CS332091A3 - Retarded forms of alpha-/2,5-dimethoxyphenyl/-beta-glycinamido-ethanol and process for preparing thereof - Google Patents

Abstract

1. Claims for the Contracting States : BE CH DE FR GB IT LI LU NL SE Oral sustained-release forms of alpha-(2,5-dimethoxyphenyl)-beta-glycinamidoethanol (midodrin) in the form of solid shaped pharmaceutical articles, produced by compressing, and consisting of the active compound, a polymeric support material and, if appropriate, auxiliaries and additives customary in pharmaceutical formulation, characterized in that the sustained-release form contains 1 to 15 parts by weight of poly-D(-)-3-hydroxybutyric acid having a molecular weight of at least 50,000 and a selected particle size fraction in the range from 0.05 to 0.6 mm to one part by weight of alpha-(2,5-dimethoxyphenyl)-beta-glycinamidoethanol in the form of the hydrochloride (midodrin hydrochloride) in a homogeneous mixture. 1. Claims for the Contracting State : AT Process for the preparation of oral sustained-release forms of alpha-(2,5-dimethoxyphenyl)-beta-glycinamidoethanol (midodrin) in the form of solid shaped pharmaceutical articles, produced by compressing, and consisting of the active compound, a polymeric support material and, if appropriate, auxiliaries and additives customary in pharmaceutical formulation, characterized in that the active compound alpha-(2,5-dimethoxyphenyl)-beta-glycinamidoethanol in the form of the hydrochloride (midodrin hydrochloride) is mechanically mixed in a weight ratio of 1:1 to 1:15 with poly-D(-)-3-hydroxybutyric acid having a molecular weight of at least 50,000, which has been obtained from the fermentation product in a selected particle size fraction in the range from 0.05 to 0.6 mm by grinding and sieve analysis, homogenized and compressed to give shaped pharmaceutical articles, if appropriate with the addition of auxiliaries and additives customary in pharmaceutical formulation, under a pressure of 0.1 to 10 tonnes/cm**2 , corresponding to 9.81 to 981 N/mm**2 .

Description

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Field of the Invention

The present invention relates to oral retarded phosphatase (2,5-isethoxylphenyl) -3-glycamidoethanol (kidcdrin) and is produced by the process. 1 " retarded formulations are press molded dosage forms containing polysilicates having a molecular weight and selected particle size as the carrier material and, after oral administration, releasing the active ingredient in a controlled manner in the stomach intestinal tract.

BACKGROUND OF THE INVENTION In the case of midodrine (alpha- (2, p-liraethoxylphenylsincinolidoethanol) and its hydrochloride, it is an active substance known for years (Dn-PS 1493917). ® has been confirmed by clinical tests many times, kidodrine hydrochloride has a selective effect on peripheral o -receptors and is an area of use unlike other known oocyte-α / β-receptor agonists. For example, hypotonic infections, convalescence, surgery and delivery, hypotonic lability in the onset of complaints of early and fever, or morning waking difficulties, have been reported to be of use. patients immediately after getting up in the first morning especially with hypotonic isymptoms such as dizziness and weakness, headache, inadequate to activity etc. ~ 0_

Therefore, the delayed forms of midodrine hydrochloride are particularly preferred and desirable, which provide an effective drug dosage on the eve so regularly and retarded that the therapeutic blood level will be maintained over a large interval overnight until the next morning, allowing patients to stand up without difficulty .

More recent investigations have led to the finding that administration of midodrine hydrochloride to patients suffering from the most severe forms of circulatory disorders, such as idiopathic orthostatic hypotonia or Syndragger's syndrome, represents in many cases the only effective medication treatment hitherto known (see, eg, Midodri, and the new agent of management of idiopathic orthostasis hypotention and Sh, y-Jrager syndrome by Alexander Schirner et al., Luayo Clin .Proc.Juli 1981 1981, vol. 56, p.429-433). As these patients with such clinical disease outcomes are dependent on long-term treatment with midodrine hygrochloride, reducing the number of daily drug intakes for these patients would be an improvement in their situation, which is significant for long-term medication.

On the basis of these obvious advantages of retarded form, dodrine hydrochloride is not lacking in its preparation.

For example, the pharmaceutical retarded forms may be formulated such that the active ingredient is formulated with excipients such that it is slowly released, e.g., by incorporation in an insoluble or slowly soluble matrix. When using these methods for midodrine hydrochloride, it has been found that, although known retention of the active substance can be achieved with known matrix systems such as cellulose derivatives, polyvinyl acetate, polyethylene, polyvinyl chloride or known polymethacrylate. the disadvantage is that in these retarded forms of midodrine hydrochloride, the release of the initial doses at the beginning of the medication is too slow. -3-

Author Krátko a rool., Ťharm.Ind. 1983, 45 (5, 5), suggesting that implant tablets composed of poles of HB and 7-hydroxyethylthiophane active compounds exhibit good retardation properties. In the preparation of retarded tablets of η π l 't' and ~ i In addition to the release of the active ingredient, the isocyanate is eliminated in the presence of a problem that has arisen, and the new drug base dose of the active compound required is applied. However, the production of such mixed dosage forms is technically very complex and regularly leads to undesired losses of the active ingredient.

SUMMARY OF THE INVENTION

The first was surprisingly found in the retarded form of midodrine hydrochloride in which a sufficient initial dose is released after administration directly from a suitable retarded form and which maintains a uniform level of midodrine hydrochloride in the blood for a long time. At the same time, these delayed forms have the advantage that they can be prepared in a simple manner in the form of conventional oral dosage forms, for example tablets, and that the above-mentioned disadvantages of the known matrix forms of the problem according to the invention do not occur when the dosage forms are reduced. the semidrin-hydrochloride is blended in a certain weight ratio with a sufficiently high molecular weight, poly-D (-) - hexavaline butyric acid produced by a sufficiently high molecular weight and defined by particle size and processed by compression molding.

The present invention relates to oral retarded forms of .alpha.1,5,5-dimethoxyphenyl) -2-glycine amidoetbanol (microcrystalline) in the form of a solid, by microbial process, by the production of medicaments. the obtained pol-3 (-) - 3-hydroxybutyric acid (PHB) and, optionally, galenic galvanic auxiliaries and additives, the chair is characterized in that the retarded form comprises one part by weight of α - (9,5-dimethoxyphenyl) - / 3-glycine amidoethanol in the form of hydrochloride (midodrine hydrochloride) 1 to 15 parts by weight of pol-D (-) - 3-hydroxybutyric acid with a molecular weight of at least 5000 and particle sizes in the range of 0.05 to 0.5 mm in a homogeneous mixture.

Suitable formulations for the retarded forms according to the invention are moldings of any size and shape suitable for oral administration such as tablets, dragee cores, sticks and the like. However, other press-formed dosage forms are also suitable for this purpose, for example comminuted compresses, which are finally filled into capsules or multilayer tablets or dragees, in which non-retentive active substances may be present in a different layer next to the retarding layer. Particularly preferred dosage forms of the present invention are tablets, which can be produced in a simple manner in one working step and are well known to the patient and thus particularly well received. These tablets may be provided with one or more grooves that allow the patient to take tableturosulfurate and preoarate in dosages prescribed by a physician or convened at their own discretion.

Polv-O (-) - 3-hydroxybutyric acid (PHB) used as a drug carrier and retardant is a substance obtained by the fermentation process from cellular material of microorganisms of a character which is capable of producing PHB as a reservoir energy and carbon. PHB-producing microorganisms are found between about 50 different species of bacteria in about 150 different strains and find senap. between phototropic bacteria, gram-negative aerobic and cocci, gram-negative cocci and cocobacillus, pp? 9 o t, v.] CΊ / Ί ° .'MOT5 O ΐ, Ρ O ní 5 P? "1 O? 3 ri—

£ £ 1 1ΓΓΡ b'7 Pk3ΓΓ · Ι Ί ΪΡ V? ί.; ^ Ρ ~ 'y ^ C' mo h · 'ίκ'ον,', ΰ] b ^ · "'?., · 4 V - V' * p-> · -» <p ”'rο r } v - η y- «£ · - η + rj" * η1 * V / '-' "1 i Λ" '' '. ?? es-ími bakt ·· ’?? with ..i, poodle: - + • * · - r -)? pn- + O / - »<9 Ί zoiací z microbial bur. * čn-ó hiot” 1 chemical structure Lij? 11 r? I -lpi •• 'Lt »-» λ * o · -> + v ^. VV? rj - * V p 2? 1 τ '* χΉ Η 7'O2_P2? LI, * "* sož.r.-i find about whip already 303 :) vrakující?» j ^ notek. F: catricp podl ^ v-ncálesu polymers having a molecular weight of at least 50,000 to about 1,500,000 are suitable, and polymers having a molecular weight of at least 50,000 to about 1,500,000 are suitable. Fermentation production of PHB and isolation from cell material has been described, e.g., by Laffer et al. The advantage of the present invention is that the release rate of the active compounds from the delayed form in the matrix system of the invention over a desired period of multiple hours is practically arbitrary. dependent on the PHB particle size and on the weight ratio of the FHB matrix to the active agent, midodrine hydrochloride, these parameters being chosen for optimum efficacy of the hypotonia retarded nidodrine hydrochloride by during the first 20-60 minutes after administration, reaches a therapeutically effective blood level and b) to maintain blood levels during the physiologically necessary period for passage through the stomach and intestinal tract, which is about 4-12 hours with an optimum of about 6-10 hours it is possible to release the active substance completely independent of the pH of the gastric and intestinal tract. [0007] Surprisingly, polyether D (-) - can be obtained by retarding as a polymeric support material by means of preparations of doirin hydrochloride which satisfy the above requirements in each direction. 3-hydroxybutyric acid having a particle size of 0.05 to 0.6 mm, preferably a particle size of 0.2 to 0.5 mm, and preparing such a polymer matrix and active ingredient containing 1 wt. 1 to 15 parts by weight, preferably 2 to 6 parts by weight. particularly preferably 3 to 5 parts by weight of PHB. These blends are then compressed into the depot dosage forms of the invention. With a fraction having a particle size of less than 0.05 mm, the same weight release rates of the active substance in the physiological interval are delayed. In the case of fractions with a particle size above 0.6 mm, in many cases pressing of the mixture is observed in the pressing, which deteriorates the possibility of processing the additions. In heavier or pathological cases of hvpotonia non-therapeutic bases, a high initial dose during the first 30 minutes and a high dose for 1 to 4 hours is required.

Retarded forms according to the invention are then suitable, with 1 part by weight of midodrine hydrochloride containing 1-2 parts of PHB. When therapy requires maintenance of an even dose for several hours after the release of the active dose, it is possible to recommend potent dosage forms which can provide an effective dose in the range of δ to 10 hours, wherein the midodrine hydrochloride: PHB ratio is from 1: 3 to 1: 5. If retarded effect is desired after more than 10 hours, dosage forms of 6 to 15 parts by weight of PHB are used.

Mdodrin hydrochloride is a very effective drug that is administered to patients at lower doses. The dosage is -7- in the retarded forms of the invention between 3.5 and 20 mg of mi-dodrine hydrochloride per dosage unit, preferably between 7.5 and 15 mg. per dose unit of retarded form. a further aspect of the invention is a process for the production of these retarded forms of midodrine hydrochloride. The PH3 obtained by fermentation and isolation from biomass exhibits, in contrast to polylactides or other galenic biodegradable polymers, improved physiological properties such as less elastic properties and reduced tendency to charge and also have good lubricating and binding properties. therefore, it is surprisingly possible to prepare the retarded forms according to the invention in a simple manner both in terms of technical design and equipment.

The fermentation product is ground by milling and the obtained young material is made for. The fraction of particles with a particle size in the range of 605-0.06 mm for the production of rosin is obtained and obtained.

The substance is mixed mechanically with PHB in the desired weight ratio and homogenized. In the case of a small amount of material, the homogenization is carried out by means of a mortar and pestle or mortar, and the large quantities are homogenized using rotary drums, cubus mixers, blade mixers, plate mixers, mixing screws, finned mixers, cone mixers, double cone mixers, V -mixers -8- / ϊν; ίη hell-blendon) and similar devices. The homogenates obtained in this manner are compressed by a suitable process directly without further additives into tablets, dragee cores, rods or other compresses. The agent may also be treated with PHB and optionally other directly tableted excipients, lubricants, etc. onto the directly tabletable composition. The manufacture of the dosage forms according to the invention can be carried out by manual or automatic pressing. The pressing pressure -2 can range from 9.81 to 982 H.m and is selected according to the type and form of the moldings. The release rate of the active ingredient does not exhibit any significant dependence on this pressure change range. Naturally, the active ingredient homogenate and the PHB may be first processed by wet or dry granulation in a conventional manner to form a granulate, and the granulate may optionally be compressed into dosage forms after mixing with the conventional excipients. It is also possible to first convert the active ingredient, if appropriate with wet auxiliaries, with a wet or dry granulation granulate, to which PHB is added and then compressed into a dosage form. The use of this granulation method requires an additional step and has no advantages over direct compression of the homogenate.

The simplicity of the present invention to provide optimum oral solid-release forms of midodrine hydrochloride could not be predicted. Because of the difficulties that have been encountered in the retardation of midodrine hydrochloride and have been associated with previously known biodegradable formulations in the preparation of dosage forms, this is an unexpected result. It is possible to produce in the matrix system of the present invention by simple mixing with the sustained release form of midodrine hydrochloride by virtually any variable release rates. A further unexpected advantage of the retarded forms of the present invention is that during the first 20 to 60 minutes after dosing, the required starting dose of the active ingredient required to produce a therapeutically effective blood level is released directly from the matrix system. In contrast to most retarded dosage forms, other measures are also taken to ensure release of the initial dose, such as spraying, coating or coating the retarded form with the active ingredient in an inert form. In this way, the usual losses of active substance can be reduced by these measures and the production can be simplified.

The uniform and delayed release of the active ingredients of the present invention can be demonstrated in animal experiments as well as in vitro. For example, the midodrine hydrochloride retarded tablet of the present invention contains Gutron 7.5 mg and 22.5 mg PHB with a particle size of 0.2-0.315 mm and a molecular weight of 1.0610 µl in a homogeneous mixture, in in vitro experiments for one hour, the release rate is 47.33%, corresponding to 3.5 mg midodrine hydrochloride, whereas after 7 hours it is effective. the substance is released from the retarded form of 1 00 u. ca caor reparation chn: η o v:

) ú λ -3 -3 * -3 L. U - *

LiVhjr.ovj ;; after administration of 57.55% of the ρβ, 1Ρ a, the amount of active substance present in the retarded β-β-β-β-β-β-β-β-β-β-β-ε-1 is not limited thereto. OF THE INVENTION AND IN. -1 ·, <-1 Example of the Invention Example 1

Ingredients 1 in 5000 pieces of midodri n-hydrocyclide 15.0 mg 75 g of pol-D (-) - 3-hydroxypropylsulphate with 1 inPHB) 15.0 mg 75 g mol. . 1.06.10 ^ particle size: 0.2 - 0.315 sec

Treatment:

The ingredients were sieved and screened in a sieve.

Hoirogonate was compressed under compression pressure of 313.92 Nmm-per tablet.

Tablet weight: 30 mg

Tablet size: diameter 4.0 mm, height 2.0 mm

Breaking strength: 9.8 kpttv of midodrine hydrochloride in vitro:

Conditions: U.S.P.XX - stirrer method, 100 rpm min37 ° C. Physiol. HaO1 solution

Analytical Assay: Direct Spectrophotometer = 279 nm

The in vitro release was carried out in the following examples under the following conditions: mid-trine hydrochloride 33.66 55.88 91.92 99.42 100 +/- 0.30 1.29 0.95 1.84 n = 1 0 -1 1 - Example 2

Ingredients ___ 1 _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ __________________________________________________________________________ n-hydrochloride 7.5 mg 75 g PHB 22.5 mg L5 g mol. Particle size: 0.315-0.4 mm

Tablet processing was carried out analogously to Example 1, 0

Pressing pressure: 313.92 Nmm

Tablet weight: 30 mg

Tablet size: diameter 4.0 mm, height 2.00 mm

Breaking strength: 10.4 kp

Release of midodrine hydrochloride ir. vi.tro:

Hour 1 2 3 4 5 6 h0L07 mi dodrine-hydrocloride 47.33 75.30 81.40 91, 30 95.60 97.33 1 00 +/- 4.10 9 C 1 0.46 0.65 0.81 0.13 - n = 10

Release of midodrine bvdrochloride du in vi:

Conditions:

Tablets injected in rats using a special probe were tested for consumed amounts of midodrine hydrochloride in algae (2.4.6.8 hours) by determining the amount remaining. Therefore, the animals were killed by a ligament wound and a tablet wound from the gastrointestinal tract. After purification, the tablets were crushed mechanically, disintegrated in water, and processed in an ultrasonic bath to completely release the dodecrine hydrochloride. After centrifugation, midodrine hydrochloride was determined directly from the solution. -12-

Hour y 4 6 8 midodrine hydrochloride 67.65 86.48 91, 22 96.18 +/- 0.93 1.46 1, 73 1.03 n = 6 Example 3 Composition 1 piece for 10000 pieces of midodrin hydrochloride 7 , 5 mg 75 g PHB 52.5 mg 525 g mol. 2.6.10 ^ particle size: 0.2-0.5 mm The processing of the tablets was carried out analogously to Example 1 under different compression pressures. Pressing pressure: 49.05 N.mm 98.1; 147.15; 196.2 N.mm ''

Tablet size: diameter 6.0 mm, height 2.2 mm, groove 1.45 mm

In vitro release of midodrine hydrochloride:

Hodina_______1 2_3___4__5_____6__7___8__ midodrin- 20.6 29.28 39.08 47.99 54.35 67.37 68.53 72.06hvdrochloride +/- 1.77 1.78 2.04 1.86 2.09 2.45 2 , 65 3.12

The release rates are independent of the pressure which in the range of 49.05 to 196.2 N.mm used in Example 3 to compress tablets. Example 4 Composition ___1 one 5000 pieces of midodrine hydrochloride 15.0 and 75 g PHS 45 mg 225 g mol. Particle size: 0.1-0.4 mm

Flushing no tablotv b ň n o o ovací ovací ovací ovací ovací ovací ovací ovací ovací ovací 1 1 1

Tablet weight; '·; 60 mg Tablet size;. '·: Or ^ ^ 6,0 sr., Height: Strength: greater than 20 kp

Release

Midodrine Eidoirin Hydrochloride Hour in Vitro: 0.50 1 _______ 2 ___ 3__ £ _..... '5' 30.0 39.55 53.16 65.58 72.60 30.72 xclose 1. 1.45 .6 "7 8 87,87 94,40 100 Hydrochloride +/- 1,27 2,36 1,95 3,34 3,35 3,00 1,34 1,87 - n = 1 0 Example 5

Composition 1 piece for midodrine hydrochloride 15.0 Lo? 150 gPHB 75.0 mg 750 gmol. Particle size: 0.2-0.315 mm

Tablet processing was analogous to Example 1.Pressure pressure: 98.1 - 196.2 N.mm ""

Tablet weight: 90 mg

Tablet size: diameter 8.0 mm, height 1.6 mm for strength: greater than 20 kp -14-

Mido drin-hydrine release 1 hour 0.5 12 4 midcdrin- 21.28 32.22 46.26 64.43hydrochloride +/- 0.56 0.37 0.28 0.26 n = 1 0 wind: 6 8 10 12► - w_—, .- 1 -. | '- - Τ-1 78.33 86.34 91.52 95.02 1.50 0.80 0.16 0.27 Example 6

Composition 1 piece for 10000 pieces Midodrine Hydrochloride 15.0 mg 150 g PHB 105 mg 1050 g Mol. 6.2.10 ^ particle size: 0.05-0.2 mm

Treatment of tablets was analogous to Example 1.

Pressing pressure: 40.05 N.mm '^

Tablet weight: 120 mg

Tablet size: diameter 8.0 mm, height 1.6 mm

Strength: 13.0 kp v

In vitro release of midodrine hydrochloride: ________________8 10 12 23.73 32.39 45.57 53.71 61.93 69.7777.87 1.17 1.03 1.58 1.79 2.38 2.83 3, 56

Hodina_0,5 Thidodrin-18,02hydrochloride +/- 0,85 n = 1 -15-Example 7

Ingredients __________1 piece____for 500 0 pieces of hydrazine hydrochloride 7.5 cg 375 g

PdB 52.5 mg 2 65 g 5 mol. hraotn. 2.6t10 particle size: 0.2-0.315mm

Tablet processing was analogous to Example 1. τ. -2 compression pressure: £ 8.1 N.mm

Tablet size: diameter 6.0 mm, height, 2.1 mm, groove 1.6 mm. Strength: 15.8 kp

In vitro release of midodrine hydrochloride:

Hour 0.5. 1 - 2 .3 4 5 6 midodrin- 30.32 40.85 54.74 64.27 71.05 78.76 82, 06 hydrochloride +/- 1, 06 0.41 0.06 0.82 0.39 0.45 0, 63 flndlna 7 8 84.06 90.89 0.26 0.34 n = 10 Example 8 Composition 1 piece for 20000 pieces midodrine hydrochloride 3.75 mg 75 g FHB 56.25 mg 1 125 g mol .hmotn. 2.6.10 ^ particle size: 0.4-0.6 mm

Workup to tablets analogous to Example 1. -16-

Liscvaoí pressure:> 8.1 N.sa "" '

Tablet weight: 60 mg

Tablet size: diameter 6.0 mis, height 2.2 mm, groove 1.6 mm strength drop: 15.8 kp in o. O o o o o • hydrochloride in vitro: 5 Hour _0 ^ 5 _ 1 9 3 4 midodrin- 22.42 29.35 41.15 50.85 51, 20 68.23 hydrochloride +/- 0.31 0.09 0.84 0.16 0.25 0.00 Hour 6 7 8 midodrin - 74.85 81.04 87.07 Hydrochloride +/- 0.50 0.23 0.46 AA. JUDr. Zdeňka K0REJZ07Áadvokátka

Claims (6)

* Tu I -1 7- • cί - <PATENT Ν 'á R Ο 7 Υ A process for preparing retarded forms of alpha- (2,5-dimethoxyphenyl) -beta-glycine-amidoethanol midodrine in the form of solid molded pharmaceutical compositions prepared by compression and containing an active compound, a semisolid carrier and, if appropriate, excipients and additives customary in pharmaceutical formulations, characterized in that the active compound alpha- (2,5-dimethoxyphenyl) -beta-glycine-amidoethanol in the form of the hydrochloride midodrine hydrochloride is mechanically mixed in a weight ratio of 1: 1 to 1:15 with poly-D- [beta] -hydroxybutyric acid having a molecular weight of at least 50000 which was obtained from a fermentation product having a particle size in the range of 0.05 to 0.6 mm, milling with asitic analysis and homogenizing the mixture and compressing the formed pharmaceutical products, if appropriate, with auxiliaries and additives customary in the pharmaceutical preparation from 9,81 to 981 Nmm 2. A process according to claim 1, wherein poly (D) -3-hydroxybutyric acid having a molecular weight of from 50,000 to 1,500,000 is used. 3. A process according to claim 1, wherein poly-D &lt; 3 &gt; -hydroxybutyric acid having a particle size in the range of 0.2 to 0.5 mm is used. 4. A process according to any one of claims 1 to 3 wherein 1 part by weight of midodrine hydrochloride is treated with 3 to 5 parts by weight of poly (D) -3-hydroxy-butyric acid to form a homogeneous mixture. 5. A process as claimed in claim 1, wherein retarded forms are prepared having a total active ingredient content of from about 5 mg to about 15 mg of midodrine hydrochloride per dosage unit. 6. A process according to any one of claims 1 to 5, wherein the homogeneous mixture of midodrine hydrochloride and poly-D-.beta.-3-hydroxybutyric acid is directly compressed into a shaped drug product. 7. A process according to any one of claims 1 to 5, wherein the homogeneous mixture of midodrine hydrochloride 8-D-.beta.-3-hydroxybutyric acid is compressed in a tablet which can optionally contain one or more multi-bead grooves. JUDr. Zdenek KOREJ;