HK1058152B - Coated medicament forms with controlled active substance release - Google Patents

Description

Coated pharmaceutical dosage form with controlled release of active substance

Prior Art

The present invention relates to the field of coated pharmaceutical dosage forms with controlled release of active substances.

EP-A0463877 describes a medicament with a sustained release of active substance, which comprises a core containing a pharmaceutically active substance and a single-layer coating film containing a hydrophobic salt and a water-insoluble copolymer of ethyl acrylate, methyl methacrylate and trimethylammonium ethyl methacrylate chloride. The hydrophobic salt may be, for example, calcium stearate or magnesium stearate. A sigmoidal release profile can be obtained.

EP-A0225085, EP-A0122077 and EP-A0123470 describe the use of organic acids for drug cores which are coated with different organic solutions. Ultimately having substantially S-shaped release characteristics. EP-A0436370 describes medicaments with a slow-release action of the active substance, which comprise a core with a pharmaceutically active substance and an organic acid and an outer coating of a copolymer of ethyl acrylate, methyl methacrylate and trimethylammonium ethyl methacrylate chloride applied by aqueous spraying. Here too, an S-shaped release profile can be obtained. The use of organic acids in the form of salts is not considered in the citation.

Task and solution of the invention

The object of the present invention was to further develop the pharmaceutical preparations known from EP-A0463877 and EP-A0436370. In which case a sigmoidal release profile should be obtained, in particular, with a relatively small layer thickness. This is usually only achieved if more coating agent is applied. This task is achieved by a pharmaceutical preparation comprising:

(a) a core, which contains the active substance, optionally a carrier and customary pharmaceutical additives, and also an organic acid salt in an amount of from 2.5 to 97.5% by weight, based on the weight of the core, and

(b) an outer coating film consisting of a copolymer of one or more (meth) acrylic esters and optionally customary pharmaceutical auxiliaries,

wherein 40-100% by weight of the (meth) acrylate copolymer is composed of up to 93-98% by weight of free-radically polymerized C1-C4 alkyl esters of acrylic or methacrylic acid and 7-2% by weight of (meth) acrylate monomers having a quaternary ammonium function in the alkyl radical, and is optionally present in the form of a mixture mixed with:

1-60% by weight of one or more other (meth) acrylate copolymers different from the (meth) acrylate copolymers described above, consisting of up to 85-100% by weight of free-radically polymerized C1 to C4 alkyl esters of acrylic or methacrylic acid, and optionally up to 15% by weight of other (meth) acrylate monomers having a basic or acidic group in the alkyl group.

Practice of the invention

Core (a)

In the simplest case, the core consists only of the active substance and the organic acid salt, and generally additionally comprises a carrier, for example coloured sugar particles (Nonpareil) and pharmaceutical auxiliaries, for example highly disperse silicic acid or polyvinylpyrrolidone (PVP).

Thus, the core (a) comprises:

97.5-2.5% by weight, preferably 80-5% by weight, of active substance

One or more organic acid salts, 2.5 to 97.5% by weight, preferably 5 to 80% by weight, in particular 10 to 50% by weight

Pharmaceutical auxiliary agents, 0 to 95% by weight, preferably 10 to 50% by weight

A carrier, 0 to 95% by weight, preferably 10 to 50% by weight

The cores can be prepared by direct extrusion, extrusion and subsequent rounding, wet or dry granulation or direct pelleting (for example on a disk) or by bonding (powder layering) the powder to the inactive substance spheres (colored sugar particles) or active substance-containing granules.

In addition to the active substance, pharmaceutical auxiliaries such as binders, for example cellulose and its derivatives, polyvinylpyrrolidone (PVP), gelatin, (meth) acrylates, starch and its derivatives or sugars may also be present.

The core may be a homogeneous or layered structure, with the active substance preferably being present in the outer layer.

Organic acid salt

The organic acid salts used must be non-toxic and can be used in medicaments. Alkali metal salts (ammonium, lithium, sodium, potassium) are preferred. The preferred type depends on the particular formulation; in addition to the function according to the invention, the pharmacological influence of the ions is also taken into account. Salts of weak organic acids, such as citric, fumaric, formic, acetic, maleic, tartaric, glutaric or lactic acid are preferred.

Particularly suitable are sodium succinate, sodium citrate and sodium acetate. The use of acetic acid in the form of sodium acetate has the advantage that it is not processed in liquid but in solid form.

The type of acid controls the slope of the active agent release profile, particularly for sigmoidal release profiles.

In the formulation of the invention, the salt serves as the outer layer of the core and is attached by an adhesive. They are applied by solution spraying or by powder coating with the addition of a binder solution.

However, it is also possible in individual cases to apply the active substance as a mixture with the salt or to apply a separating layer between the active substance layer and the salt layer. The organic acid salt may also be applied to the core to form the outer layer.

The organic acid salt component represents from 2.5% to 97.5% by weight, preferably from 5 to 80% by weight, in particular from 10 to 50% by weight, of the core.

Overcoat film (b)

The overcoat film is composed of one or more (meth) acrylate copolymers and optionally customary pharmaceutical auxiliaries, such as plasticizers, pigments, pore formers, wetting agents, release agents, etc.

The principle of the invention is based on the presumed interaction between organic acid salts and (meth) acrylate copolymers consisting of up to 93-98% by weight of C1 to C4 alkyl esters of acrylic or methacrylic acid and 7-2% by weight of (meth) acrylate monomers with quaternary ammonium groups in the alkyl radical. To ensure this interaction, the (meth) acrylate copolymers mentioned are at least 40% by weight of the coating structure in order to achieve the desired interaction. Such (meth) acrylate monomers are commercially available and have long been used in delayed action coatings. They are practically insoluble in water. They may be used alone or in admixture with other (meth) acrylate copolymers. If it is desired to achieve a sigmoidal active substance release profile, the coating (b) must contain at least 80 wt.%, preferably 90 or 100 wt.%, of the above-mentioned copolymer types.

Preferred C1 to C4 alkyl esters of acrylic or methacrylic acid are methyl acrylate, ethyl acrylate, butyl methacrylate and methyl methacrylate.

As the quaternary ammonium-bearing (meth) acrylate monomer, trimethylammonium ethyl methacrylate chloride is preferred, and 2-trimethylammonium ethyl methacrylate chloride is particularly preferred.

The corresponding copolymers may, for example, consist of 50 to 70% by weight of methyl methacrylate, 20 to 40% by weight of ethyl acrylate and 7 to 2% by weight of trimethylammoniumethyl methacrylate chloride.

A preferred copolymer contains 65% by weight of methyl methacrylate, 30% by weight of ethyl acrylate and 5% by weight of 2-trimethylammoniumethyl methacrylate chloride (EUDRAGIT)^*RS)。

Mixtures of (meth) acrylate copolymers

The above copolymers are optionally mixed with other (meth) acrylate copolymers to achieve modulation of the individual active agent release profiles. Thus, optionally, not a sigmoidal curve is obtained, but also, for example, an immediate release curve or, for example, a continuous release curve or a curve 0(nullter) or 1-sequence curve. Transition curves of the type mentioned above can also be achieved depending on the active substance requirements.

According to the invention, the top coat film (b) can therefore also be a mixture comprising at least 40% by weight, preferably 40 to 99% by weight, of the abovementioned (meth) acrylate copolymers composed of up to 93 to 98% by weight of C1 to C4 alkyl esters of acrylic or methacrylic acid and 7 to 2% by weight of (meth) acrylate monomers bearing quaternary ammonium groups in the alkyl radical, and 1 to 60% by weight, preferably up to 40 to 60% by weight, of one or more, preferably one other type of (meth) acrylate copolymers composed of up to 85 to 100% by weight of C1 to C4 alkyl esters of acrylic or methacrylic acid and optionally up to 15% by weight of other (meth) acrylate monomers bearing basic or acidic groups in the alkyl radical. When the alkyl group contains more than 15% by weight of basic groups or acidic groups, the interactions of the components can influence one another in an undesirable or hardly predictable manner.

Suitable (meth) acrylate copolymers for such mixtures may, for example, be composed of 85 to less than 93% by weight of C1 to C4 alkyl esters of acrylic or methacrylic acid and more than 7 to 15% by weight of (meth) acrylate monomers bearing a quaternary ammonium in the alkyl group. Such (meth) acrylate monomers are commercially available and have long been used in delayed action coatings.

A particularly suitable copolymer contains, for example, 60% by weight of methyl methacrylate, 30% by weight of ethyl acrylate and 10% by weight of 2-trimethylammoniumethyl methacrylate chloride (EUDRAGIT)^*RL)。

Another suitable (meth) acrylate copolymer for the mixture consists of up to 95 to 100% by weight of C1 to C4 alkyl esters of acrylic or methacrylic acid and 0 to 5% by weight of acrylic or methacrylic acid. Such (meth) acrylate monomers are commercially available.

General procedure for the preparation of (meth) acrylate copolymers

The (meth) acrylate copolymers are obtained by free-radical, bulk, solution, suspension or emulsion polymerization in a known manner. They may be present in the form of extruded particles, ground powders, solutions or dispersions.

Coating layer

The polymer coating depends on the size and surface area of the core, the solubility of the active substance and the release profile sought. It is 5 to 80% by weight, preferably 10 to 60% by weight, of the core.

The coating may be applied in multiple layers or as a mixture. The mixture of polymers makes it possible to establish a certain gradient in the second phase of the release profile. The quaternary ammonium content of the coating regulates permeability and thus the diffusion rate of dissolved substances (McGinity, Ed., Aqueous Polymeric Coatings for Pharmaceutical dosage forms, Marcel Dekker, Inc., Chapter 4, p. 208-. The higher the content of hydrophilic quaternary ammonium groups, the faster the release rate. This gives the option of modulating the release of the active substance in the second phase of the release profile.

Other additives

They are primarily used as processing aids and should ensure a safe and reproducible production process and good long-term storage stability. They can influence the permeability of the coating, which is optionally also utilized as an additional regulating parameter.

-a plasticizer:

suitable materials as plasticizers generally have a molecular weight of 100-. Examples of suitable plasticizers are alkyl citrates, glycerol esters, alkyl phthalates, alkyl sebacates, sucrose esters, sorbitan esters, dibutyl sebacate and polyethylene glycols 4000 to 20000. Preferred plasticizers are triethyl citrate and acetyl triethyl citrate. Esters which are generally liquid at room temperature: citrate, phthalate, sebacate, castor oil.

Anti-adhesive agent

These substances, which are generally lipophilic in nature, are added to the spray suspension to prevent agglomeration of the nuclei during film formation. Preference is given to using talc, finely divided silicic acid or nonionic emulsifiers having an HLB value of from 3 to 8. The amount is 3 to 100% by weight of the polymer.

As further additives, for example stabilizers, dyes, antioxidants, wetting agents, pore formers, pigments, gloss agents, etc. can be added in a known manner.

Coating of the thin film coating:

the coating process is carried out by spraying from an organic solution or an aqueous dispersion, by melting or direct powder coating. It is critical to this embodiment here that a uniform, non-porous coating be produced.

The coating process is based on the prior art described in Bauer, Lehmann, Osterwald, Rothgang, "coating Agents" ("* berzogene Arzneiformen"), scientific publishing company (Wissenschaftliche Verlagsgesellschaft mbH), Stuttgart, Chapter 7, p.165-196.

For the application, the relevant properties, required tests and instructions are listed in the pharmaceutical literature.

Details are cited from general textbooks, for example:

-Voigt, R. (1984): textbook on pharmaceutical technology (Lehrbuch der pharmazeutischen Technologie); verlag Chemie Weinheim-Beerfield Beach/Florida-Basel.

-packer, h., Fuchs, p., Speiser, p.: pharmaceutical technology (Pharmazeutische technology), Georg Thieme Verlag Stuttgart (1991), in particular chapters 15 and 16, pages 626-.

Gennaro, A., R. (eds.), Remington's pharmaceutical Sciences, Mack Publishing Co., Easton Pennsylvania (1985), Chapter 88, p. 1567-1573.

List, P.H (1982): textbook for pharmaceutical dosage forms (Arzneiformenlehre), Wissenschaftliche Verlagsgesellschaft mbH, Stuttgart.

Active substance (bioactive substance):

the pharmaceutical materials to be used according to the invention are used in and/or outside the human or animal body for

1. Cure, alleviate, prevent or identify diseases, disorders, physical injuries or ailments.

2. The performance, status or functional or mental state of the body is identified.

3. Instead of active substances or body fluids produced in the human or animal body.

4. The pathogen, parasite or foreign material is resisted, eliminated or harmlessly treated.

5. Affecting the physical performance, state or functional or mental state.

Commonly used pharmaceutical materials are cited in the reference books, e.g. Roten Liste or Merck Index.

According to the invention, all active substances which satisfy the desired therapeutic effect in the sense defined above and have sufficient thermal stability can be used.

Important, but non-limiting examples (of one class or a single substance) are as follows:

an analgesic drug, which is a drug that has the effect of relieving pain,

anti-allergic agents, anti-arrhythmic agents,

antibiotics, chemotherapeutic agents, antidiabetics, antidotes, antiepileptics, antihypertensives,

anticoagulant, antimycotic, anti-inflammatory,

beta-receptor blockers, calcium antagonists and ACE-inhibitors, broncholytics/antiasthmatics, cholinergics, corticosteroids (internal), dermatological agents, diuretics, enzyme inhibitors, enzyme preparations and carrier proteins, expectorants, geriatric agents, gout drugs, influenza drugs, hormones and inhibitors thereof, hypnotics/hypnotics, stimulants, lipid-lowering agents, parathyroid hormone/calcium exchange modulators,

psychotropic agents, sex hormones and inhibitors thereof,

antispasmodics, sympathomimetics, vitamins, wound healing agents, and cell suppressants.

Preferred active substances for delayed active substance release are:

nifedipine, diltiazem *, theophylline, diclofenac sodium, ketoprofen, ibuprofen, indomethacin, Diltianzem, ambroxol, terbutaline, vincamine, propranolol, tobramycin (pentaxyphyllin), codeine, morphine, etifolin, carbamazepine, and their corresponding therapeutically useful salts.

Application modes and other arrangements

The above pharmaceutical dosage forms can be administered essentially directly by oral administration. Preferably, in the case of multiparticulate form (multiple unit dosage form), further processing steps are additionally provided:

the coated forms prepared according to the invention can be filled in individual dosage forms in gelatin capsules and sachets (sachets) or in suitable multi-metered containers using metering equipment. The medicament is administered in solid form or suspended in a liquid.

Tablets are obtained from the granules, optionally after mixing with other auxiliaries, by compression, which tablets after administration release the dissolved, slow-release subunits. It is also contemplated that the agglomerates may be embedded in polyethylene glycol or lipids to prepare suppositories or vaginal pharmaceutical dosage forms.

Coating (b) may also incorporate or be coated by prior art coatings. Suitable for this purpose are, in particular, (meth) acrylate copolymers which contain up to 10 to 60% by weight of methacrylic acid residues, whichThe remainder consisting, for example, of methyl methacrylate and/or ethyl acrylate (TypEUDRARIT)^*L or S). In this way, additional taste-insulating features or formulations for targeted release in the colon can be achieved in combination with the formulations of the present invention.

Examples

Copolymers used

Copolymer 1:

65% by weight of methyl methacrylate, 30% by weight of ethyl acrylate and 5% by weight of 2-trimethylammoniumethyl methacrylate chloride (EUDRAGIT)^*RS)。

Copolymer 2:

60% by weight of methyl methacrylate, 30% by weight of ethyl acrylate and 10% by weight of 2-trimethylammoniumethyl methacrylate chloride (EUDRAGIT)^*RL)。

Copolymer 3:

30% by weight of ethyl acrylate, 69% by weight of methyl methacrylate and 1% by weight of methacrylic acid (EUDRAGIT)^*NE 30D)。

Preparation of coated theophylline preparation

The active substance-containing cores are produced in a known manner in a conventional sugar-coated container (Dragierkessel) by the dusting process. Here, the carrier cores (colored sugar particles) are rotated in a container, continuously moistened with a binder solution (spray, nozzle diameter 1mm, spray pressure 0.5 bar, spray velocity 3-6 g/min), and formed into pellets with the powder mixture (sprinkled in). The product was then dried in a drying oven (40 ℃, 24 hours) and sieved to obtain the desired particle size fraction.

Colored sugar particles (0.5-0.6mm) were used as carriers in all examples. Theophylline, the organic acid salts used in each case, as active substance were applied thereto in different amounts. Polyvinylpyrrolidone (Kollidon 25) and highly dispersed silicic acid (Aerosil 200) or sucrose are used as pharmaceutical adjuvants. The scattering time is 77-142 minutes. The vessel was rotated 40 weeks per minute.

The coating is applied in a known manner using a fluidized bed apparatus. An aqueous dispersion containing 30% by weight of copolymer was used. Triethyl citrate was used as plasticizer and talc as release agent.

Testing of theophylline Release

The determination of the release of active substance is carried out in a known manner according to pharm. The amount of active substance released is determined photometrically. The measurement time is determined according to the established release profile, between 10 and 24 hours, with one measurement point every 1 or 2 hours. After the end of the measurement, the test solution is homogenized with the remaining residual pill, containing 100% by weight of active substance as a basis for calculation.

Example 1:

effect of different amounts (21, 32 and 43wt. -%) of sodium acetate on the theophylline/sodium acetate core release profile with a 30 wt. -% copolymer 1 over-coating.

Example 2:

the influence of different layer thicknesses (20, 30 and 40% by weight) of copolymer 1 on the release profile of the theophylline/sodium acetate core.

Example 3:

theophylline/sodium succinate was compared to theophylline/succinic acid formulations for theophylline release with an overcoat of 42-60 wt% copolymer 1.

Example 4:

effect of different layer thicknesses (10, 20, 30 and 40% by weight) of the mixture of copolymer 1 and copolymer 2 (1: 1) on the theophylline/sodium acetate core release profile.

Example 5:

effect of different thicknesses (10, 20, 30 and 40% by weight) of the mixture of copolymer 1 and copolymer 3 (1: 1) on the theophylline/sodium acetate core release profile.

The formulations of examples 1 to 5 are summarized in the following table (all data in grams):

examples	1	2	3	4	5
						Core1)Scattering and mixing
Colored sugar particles	700	700	700	700	700
						Theophylline	901/675/450	675	420	675	675
Sodium acetate	450/675/901	675	-	675	675
						Sodium succinate/succinic acid			960/700
Kollidon 25	42	42	43/35	42	42
						Aerolsil 200	7	7	7/6	7	7
2) Adhesive solution
						Kollidon30	20	20	-	20	20
Sucrose	-	-	276/97	-	-
						Ethanol	-	-	135/28	-	-
Water (W)	380	380	430/85	380	380
						Core + coating
Amount of coated core	500	500	500	500	500
						30% Dispersion of copolymer 1	500	333/500/667	1005	83/167/250/333	83/167/250/333
30% Dispersion of copolymer 2	-	-	-	125/167/250/333	-
						30% Dispersion of copolymer 3	-	-	-	-	83/167/250/333
Citric acid triethyl ester	30	27/40/53	38	10/20/30/40	10/20/30/40
						Talc	75	50/75100	159	25/50/75/100	25/50/75/100
Water (W)	670	447/670/893	1179	225/447/670/893	225/447/670/893

Claims (11)

1. A pharmaceutical formulation comprising:

(a) a core containing the active substance, optionally a carrier and customary pharmaceutical additives, and also an organic acid salt in an amount of 2.5 to 97.5% by weight, based on the weight of the core, and

(b) an outer coating film consisting of one or more (meth) acrylate copolymers and optionally customary pharmaceutical auxiliaries,

wherein 40-100% by weight of the (meth) acrylate copolymer is composed of up to 93-98% by weight of free-radically polymerized C1-C4 alkyl esters of acrylic or methacrylic acid and 7-2% by weight of (meth) acrylate monomers with quaternary ammonium groups in the alkyl radical, and is optionally present in the form of a mixture mixed with

1 to 60% by weight of one or more other (meth) acrylate copolymers different from the (meth) acrylate copolymers described above, consisting of up to 85 to 100% by weight of free-radically polymerized C1 to C4 alkyl esters of acrylic or methacrylic acid and optionally up to 15% by weight of other (meth) acrylate monomers having a basic or acidic group in the alkyl radical.

2. A formulation according to claim 1, characterized in that the (meth) acrylate copolymer component of the outer coating film (b) is a mixture comprising

99-40% by weight of a (meth) acrylate copolymer consisting of up to 93-98% by weight of C1 to C4 alkyl esters of acrylic or methacrylic acid and 7-2% by weight of (meth) acrylate monomers with quaternary ammonium groups in the alkyl groups, and

1-60% by weight of a (meth) acrylate copolymer consisting of up to 85 to less than 93% by weight of C1 to C4 alkyl esters of acrylic or methacrylic acid and more than 7 to 15% by weight of (meth) acrylate monomers bearing quaternary ammonium groups in the alkyl groups.

3. A formulation according to claim 1, characterized in that the (meth) acrylate copolymer component of the outer coating film (b) is a mixture comprising

99-40% by weight of a (meth) acrylate copolymer consisting of up to 93-98% by weight of C1 to C4 alkyl esters of acrylic or methacrylic acid and 7-2% by weight of (meth) acrylate monomers bearing a quaternary ammonium in the alkyl group, and

1-60% by weight of a (meth) acrylate copolymer consisting of up to 95-100% by weight of C1 to C4 alkyl esters of acrylic or methacrylic acid and 0-5% by weight of acrylic or methacrylic acid.

4. A formulation according to any one of claims 1 to 3, characterized in that as (meth) acrylate monomer with quaternary ammonium in the alkyl group, trimethylammonium ethyl methacrylate chloride is used.

5. The preparation according to claim 4, wherein the trimethylammonium ethyl methacrylate chloride is 2-trimethylammonium ethyl methacrylate chloride.

6. Formulation according to one of claims 1 to 3, characterized in that the organic acid salts used are ammonium, lithium, sodium or potassium salts of citric acid, fumaric acid, formic acid, acetic acid, maleic acid, succinic acid, tartaric acid, glutaric acid or lactic acid.

7. Formulation according to any one of claims 1 to 3, characterized in that it is compressed into tablets.

8. The formulation according to any one of claims 1 to 3, characterized in that it is encapsulated in a gelatin capsule.

9. Preparation according to one of claims 1 to 3, characterized in that it is additionally coated with a (meth) acrylate copolymer containing 10 to 60% by weight of methacrylic acid residues.

10. A formulation according to any one of claims 1 to 3, characterized in that the organic acid salt forms the outer layer of the core.