuttgart (1991), especially Chapters 15 and 16, pp. 626-642.

A. R. Gennaro (Editor), Remington's Pharmaceutical Sciences, Mack Publishing Co., Easton, Pa. (1985), Chapter 88, pp. 1567-1573.

P. H. List (1982): Arzneiformenlehre [Science of drugs], Wissenschaftliche Verlagsgesellschaft mbH, Stuttgart.

Biologically Active Substances (or Active Pharmaceutical Substances)

Biologically active substances (or active pharmaceutical substances) which can be formulated with the present coating material are those which are intended to be applied to or in the human or animal body, in order to:

1. cure, alleviate, prevent, or diagnose diseases, pain, physical injuries, or ailments.

2. to aid in determining the quality, condition, or functions of the body or mental conditions.

3. to replace active ingredients or bodily fluids generated by the human or animal body.

4. to combat, eliminate or render harmless agents of disease, parasites, or substances foreign to the body or

5. to influence the quality, condition, or functions of the body or mental conditions.

Conventional pharmaceutical substances can be found in reference books, such as the Red List or Merck Index.

According to the invention, all active ingredients can be used that fulfill the desired therapeutic effect in the sense of the above definition, and have sufficient thermal stability.

Important examples (groups and individual substances) without claiming to be comprehensive are the following:

analgesics

antiallergy and antiarrhythmic drugs

antibiotics, chemotherapeutics, antidiabetics, antidotes,

antiepileptics, antihypertensives, antihypotensives,

anticoagulants, antimycotics, antiphlogistics,

beta blockers, calcium antagonists, and ACE inhibitors,

broncholytics/antiasthmatics, cholinergics, corticosteroids (internal)

dermatics, diuretics, enzyme inhibitors, enzyme preparations and transport proteins

expectorants, geriatric agents, antipodagrics, flu remedies,

hormones and their inhibitors, hypnotics/sedatives, cardiac drugs, lipid reducing agents

parathyroid hormones/calcium metabolism regulators, psychopharmaceuticals,

sexual hormones and their inhibitors, spasmolytics, sympatholytics,

sympathomimetics, vitamins, wound treatment agents, cytostatics.

Preferred active ingredients for delayed release of active ingredients include:

Nifedipine, diltiazem, theophylline, diclofenac sodium, ketoprofen, ibuprofen, indomethacin, ambroxol, terbutaline, vincamine, propranolol, pentoxifylline, codeine, morphine, etilefrin, carbamazepine, and their salts that are used in therapy.

Application Forms

Fundamentally, the described drugs can be administered directly by oral application. The granular powders, pellets, or particles produced according to the invention may be filled into gelatin capsules, bags (sachets), or suitable multidose containers with a dosing device. Intake is in solid form or as liquid suspensions.

Through compression with or after the admixture of other inactive ingredients, tablets are obtained that disintegrate after intake and release the subunits that usually are coated. Also conceivable is the encapsulation of agglomerates in polyethylene glycol or lipids for the production of suppositories or vaginal drugs.

Coated tablets are packed in blister or multiple-dose containers and removed by the patient directly before intake.

Claim 1 of 17 Claims

What is claimed as new and is intended to be secured by Letters Patent is:

1. An aqueous dispersion for the production of quickly disintegrating binders or coatings for solid oral drugs containing 90-40 wt. % water and 10-60 wt. % solids whereby said solids are composed of:

(A) 10-99 wt. % of a polymer mixture consisting of;

(a) 75-99 wt. % of a polymethacrylate copolymer consisting of 98-85 wt. % of alkyl(meth)acrylate monomers with C₁ -C₄ alkyl residues and 2-15 wt. % of alkyl(meth)acrylate monomers with a quaternary ammonium group in the alkyl residue, and (b) 25-1 wt. % of an alkali salt of carboxymethylcellulose having a weight average molecular weight of less than 150,000, and

(B) 90-1 wt. % of at least one pharmaceutically acceptable ingredient.

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