SI8710339A8 - Process for obtaining pharmaceutical composition of metoprolol with controlled release - Google Patents

Description

PROCEDURE FOR THE PREPARATION OF ^ PREP ^ RftTA ^ STnCONTROLTED RELEASE

The invention relates to the preparation of new pharmaceutical products, and in particular relates to a process for the preparation of metoprolol controlled release preparations. The preparation- manufactured according to the invention is used for the treatment of cardiovascular diseases.

The invention solves the problem of obtaining a preparation that provides an equal concentration of drug in the blood thanks to controlled release, and is given only once a day.

State of the art

Metoprolol, which has a structural formula

is known from e.g. DE-2 106 209. A drug that is a beta-adrenoceptor antagonist is preferably used as a salt, e.g. tartrate.

Metoprolol blocks adrenergic stimulation of the heart and thus reduces the requirement of cardiac tissue for oxygen. Obviously, this explains its beneficial effects in angina and cardioprotective action in myocardial infections. In addition, metoprolol norm. lyses blood pressure in a large number of patients with arterial hypertension, which is probably the result of an additional effect on the control of peripheral resistance to blood flow.

For patients suffering from cardiovascular disorders, it is preferable to have a constant concentration of the drug administered f Controlled release is therefore desirable. of medicine during idGž ^ g'A ^ brib'dai <gi;. ^ nena

According to the most common method of treatment, the patient is given ^ pov.jed-najKtah.lgfee.

You wanted; 331-970. 34S-; S3 ko-ia dissolves rapidly twice anew. It gives Dramatic.eruγη i

concentrations with high peak and down wave values when using the drug during the day.

For once-daily dosing, metoprolol was administered in controlled release type tablets with insoluble matrix, eg Durules ¹ *. However, the release of the drug from the matrix tablets is not satisfactory as about 50% of the dose is released within hours after administration. Therefore, a request was made to find a way to obtain a drug preparation having a more constant controlled release of the active component over about 20-24 h, whereby more uniform blood concentrations and effects would be obtained for the entire dosing interval.

A drug release system called Oros ^ can be used to obtain controlled release e.g. metoprolol for one daily dose. The system is described in U.S. Patent 4 036 227 and attached to the British Journal of Clinical Pharmacology · (1985), 19, 69S-76S by Theeuwes F. et al. Oro ^^ is a system of one unit and consists of an osmotically active nucleus, consisting mainly of a drug substance wrapped in a sempermeable membrane through which only a small opening is drilled. The release of the drug from the system is constant as long as a constant osmotic pressure is maintained on the membrane. 50-60% of the total drug content is released at a constant rate.

It is proposed in SE-A-8400085 to make one inner coated product, containing e.g. metoprolol, and with the slow release of the active compound near the colon. Such a preparation does not provide a constant and slow release of metoprolol independently of pH, which the preparation of the present invention provides.

Depot preparations consisting of a large number of small units are also known from EP 13263. This patent describes a pharmaceutically indifferent core coated with an active compound. The nuclei are a way of dissolving material, e.g. lactose. .

Depot preparations containing a large number of small units, each of which releases the drug at a controlled rate, are preferred over depot preparations consisting of one small unit, e.g. matrix tablets or wrapped tablets controlling release. For example, it is possible to obtain reproductive emptying of units from the abdomen when fragments smaller than 1-2 mm are used. Cf.Bogentoft

- ret al .: Effect of food on the absorption of acetylsalieic acid from internally-coated dosage forms. Europ J Ciin Pharmacol 1978, 14, 351-355. Dispersion over a large area of the gastrointestinal canal gives the evening total reproductive passage time which is favorable for absorption. Cf.Edgar B, Bogentoft C and Lagerstrom PO: Comparison of two acetylsalicylic acid internally-coated preparations by monitoring steady-state levels of salicylic acid and its metabolites in plasma and urine. Biopharmaceutics & Drug Disposition 1984, 5, 251-260. In addition, multiple unit dose preparations are more appropriate than a single unit dose formulation since the dose is dispersed in the intestine. The risk of local irritation and the accumulation of several doses due to contraction in the alimentary canal is also significantly lower.

A further convenience. with a multiple unit preparation it 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.

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The invention relates to a process for the preparation of a composition comprising metoprolol as an active ingredient and having a controlled rate of drug release for at least 15 h. By making a preparation containing a large number of small compact particles, each containing metoprolol salt as the main solubilizing component and coated with a polymeric membrane containing cellulose derivatives without protolyzable groups, it is possible to prepare suitable dosage forms which have. controlled release rate of metoprolol, completely pH independent, for about 16 to 24 hours.

Little bits, layers. containing metoprolol have a size of 0.25-2 mm, preferably 0.35-1.0 mm.

The layers may contain metoprolol alone or may consist of an insoluble core coated with metoprolol. The layers have a very high metoprolol content, preferably 95-100 w / w% of the soluble part of the layers. The insoluble nucleus has a size of | ΰ. 1-1 .0 'mm, preferably 0.15-0.3 mm. Examples of insoluble cores of the invention are silicon dioxide and small particles of glass. -jr. in.; ··· - · *.

The layers used in the post-feupe preme 'invention are compact, meaning that their porosity is less than 15 percent.

As can be seen from FIG. 1, the new preparation obtained by the process of the invention is characterized in that at least 75% of metoprolol is released within 20 h and at least 50% of the metoprolol dose is released at a rate of 3-7 m / m% / h.

The metoprolol used in the preparation may be in the form of a racemate, or one of the enantiomers or S-isomers. (Preferably, the S-isomer concentration should be at least 95% relative to the R-form).

Suitable metoprolol soluble salts have a solubility of less than 600 mg / ml in water at 25 ° C, preferably 30-600 mg / ml in water at 25 ° C. Examples of suitable salts are salts formed from organic carboxylic acids, preferably of lower molecular weight. Particularly preferred salts are succinate, fumarate or benzoate of racemic metoprolol and benzoate or sorbate of the S-enantiomer of metoprolol.

Highly soluble salts, e.g. tartrate, hydrochloride are less suitable according to the present invention.

Examples of suitable polymeric materials are ethyl cellulose or a mixture of ethyl cellulose with hydroxypropylmethyl cellulose, hydroxypropyl cellulose, Eudragit RL or Eudragit RS.

Ethyl cellulose is usable in variants of varying degrees of viscosity. According to the invention, it is advantageous to use ethyl cellulose with a viscosity of 10-50 cps, but other types of ethyl cellulose may also be used.

Eudragit- 'is the trade name for many acrylic resin film-coated substances manufactured by Rohm Pharma.

Eudragit RL | L RS are copolymers synthesized from acrylic and methacrylic 'acid esters with a low content of quaternary ammonium ·' groups. The molar ratio of these ammonium groups to the remaining neutral (meth) acrylic acid esters is 1:20 for Eudragit RL and 1:40 for Eudragit RS, resulting in different permeability characteristics.

Plasticizers and / or pigments may be added to the polymerscoat to improve the technical properties of the layer or

coatings. Examples of known plasticizers are citrate esters, acetylated monoglycerides, and glycerylthiriacetate, especially acetyltributyl citrate.

A polymeric membrane is made of one or more polymers which give a membrane with permeability characteristics completely independent of pH in the pH range of 1.0-8.0.

Each coated layer of metoprolol according to this invention forms a unit whose release is individually controlled, with the drug being released at a predetermined rate. Therefore, the coated layers according to the present invention allow for the formation and delivery of the preparation in various dosage forms. They charge the kioga in e.g. solid gelatin capsules or casings or compressed tablets and still give the desired concentration profile and duration of effect in the blood.

When small coated metoprolol particles are tableted, they are mixed with additives e.g. microcrystalline cellulose such as

Avicel · ^, which improves tableting properties and facilitates tablet desintetration, thereby releasing individual layers.

The invention allows the formulation of pharmaceutical dosage forms that can be administered once a day and still produce near-constant concentrations of the drug in the blood over the entire dosing interval until the next dose.

Getting it

The process for the manufacture of controlled release preparations will be described in more detail below. As the metoprolol-containing layers are first formed, the resulting layers are coated with the polymer layer described in the examples. The polymer mixture is dissolved in an organic solvent such as ethanol, isopropyl alcohol and / or methylene chloride. Spraying can be done in a coating tower, but preferably in a fluidized bed. Ethyl cellulose can also be applied from aqueous dispersion (latex).

The preparation obtained by the method according to the invention is particularly suitable for the treatment of cardiovascular disorders ^ V: -

The invention is described in detail in the following examples:

EXAMPLES

Example 1

Metoprolol fumarate

Methylene chloride

Ethanol 95%

Si02 (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 6141 g 1544 g

In the fluidized bed of the granulator, metoprolol fumarate is sprayed over a silica core from a solution of 96% ethanol. 400 g of the so-formed layers (granules) (0.4-0.63 mm fractions) were coated with a polymeric layer containing 10 cps ethyl cellulose, hydroxypropylmethyl cellulose and acetyltributylcitrate by spraying a solution of said substances in methylene chloride and isopropyl alcohol. The coated layers were then filled into hard gelatin capsules.

Example 2

Metoprolol succinate

Methylene chloride

Ethanol 95%

SiO- (0.15-0.25 mm) .I

Polymeric sldj

Ethylcellulose 50 cps

Hydroxypropylmethyl cellulose Acetyltributylcitrate Methylene chloride Isopropyl alcohol

1440 g 9618 g 3888 g

375 g

168.1 g 36.9 g 22.8 g 4167 g

815 g

Tablet additives

Microcrystalline cellulose ¹ 470.3 g Corn starch 117.6 g Potato starch 10.6 g Purified water 342.2 g Magnesium stearate 1.2 g

Metoprolol succinate was sprayed over silica gel core

and .. Th ”according to the procedure described in Example 1. 400 g of the thus-formed granules were coated with a polymer film containing ethyl cellulose 50 cps., hydroxypropylmethyl cellulose and acetyltributyl citrate. The additional tabletting mass was made by wet granulating a dry mixture of microcrystalline cellulose and corn starch with a 'solution of potato starch and water in a planetary mixer. Equal amounts (600 g) of active and additional granules were finally mixed with Mg-stearate 0.1% and compressed into tablets.

Example 3

Metoprolol succinate 100% in the form of compact spherical granules and with an average particle size of 0.42 mm

400 g of metoprolol sulccinate in granules with particles smaller than 0.63 mm were coated with

Ethylcellulose 10 cps

Hydroxypropylmethyl cellulose Acetyltributylcitrate Methylene chloride Isopropyl alcohol

The resulting layers were formulated in as described above.

177.1 g 38.9 g 24.0 g

4094 g 1029 g pharmaceutical preparations such as

Example 4

Metoprolol succinate Methylene chloride Ethanol 95%

SiO2 (0.15-0.25 mm)

1440 g 9618 g 3888 g

375 g

Polymer layer

Ethylcellulose N-10 166.2 g Hydroxypropylmethyl cellulose 39.0 g Acetyltributyl citrate 22.0 g Methylene chloride 3889 g Isopropyl alcohol 978 g Tablet additives

Microcrystalline cellulose 429.3 g Cornstarch 67.1 g Lactose powder 40.3 g Polividone 55.5 g Purified water 314.7 g Magnesium stearate 1.2 g

Tablet Coating (12,500 Tablets)

Hydroxypropylmethyl cellulose 159.6 g Polyethylene glycol 6000 39.9 g Titanium dioxide color 39.9 g Purified water 1356 g Special paraffin 1.6 g

Metoprolol succinate was sprayed over silica cores according to the procedure described in Examples 1 and 2. 400 g of the layers thus formed (0.4-0.63 mm fractions) were coated with the polymer mixture also described above. Coated layers of metoprolol succinate which are also. they were mixed with the additives in equal amounts and after the addition of 0.1% Mg stearate, the dry mixture was compressed into tablets. Finally, the tablets are coated in the tablet coating tower described above.

Example 5 j: *

S-enantiomeric metoprolol sorbate in the form of compact spherical granules in fractions 0.4-0.63 mm g of metoprolol sorbate in granules with particles smaller than 0.63 mm together with 360 g of non-pareil granules with particles between 0.75-1.Omm was coated with

Ethylcellulose 10 cps

Hydroxypropylmethyl cellulose Acetyltributylcitrate Methylene chloride Isopropyl alcohol

51.7 g 11.3 g

7.0 g

1194 g 300 g

The resulting layers were formulated into pharmaceutical preparations as described above. . <4

Biopharmaceutical study

Concentrations of metoprolol in blood after one dose of controlled release preparation containing 190 mg of metoprolol succinate according to example 4 of this description and blood concentrations after one dose of Durulei containing 200 mg of metoprolol tartrate are shown in the accompanying drawing 2. 190 mg of succinate salt is equivalent to 200 mg metoprolol tartrate. Comparisons were made on 10 subjects. Each point represents the mean of 10 subjects. As can be seen, the composition of the invention provides a nearly constant concentration of metoprolol for more than 20 hours, while the insoluble matrix-based preparation gives an undesirably high blood concentration during the first hours after administration.

Reduction of heart rate of subjects received once daily tablet containing 100 mg of metoprolol tartrate and decrease of heart rate on day 5 of treatment was measured and compared with decrease of heart rate on day 5 of subjects receiving the controlled release preparation according to example 4 of the invention, containing 95 ml of metoprolol succinate (equivalent to 100 mg of metoprolol tartrate). The decrease in heart rate is illustrated in the drawing

3. As can be seen, the composition of the invention has a pharmacodynamic effect over 24 hours.

The best way of performing the invention is to be considered as exemplified by Example 4.

Table I illustrates the in vitro release of metoprolol from the preparation of Examples 1-4. As can be seen from the table, at least 50% of the metoprolol dose is released at a rate that varies between 3-7 m / m% / h

- 10 o

CM - cO oo oo

O Ό

Ca) 00 oo co

CO., LTD

CM r *. oo «r cm

P ** co

Table 1. Cumulative in vitro dissolution of metoprolol in phosphate buffer pH Method: USP apparatus No.II, rotation at 100 o.p.m.

CO eJO

CM (0

C

OJ

• n

C (0 • o

Ό (0 «

O + J c

OJ u

o u

&

oo co co

CM * 3 \ o p>% r *. co co ρά σ> oo o

CO CO CO., LTD

CM cn CM co to m

CM O «3m m« 3cn o

CO »a- CO tO O p>.

CM CM CM en

Γά

CO CO CM

CM r— Well

co σ> i co i— ρά co «o

CM I co

CO. Well

Sr · sr co and co

CO <-

CM CM oo

Pa CO I co pa «3-

-r, L '

Dos.2037

K δϋ'ί-1 YU

20.02

P-339/87

THE APPLICANT'S STATEMENT ON THE BEST OF ITS PG3NOTH WAY FOR THE ECONOMIC USE OF THE APPLICATION FOUND

Metoprolol succinate

Methylene chloride

Ethanol 95%

SiO ₂ (0.15-0.25 nun)

Polymer layer

Ethylcellulose 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)

1440

9618

3888

375 g

g g

166.2 g

39.0 g

22.0 g 3889 g 978 γ g

429

314 g

g 3 g 5 g 7 g g

Hydroxypropylmethyl cellulose 159.6 g

Polyethylene glycol 6000 39.9 g

Titanium dioxide color 39.9 g

Purified water 1356 g

Special paraffin 1.6 g

Metoprolol succinate was sprayed over silica cores according to the procedure described in Examples 1 and 2. 400 g of the layers thus obtained (0.4-0.63 mm fractions) were coated with the polymer mixture! which is also described above. The coated layers of metoprolol succinate also obtained were mixed with the additives in equal amounts and after the addition of 0.1% Mg stearate, the dry mixture was compressed into tablets. Finally, the tablets are coated in a coated tablet for the tablets which are described herein.

Claims (13)

PATENT REQUIREMENTS: Ί A process for the preparation of a controlled release metoprolol pharmaceutical composition of the active component continuously for a period of at least 15 hours without affecting the pH of the gastrointestinal tract, wherein a plurality of particles comprising at least 95 m / m% metoprolol salt with solubility are included below 600 mg / ml in water at 25 ° C, spray coating the membrane-forming solution to form a polymeric membrane containing cellulose derivatives, preferably ethyl cellulose, to obtain the product with the release of the active component at a rate of 3-7 m / m% / h. Method according to claim 1, characterized in that the particle dimensions are in the range of 0.25-2 mm. Method according to claim 2, characterized in that the particle dimensions are in the range of 0.35-1.0 mm. 4. The method of claim 1, characterized in that the metoprolol salt has a solubility of 30-600 mg / ml. 5. The process of claim 4, wherein the salt is formed with an organic carboxylic acid. 6. The process of claim 5, wherein the metoprolol salt is succinate or fumarate of racemic metoprolol. The method of claim 5, wherein the metoprolol salt is benzoate or the s-enantiomer of metoprolol. The process of claim 1, wherein the uncoated layers comprise a metoprolol salt applied to the insoluble core. time, time, time, what time, what time, what A method according to claim 8, characterized in that the insoluble cores have dimensions of 0.'1-1.0 mm, preferably 0.150.3 mm. 10. The method of claim 8, wherein the insoluble cores have a size of 0.15-0.3 mm and are coated with a metoporlol salt to give layers of size 0.35-1.0 mm which are overcome by the polymer membrane. 11. The method of claim 1, wherein the uncoated layers have dimensions of 0.35-1.0 mm of the metoprolol salt per se and are coated with a polymeric membrane. -U 12. The method according to claim 1, wherein the polymeric membrane is composed of ethyl cellulose. 13, The method according to claim of the polymer membrane is composed of xy propylmethyl cellulose. 1, indicated by ethyl cellulose n thereby, together with hydro