SI8710340A8 - Process for obtaining novel pharmaceutical composition consisting of layers, which assure controlled release of active compound - Google Patents

Description

The invention relates to the manufacture of novel pharmaceutical preparations ^J and particularly relates to a process for the preparation of a novel controlled release drug preparation of a pharmaceutically active compound.

Τθίϊϊϊί2? £ ί_ΕΪ 2Ϊ2ΐθ? Ϊ

The invention solves: solves the problem of realization of pharmaceutical preparation with delayed, constant, controlled release of the active ingredient.

In the medical treatment of various diseases, e.g. cardiovascular gastrointestinal and chemotherapeutic areas, is anterior to when a constant concentration of the drug is administered in the blood. Therefore, controlled release of the drug from the pharmaceutical 'preparation is required.

It is important that controlled release preparations deliver the required amount of drug to maintain an adequate and equal effect throughout the therapeutic dosing interval. This usually means that the drug must be given at a constant rate in order to. achieved equal concentrations of the drug given in the blood, which is of particular importance for drugs that have low therapeutic indices,

i.e. little difference between effective and toxic concentration. Delayed and constant release of the drug will also be important in the code. local irritation checks that are spared by the potential risk of gastrointestinal disorders when given ύ high local concentrations or for drugs that have a short elimination half-life. In the latter case, it is less frequent to administer and thus better adjust the patient (cf.Haves R.B. et al.

Ciin.Pharm.Therap. (1977), 22, pp. 125-130) can be achieved with controlled release preparations as compared to conventional dosage forms.

The drug can be administered in a controlled manner via _; - any. in the administration route, but preferably the preparations should have a clear, common, e.g. to give a controlled and reproductive release of the drug ji ' _t ·. ..... · '-:' v ** ϊΆ-7 '/ * (' and because of the reductive absorption, that it is not toxic 'or - irι-tire. South j' · * · -7 · '·· - · '' •• all ingredients and to be suitable; for high dose medicines ^! '-''U-Uk-sj -J i'. <I:?} 0 j ;;:;

and je_tehnike

Examples of controlled release drug delivery systems for the oral administration are e.g. sustained release type insoluble matrix tablets such as Durules and an osmotic R R active tablet, OROS. The OROS system is described in U.S. Patent 4 036 227 and in the British Journal of Clinical Pharmacology (1985), 19, 69S-76S by Theeuwes F et al. It consists of a tablet core made up of a drug substance as a major constituent surrounded by a semi-permeable polymer membrane through which small openings are drilled. DE-A-2030501 describes a matrix type preparation containing amorphous silica. The active compound is released by diffusion through the matrix. The above examples are single-unit systems with their drug substance concentrated in one unit, while the present invention is multi-unit.

GB-A-1542414 discloses a composition comprising an organic carrier material for which the active compound is physically or chemically bound and a glassy material in contact with said carrier material. Glass contains soluble metal ions. The release of the drug is guided by the dissolution of the metal ions from the glass material through the ion exchange process. Obviously, glass is not an insoluble inert compound in the preparation.

Several advantages with depot preparations include the large number of small units described in the literature. It is, for example, 'that it is possible to obtain reproducibility of emptying units from the stomach into the small intestine when the fragments are less than 1-2 mm (cf.Bogentoft C. et al: Effect of food on the absorption of acetylsalicylic acid from internally coated dosage forms. Europ. J.Ciin.Pharmacol. (1978), 14, 351-355). Dispersion over a large area in the gastrointestinal canal may give the total reproductive passage time in the evening, an advantage in the absorption process (cf.Edgar B. et al: Comparison of two internally coated acetylsalicylic acid preparations by monitoring constant levels of salicylic acid and its metabolites in blood and urine Biopharmaceutics & Drug Disposition, (1984), 5, 251-260). In addition, a multi-unit preparation is more appropriate than a single-unit preparation when the dose is distributed internally. The risk of local irritation and the accumulation of several doses due to contraction in the duct, the intake of the intentions is also considered to be low, (cf.McMahan * F.G.

et al; Upper gastrointestinal lesions after potassium chloride supplementation: Controlled clinical trial of The Lancet, Nov 13, 10591061).

A further advantage with a multiple unit preparation is that it can be divided into smaller portions, all of which have the same absorption properties. This allows for greater flexibility and selectivity for dose size.

Description_solving_technical_problems_of_example examples

The present invention relates to a process for the preparation of a new type of formulation that provides controlled release of one or more pharmaceutically active compounds.

The preparation consists of a large number of small insoluble particles, cores, which are coated with a pharmaceutically active compound. The cores are 0.1-2 mm in size, preferably 0.1-0.5 mm in size and consist of insoluble inert material. Insoluble means that the material is insoluble in water, saline fluids or liquids commonly used for intravenous infusion. Examples of insoluble inert materials are silica, or fragments of plastic resins. Suitable types of plastic materials are pharmaceutically acceptable plastics, such as polypropylene or polyethylene, preferably polypropylene. The core material should have i

standard size and shape, preferably spherical with a uniform surface. Preferably, the core material should have a sufficiently high density to allow the fluidization process.

Further, it is important that the core material has a high degree of purity, ie that it is free of soluble contaminating compounds.

The pharmaceutically active compound is applied to the core material by spraying from solution. The active compound thus forms a compact layer on the insoluble core. Pharmaceutically active compounds used are compounds with cardiovascular, gastrointestinal or chemotherapeutic effects, in particular adrenergic beta-blocking agents and antibiotics. Examples of suitable pharmaceutically active compounds which can be applied to the core material in the salts of alprenolol, metoprolol, quinidine, magnesium and ampicillin. The resulting fragments or layers have the size dd, ··

·. ^! k; i

0.2-3.0 mm, preferably 0.3-1.0 mm. It is possible, however, to form controlled release preparations according to the above method for most drugs for which such a preparation is required, provided that they can be dissolved in a solvent that can be dried during processing.

The layers according to the invention are compact, which means that their porosity is less than 15 percent.

The layers are coated with a polymeric membrane that modifies and controls drug release. The polymeric membrane can release the drug according to different release profiles, e.g. pH-dependent, inner liner, pH-independent, with or without time lag. The most significant application is pH-independent controlled release in the pH range of 1-8. Ptimers of suitable polymeric materials are ethyl cellulose, hydroxypropylmethyl cellulose, hydroxypropyl cellulose, hydroxypropylmethyl

R phthalate (e.g. HP 55), cellulose acetate phthalate, Eudragit RL,

R

Eudragit RS. Ethyl cellulose can be used alone or in combination with e.g. a water soluble polymer such as hydroxypropylmethyl cellulose to adjust the permeability of the coated layer.

Ethyl cellulose is available with varying degrees of viscosity.

In the examples below, the qualities of ethyl cellulose of 10, 50 or 100 cps were used, but other types of ethyl cellulose are also suitable.

R

Eudragit is the trade name for a large number of acrylic resin film coating substances manufactured by Rohm Pharma.E.g.

Eudragit RL and RS are copolymers synthesized from acrylic and meracrylic acid esters with a low content of quaternary ammonium groups. The molar ratio of these ammonium groups to the neutral residue n ((esters (meth) of acrylic acid is 1:20 for Eudragit RL and 1:40 for p

Eudragit RS resulting in different permeability characteristics. Other Eudragit variants that can be used are Eudragit L, Eudragit S and Eudragit E.

Pigments and / or plasticizers may be added to the polymer solution to improve the technical properties of the membrane or to modify the release characteristics. Examples of plasticizers that may be used are citrate esters, acetylated monoglycerides, and glycerin triacetate.

The new composition obtained by the process of the invention has several advantages, such as that, for example, delides containing a high percentage of the active ingredient are not contaminated with soluble inert compounds, which is the case when nuclei, e.g. lactose or shader coated with a therapeutically active compound.

This is especially important when the preparation is used for parenteral administration.

By using a low-density delide e.g. silica as the core material, it is possible to obtain layers (granules) of high concentrations of the active compound, which is advantageous in high-dose preparations, e.g. magnesium chloride.

An advantage with the new preparation is that less polymeric material is usually required to achieve delayed drug release when an active compound is applied to the insoluble core as compared to preparations having a soluble core coated with the active compound (cf.Figure 1). The composition of the invention can be administered in various ways, e.g. orally or parenterally. An example of intravenous administration is the intravenous drug delivery device described in EP-B1-59694.

When coated layers of the active compound of the present invention are used for oral administration, it is possible to form a preparation in the form of granules which are dipped into hard gelatin capsules, filled into casings or formed into tablets, while still providing the desired blood concentration profile and effect duration after administration.

When small layers are tableted, they are mixed with additives containing e.g. microcrystalline cellulose, such as Avicel, which improves tableting properties and facilitates tablet disintegration to release individual layers.

The invention makes it possible to obtain a reduced frequency of dosage, while maintaining a near constant concentration of the drug in the blood over the entire period until the next dose is given. often, with a new preparation, only one dose per day is sufficient.

P '

In the process for the manufacture of controlled release preparations of the present invention, the pharmaceutically active compound is dissolved in a suitable solvent, e.g. methylene oxide, ethanol, isopropyl alcohol or water and sprayed over a core of insoluble material in a coating tower or. preferably in a fluidized bed and the solvent is dried. The resulting layers are then coated with the polymer layer described above. The polymer mixture is dissolved in a solvent such as ethanol, isopropyl alcohol and / or methylene chloride. Spraying may be carried out in a coating tower, but preferably in a fluidized bed. Ethyl cellulose can also be applied from aqueous dispersion (latex).

The composition obtained by the process of the invention is particularly suitable when seeking the controlled and constant release of a therapeutically active compound.

The invention is described in detail in the following examples:

EXAMPLES

Example 1

The nucleus

Metoprolol fumarate

Methylene chloride

Ethanol 95%

SiC ^ (0.15-0.25 mm)

Polymer layer

Ethyl cellulose 10 cps Hydroxypropylmethyl cellulose Acetyltributylcitrate Methylene chloride

Isopropyl alcohol

1440 g 9618 g 3888 g

375 g

265.6 g 58.4 g 36.0 g 6241 g 1544 g

In the fluidized bed granulator, metoprolol fumarate was sprayed over 95% ethanol silica cores. 400 g of the layers thus formed (0.4-0.63 mm fraction) were coated with ^ nd 'and »· ............ and with a polymer solution containing ethyl cellulose 107hps.,: Ii ^;,; '^; . i.- ../J7f;·.·,·. .3 / -

hydroxypropylmethyl cellulose and acetyltributyl citrate, spray; solutions of the said substances in methylene chloride and isopropyl alcohol. The coated layers were then filled with foot capsules. Examples 2-3 and Reference 1 in solid want- The nucleus 2 3 Reference 1 Metoprolol succinate 1440 Mr Rücker 1440 g 1440 g Methylene chloride 9618 Mr Rücker 9618 g 9618 g Ethanol 95% 3888 Mr Rücker 3888 g 3888 g SiC> 2 (0.15-0.25 mm) Continuous (0.2 mm) 375 Mr Rücker 375 g NaCl (0.15-0.25 mm) 375 g Polymer layer 400 g granules (fraction 0.4- 0.5 mm) as above, are coated with a preparation that includes Ethyl cellulose 10 cps 52.3 Mr Rücker Acetyltributylcitrate 8.6 Mr Rücker Methylene chloride 1111 Mr Rücker Isopropyl alcohol 218 Mr Rücker

Metoprolol succinate was sprayed over silica, glass, and sodium chloride nuclei, respectively, from a solution of 95% ethanol and methyl: chloride. The formed layers were coated with a polymer solution containing ethyl cellulose 10 cps and acetyltributyl citrate dissolved in methylene chloride and isopropyl alcohol by spray. Figure 1 illustrates the cumulative release of metoprolol succinate over 20 hours. As can be seen from the drawing, controlled and almost constant release of the active compound is achieved when the active compound is applied to a silicon dioxide or glass core, while the sodium chloride soluble core results in a significantly higher initial release rate, which is also illustrated in Figure 2 (Reference 2 below), where potassium chloride solution was used as the core material.

I

Reference 2

The nucleus

Metoprolol sukclnat 2000 g

KC1 (0.1-0.2 mm) 400 g

Methylene chloride 13360 g

Ethanol 95%; 7900 g

400 g of granules according to Reference Example 2 was coated with the preparation comprising

Ethyl cellulose 10 cps Eudragit ^ RS. 135.3 g 27.4 Mr Rücker Acetyltributylcitrate 27.4 Mr Rücker Methylene chloride 4469 Mr Rücker Isopropyl alcohol 661 Mr Rücker

The granules were formed as described in the foregoing examples. Examples 4-6

Core Example

4 5 6 Metoprolol succinate 1440 Mr Rücker 1440 Mr Rücker 1440 Mr Rücker Methylene chloride 9618 Mr Rücker 9618 Mr Rücker 9618 Mr Rücker Ethanol 95% 3888 Mr Rücker 3888 Mr Rücker 3888 Mr Rücker SiO2 (0.15-0.2 mm) 375 Mr Rücker SiC> 2 (0.25-0.3 mm) 375 Mr Rücker Si02 (0.4-0.5 mm) 375 Mr Rücker

400 g of the granules of Examples 4-6 were coated with the preparation comprising

granules according to examples 4 5 6 Ethyl cellulose 1- cps 187.2 Mr Rücker 144. o g 92.2 Mr Rücker Hydroxypropylmethyl cellulose 46.8 Mr Rücker 36. 0 g 23.0 Mr Rücker Acetyltributylcitrate 26.0 Mr Rücker 20. 0 g 12.8 Mr Rücker Methylene chloride 4428 Mr Rücker 3408 Mr Rücker 2168 Mr Rücker Isopropyl alcohol 1114 Mr Rücker 858 Mr Rücker 546 Mr Rücker

- 9 Preparations are formulated as described above. In the annexed Table 1, the release of metoprolol succinate is given for 20 hours. All preparations gave controlled release of the drug over a long period of time.

Example 7

The nucleus

Magnesium chloride, hexahydrate 1100 g Ethanol 99.5% 6200 g Silica (0.15-0.30 mm) 400 g Polymeric layer

Ethyl cellulose 50 cps 533 g Methylene chloride 14107 g Isopropyl alcohol 5481 g

Magnesium chloride (MgCl ₂ ) was sprayed over silica nuclei from 99.5% ethanol solution. 400 g of the layers thus formed were coated with ethyl cellulose 50 cps from a solution of methylene chloride and isopropyl alcohol to give granules containing 347 mg / g of magnesium chloride (MgCl ₂ ). In vitro drug release was 38% after 1 h, 58% after 2 h and 82% after 6 h.

Example 8

The nucleus

Ampicillin -On 600 g Ethanol 95% 894 g Purified water 1020 g Glass (0.5 mm) 500 g

Ethyl cellulose 100 cps 15 g Methylene chloride 600 g. Isopropyl alcohol 150 g

Ampicillin - Na is sprayed over glass cores and ethanol / water solution. 500 g of ampicillin-Na layers were then drawn with

- 10 polymer solution of ethyl cellulose 100 cps in methylene chloride / isopropyl alcohol. After 40 minutes of in vitro dissolution, 50% of the drug content was released from the layers.

Example 9

The nucleus

Metoprolol succinate

Methylene chloride

Ethanol 95%

SiC ^ (0.15-0.25 mm)

Ιθ 1

Ethyl cellulose N-10

Hydroxypropylmethyl cellulose Acetyltributylcitrate Methylene chloride Isopropyl alcohol

Tablet additives

Microcrystalline cellulose Corn starch Lactose powder Polividon Purified water Magnesium stearate

Tablets (12.500

Hydroxypropylmethyl cellulose Polyethylene glycol 6000 Color Titanium Dioxide Purified water Paraffin

1440 g 9618 g

3888 g 375 g

166.2 g 39.0 g. 22.8 g

3889 g 978 g

.. 429.3 g 67.1 g 40.3 g 55.5 g

314.7 g • 1.2 g ablet) cps' 159.6 g

39.9 g 39.9 g

1356 g 1.6 g

Metoprolol succinate was sprayed over silica cores according to the procedure described in the previous examples. 400 g of the layers thus obtained (0.4-0.63 mm fractions) were coated with the polymer solution described above. The coated layers of metoprolol succinate were mixed with the additives in equal amounts and after the addition of Mg-stearate 0.1%, the dry mixture was compressed into tablets.

i

Finally, the tablets were coated in a coating tower with the polymer solution described above.

Very small particles, 0.15-0.25 mm, of thick SiO ₂ used as core material, allows high drug content in the small layers that are formed (0.4-0.63 mm), thus reducing the size of the final preparation.

The plate 1 summarily shows the data on the liberation of medicament axle Examples 1-6 and 9 and Reference Examples 1 and 2. ^B is i2farniaceutske_studi

An oral administration of a preparation of the process of the invention (Example 9) is illustrated in Figure 3. A multi-unit system was applied to metoprolol succinate to obtain a once-daily dosage preparation with a profile of equal blood concentration for 24 hours.

One dose of 190 mg metoprolol succinate (equivalent to

200 mg metoprolol tartrate) in a controlled release formulation according to the present invention was administered to ten healthy male recipients. Plasma concentrations of metoprolol were compared with those of plasma after a single dose of slow-release tablet (R) Durules based on the insoluble matrix principle containing 200 mg metoprolol tartrate. As can be seen, the preparation according to the invention gave an almost constant concentration of metoprolol in the blood, while the matrix tablets gave an unwanted high peak in blood concentration during the first hours after administration.

The best way of carrying out the invention is now considered to be Example 9. f- '· -.....-

- 12 Table 1. Cumulative in vitro release of metoprolol in phosphate buffer at pH 6.8. Method: USP apparatus No.II, rotation at 100 rpm

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Dos.2038 H 809-1 YU 03/25/1988. P-340/87

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THE APPLICANT'S STATEMENT ON THE BEST KNOWLEDGE WAY FOR THE ECONOMIC USE OF THE APPLICATION FOUND

The nucleus

Metoprolol succinate

Methylene chloride

Ethanol 95%

SiO2 (0.15-0.25 mm)

Polyerone-Layer. I

Ethyl cellulose N-10

Hydroxypropylmethyl cellulose Acetyltributylcitrate Methylene chloride Isopropyl alcohol Tablet additives

Microcrystalline cellulose

Corn starch 'Lactose powder

Polividon

Purified water

Magnesium stearate

Tablet Coating (12,500 Tablets)

Hydroxypropylmethyl cellulose 6 cps

Polyethylene glycol 6000

Color Titanium Dioxide

Purified water

Paraffin

1440 g 9618 g

3888 g

375 g

166.2 g 39.0 g

22.8 g

3889 g

978 g

429.3 g 67.1 g 40.3 g 55.5 g

314.7 g 1.2 g

159.6 g

39.9 g 39.9 g

1356 g 1 .6 g

Metoprolol succinate was sprayed over silica cores according to the procedure described in the previous examples. 400 g of the layers thus obtained (0.4-0.63 mm fractions) were coated with the polymer solution described above. Coated layers of metoprolol • acc.Lnat was mixed with additives in equal amounts and after the addition of Mg-stearate 0.1%, the dry mixture was compressed into tablets. and,:, ': heard, the tablets were coated in a drag tower from above or?:;. o.im polymeric solution. : ..,

Claims (7)

1. A process for the age of January is a novel preparation consisting of layers that provide a controlled release of - - Rai, which is a pharmaceutical active substance, but the compound dissolved in the solvent is applied to a core of insoluble matter-1a in size 0.1-2 ram. 'the solvent dries to give layers coated with a compact layer of active compound 0.2-3.0 mm in size, after which the resulting layers are further coated with a polymeric membrane for controlled release. ' Method according to claim 1, characterized in that the material or core has a size of-0.1-0-.5 mm and said material The core coated with the pharmaceutically active compound has a size of 0.3-1.0 mm. 3. The process of claim 1, wherein the core material is silicon dioxide. A method according to claim 1, characterized in that the core material represented by j is divided by insoluble inert glass of size '0.1-2 mm'. 5. The method of claim 1, wherein the core-coated layers comprise a pharmaceutically active compound for which instantaneous drug release is not desired. ' 6. The method of claim 1; characterized in that it is a pharmaceutically active compound of an adrenergic beta-blocking agent. The method of claim 1, wherein the pharmaceutically active compound is an antibiotic.