KR830001644B1 - Process for preparing pharmaceutical formulation controlled release - Google Patents

Abstract

A pharmaceutical compn. with controlled release of active material in the intestinal tract was described. The compn, consisted of a tablet nucleus of active material with a coating resistant to gastric juices, and an outer layer of active material, which enabled a quick release of drug into the blood stream via the stomach and a high initial concn. in the blood. This high blood level is maintained by a further release of drug in the small intestine. A typical tablet comprised; 1) a nucleus of 4-(2-hydroxy-3-isopropylaminopropoxy) indole (I) 5, Na lauryl sulfate 2.5, Et cellulose 4.5, microcryst. cellulose 7.0, mannitol 27.5; and 2) gastric juiceinsol. layer of hydroxypropyl Me cellulose phthalate, etc.

Description

Method for preparing sustained release formulation

The present invention does not disintegrate in gastric juice in a nuclear tablet consisting of a mixture of i) aryloxy alkanes, a pharmacologically active compound selected from the amine group and ii) a physiologically resistant anionic surfactant selected from the mono-sulfuric acid ester group of higher fatty alcohols. Above pH 5, the present invention relates to a method for preparing a pharmaceutical composition in which the release rate of the active substance is controlled, optionally coated with a collapsing film and coated thereon with a drug layer that is also dissolved in gastric fluid.

It has thus been found that the use of component ii) according to the invention can preferably increase the intestinal absorption of component i) in the intestine. The compositions of the present invention can suitably control the rate at which the active compound is released in the intestinal tract as a final formulation.

The pharmaceutical compositions according to the invention are particularly suitable for administering cardiovascular and circulatory therapies such as, for example, β-sympathetic receptor blockers and arrhythmia therapeutics.

Such agents are well known in the art. For example, aryl can have up to 10 carbon atoms (eg phenyl or naphryl) and can contain one or two heteroatoms (eg nitrogen in indole, thiazolyl in indol). Nitrogen and sulfur atoms), and also the aryl moiety may contain one or two cyclic substituents, such as acetyl, allyl, allyloxy, amino carbonylmethyl, cyano, methyl, chloro, mesoxy, mesoxyethyl, amido, hydroxy , Nitro, propynyloxy, (C ₁ -C ₄ ) alkanoylamino, methylsulfamoyl, morpholino, methylthio, and tetrahydrofuryl-methyloxy substituents.

The aryl moiety may also have an alkyl chain between two adjacent carbon atoms and thus form a saturated ring. For example, the nucleus of the aryl moiety can be tetraron or tetralin.

The amino moiety conveniently has 3 to 8 branched alkyl substituents, such as isopropyl or tert-butyl. The alkanolamine moiety is conveniently a 2-hydroxy-3-alkylamino propyl moiety.

Examples of the amines for the aryloxyalkane are as follows.

Particularly important compounds are as follows.

4- (2-hydroxy-3-isopropyl amino propoxy) indole (pindolol), 4- (2-hydroxy-3-isopropyl amino propoxyl) -2-methylindole and others with low solubility in serous fluids compound.

The active compound may be in the form of a pharmaceutically acceptable acid addition salt, but the free base is conveniently in the form.

The surfactant preferably has a hydrophilic-lipophilic parallel (HLB value) of about 35 to 45. [HLB values are well known in the art. References: Pharm. Act. Helv. 44, 9 (1969) and H. P. Fiedler, Lexikon der Hilf-stoffe fur Pharmazie, kosmetik und angrenzende Gebiete, page 263, editio Cantor KG 1971].

Further, the surfactant preferably has a critical micelle concentration (CMC) of from about 10- ² to 10- ^3.

Preferred surfactants have high dissociation constants and can form stable complexes with the active compounds in strong acidic media. These complexes should preferably be able to dissolve very slowly at or below pH 3, for example in gastric juices but quickly in pH 3 to 7.5 and especially at or above 5 for example in serous fluids.

The exact choice of surfactant depends, of course, on the compatibility of the active compound used (eg molecular size and form and basicity) with other pharmaceutical diluents and carriers which may be contained. For example, above pH 5, surfactants which do not release the active compound by forming an insoluble precipitate with the active compound should be avoided.

Higher fatty alcohols may have straight or branched chains and may contain alicyclic and / or aromatic moieties. Preferably the alcohol is a primary alcohol and has 8 to 18 carbon atoms, in particular 12 to 14 carbon atoms.

If desired, it may be an ethoxylated fatty alcohol containing about 1 to 5 moles, preferably 1 to 3 moles of ethylene oxide per mole. Preference is given to 2.5 moles of ethylene oxide per mole of surfactant.

Preference is given to using salt surfactants. Preferred salt forms are water-soluble salts, including salts which can be readily dispersed in water, in particular alkaline earth metal salts such as magnesium salts, organic amine salts such as triethanolamine salts or ammonium salts. However, alkali metal salts such as sodium salts are particularly preferred.

Preferred surfactants for use with the indole derivatives described above are sodium lauryl mono sulfate.

Of course, one or more surfactants may be used as needed.

The weight ratio of surfactant to active compound used and the total amount of surfactant used are determined by the chemical and physical properties of the surfactant, the form and amount of the active compound and the other pharmaceutical diluents and carriers contained and the desired release of the active compound in the intestinal tract. It depends on the duration.

In particular, the weight ratio of the surfactant to the active compound and the total amount of the surfactant used are determined by the chemical and physical properties of the surfactant, the form and amount of the active compound and the desired duration of release of the active compound in the carrier and other pharmaceutical diluents and carriers contained. Depends on.

In particular the weight ratio of the surfactant to the active compound and the upper limit of the total amount of the surfactant used, as well as the physiological tolerance and compatibility of the surfactant (or surfactants, if present) and also the planned duration and frequency of administration Thus depends.

The weight ratio of surfactant to active compound in the mixture may be about 0.2: 1 to 2: 1, preferably about 0.3: 1 to 1: 1. In particular, when the surfactant is used in the form of a salt of a monosulfuric acid ester of alkanol, for example sodium lauryl sulfate, the active compound is preferably the above-described indolin derivative and the weight ratio of the surfactant to the active compound is about 0.25: 1. To about 1: 1, in particular about 0.4: 1 to about 0.7: 1.

In addition to the surfactant, it may further contain physiologically acceptable substances. Thus, solid pharmaceutical binders and diluents may be selected to be uniformly controlled over time. The binder and diluent preferably form a matrix in the digestive tract and substantially do not disintegrate in the intestinal fluid, or disintegrate slowly. Examples of such binders and diluents include, but are not limited to, physiologically acceptable calcium salts such as calcium sulfate or calcium hydrogenphosphate dihydrate: cellulose derivatives such as ethylcellulose; Synthetic polymers such as polyvinylacetate and polyvinyl chloride; And copolymers of vinyl pyrrolidone and vinyl acetate; Or mono-, di- or triglycerides of natural, synthetic and semi-synthetic fats such as palmitic acid and stearic acid; Hydrogenated castor oil and wax; Higher fatty alcohols such as cetylstearyl alcohol DAB7.

Otherwise the binder and diluent may be dissolved in the intestinal fluid, for example, physiologically acceptable lactose, mannitol and other sugars; Polyvinylpyrrolidone; And polyethylene glycol.

"Soluble" also means physiologically acceptable substances that are readily dispersed in serous fluids.

Other physiologically acceptable substances may be included, for example, talc and lubricant agents such as magnesium stearate.

It is convenient for the physiologically acceptable substance to contain a mixture of substances which are insoluble in serous on the one hand and substances which are dissolved in the serous on the other. The weight ratio of insolubles to solubles is highly dependent on the amount, physical and chemical properties of the active compounds and surfactants originally used, and also on the desired period of time for the release of the active compounds.

When administered in the form of the final formulation, the mixture is delivered substantially undamaged to the intestine and then rapidly exposed to the intestinal fluid, and the active compound is released from the intestine over 40 to 80%, for example 50% over 1 to 7 hours. In order to release evenly, suitable weight ratios of insoluble materials [eg, insoluble binders, diluents and lubricants] to soluble materials [eg, soluble binders, diluents and surfactants including component ii) are generally from about 1: 5 to about 5. 1: 0.3.

In particular, when the active compound is the above-described indolin derivative and the surfactant is sodium lauryl sulfate, the ratio of insoluble substance to soluble substance is about 1 in order to release about 40% of the active compound evenly in the intestine over 1 to 4 hours. : 3 to about 1: 1.5 are suitable.

According to a particularly preferred aspect of the invention, the mixture of the active compound i) and the surfactant ii) is a core tablet coated with a physiologically acceptable film which does not disintegrate in gastric juice but disintegrates in intestinal fluid.

The choice of film-forming material and its thickness depends, of course, on the solubility of the active compound, the surfactant and the active compound-surfactant complex. Generally polymers are suitable. Such polymers may be selected such that the film dissolves at pH 5-8, preferably pH 5-7 in the digestive system within about 1/4 to 2 hours, preferably 1/2 to 1 hour. The film is preferably insoluble at least 3 hours in artificial gastric juice (US Pharmacopoeia) at pH 5 or below.

Such films may be selected from known macromolecular polymers used to prepare unit dosage forms that are resistant to gastric juice but dissolve in the small intestine.

Suitable polymers are listed in the following literatures and include, for example, cellulose ester derivatives, methylacrylate copolymers and acrylic resins such as copolymers of maleic acid and derivatives. Hagers Hand buch der pharmazeutishen praxis, 4th edition , vol. 7a, pages 739 to 742 and 776 to 778 (Springer Verlag, 1971) and Remington's Pharmaceutical Sciences, 13th edition, pages 1689 to 1691 (Mack Publ, Co., 1970)].

Preferred films include cellulose acetate phthalate; Copolymers derived from methylacrylic acid and esters thereof containing at least 40% methylacrylic acid; And especially from hydroxypropyl methylcellulose phthalate.

The thickness of the film may depend on the permeability of the film to water and acid. The thickness of the film layer is preferably about 5 to about 100 mu m, particularly about 20 to 80 mu m. In general, however, the weight of the film should not exceed 15% of the coated core tablet, with 3-10% of the coated core tablet being preferred.

The film may enclose a large amount of individual pellets and granules each containing the active compound i) and the surfactant ii) in at least one pharmaceutical carrier or diluent. Otherwise the film surrounds the core tablet with the evenly dispersed active compound i) and the surfactant ii).

In addition, it is preferable to formulate in unit dosage form in which the active compound i) is released into acidic gastric fluid from an external drug layer containing an active compound, pharmaceutical carrier or diluent soluble in gastric fluid. This active compound is rapidly absorbed through the stomach wall so that the active compound can quickly reach an initial high concentration in the blood. The concentration of the active compound in the blood can be maintained by the continuous release of the active compound from the core tablets in more alkaline intestinal fluids.

Thus, for example, the film coating can be coated with a drug layer. The weight ratio of the aryloxyalkanolamine in the core tablet covered with the film and the aryloxy alkanes amine in the drug layer outside the film is, for example, about 0.75: 1 to 1.25: 1 example, 1: 1).

In some cases, other pharmacologically active compounds may be contained therein, especially when an external drug layer is used. Such agents include compounds that affect the heart and circulation, such as antihypertensives, diuretics, α-blockers, especially persistent diuretics.

Thus, aryloxy alkanol amines, such as 4- (2-hydroxy-3-isopropyl aminopropoxy) -indole, are persistent diuretics, for example 2-methyl-3-0-tolyl-6-sulfamyl-7 -Chloro-1, 2, 3, 4-tetrahydro-4- (3H) -quinazolinone or a pharmaceutically acceptable salt thereof, e.g. the latter in the outer drug layer It may be contained.

The outer layer comprises a large amount of individual granules or pellets containing the active compound (s) in at least one pharmaceutical carrier or diluent each soluble in serous fluid. The outer layer can also be surrounded by drug core tablets coated with a large amount of film. However, it is preferable that the outer layer surrounds the drug core coated with only one film. The weight of the surfactant contained is conveniently about 1 to 30%, preferably 1 to 10% of the pharmaceutical composition or drug core tablet, if one is present.

If the pharmaceutical composition is in unit dosage form, the total amount of surfactant is generally less than 50 mg.

Compositions according to the present invention can be prepared by conventional methods. Thus, for example, component i) may be mixed with component ii) and pelleted or granulated, for example using conventional wet or dry methods, and the resulting pellets or granules may be compressed to give a core tablet, or granulated or Direct compression without pelleting is formulated into a suitable pharmaceutical formulation.

As already pointed out, a preferred embodiment is to coat the mixture with a film that does not disintegrate in gastric juice but disintegrates in intestinal fluid. Such films can be applied to the mixture of components i) and ii) in a conventional manner, for example as a solution thereof at 10 ° to 60 ° C.

The following examples illustrate the invention. The materials used in the examples are all conventional materials used in the pharmaceutical field. In particular, an example of hydroxypropyl methylcellulose phthalate is HPMCP HP 50 (registered trademark, shinetsu chem. Co., Tokyo), and an example of ethyl cellulose is Etocell N (registered trademark, Dow Chemical Co., Midland, Michigan). , USA), and polyvinylpyrrolidone / polyvinylacetate is a macropolymer of vinylpyrrolidone and vinyl acetate (molar ratio 6: 4), and Rubiscol VA 64 (BASF, Ludwigshafen, W. Germany) Examples of microcrystalline cellulose are Avicel (registered trademark, FMC Corp., Marcus Hook, Palo Alto, US A), and examples of polyvinylpyrrolidone include collidone 90 (registered trademark, BASF, Ludwigshafen). have.

Precirol (registered trademark, Establis ements Gattefosse, St, Priest France) of palmate / stearic acid triglyceride mixtures, and examples of hardened pajama oil are cutina HR (Henkel, Dusseldrof, W. Germany).

Example 1 Sustained Release Tablet

Manufacturing method

The core tablets are prepared by mixing and granulating the components of the core tablets and compressing them using a 5 mm diameter spherical tablet die.

A 10% solution of hydroxypropyl methylcellulose phthalate (W / V) dissolved in ethanol / acetone (1: 1 V / V) is sprayed onto the core tablet to form a coating. The drug envelope is applied in a conventional manner, i.e., the shell active ingredient is mixed with the remaining skin ingredients except for the suspending agents (talc and magnesium stearate), the wet mass is granulated, and the lacquer is added to the film coated core tablets. Compress together to make tablets.

In a manner similar to that described in Example 1, it is possible to prepare a coated tablet containing the nucleation composition (50 mg) given in the following table.

The core tablets are coated with hydroxypropyl methylcellulose phthalate film (3 mg / tablet) and drug shell (157 mg / tablet) as described in Example 1.

In the processes used in Examples 1 and 1A to 1R, the active compound 4- (2-hydroxy-3-isopropyl-aminopropoxy) indole will replace an equivalent arylalkanol amine or aryloxy alkanes with amines. Can be.

Example 2 Sustained Release Tablet

It may be prepared by a method similar to that described in Example 1.

Claims (1)

4- (2-hydroxy-3-isopropyl-aminopropoxy) indole, 4- (2-hydroxy-3-isopropylaminopropoxy) -2-methylindole or salts thereof and C ₈ -C ₁₈ Nuclear tablets containing a mixture of physiologically toxic anionic surfactants of the monosulfuric acid ester group of fatty alcohols are coated with a film that is stable to gastric fluid but disintegrates above pH 5 and optionally coated with a drug layer that dissolves in gastric fluid. A method for preparing a pharmaceutical composition capable of controlling the release rate of an active substance in the intestinal tract, characterized by coating on the drug nucleus.