DE2357503A1 - PROCESS FOR THE PREPARATION OF SOLID PREPARATIONS CONTAINING CARBOCROME HYDROCHLORIDE - Google Patents

Description

CASSELlA FARBWERKE MAlNKUR AKTIENGESELLSCHAFT Ref. 29S3

FRANKFURT (MAIN) -FECHENHEIM November 14th 1973

/ {: Dr.Eu/E

Process for the production of solid preparations containing carbocromene hydrochloride

Solid medicinal preparations containing carbocromene hydrochloride are produced either as soft gelatine capsules or as coated tablets. The soft gelatin capsules contain an oily one Suspension of the active ingredient carbocornene hydrochloride and prove like the coated tablets containing carbocromene hydrochloride in stability tests at elevated temperatures as unstable. This instability is due to the fact that the active ingredient over time under the influence of moisture and higher temperature is hydrolytically decomposed. As a result, ζ. B. when using the previously known carbocromene hydrochloride-containing dosage forms Particularly unusual packaging precautions had to be taken in the tropics, to prevent damage to the active ingredient through hydrolysis.

Another disadvantage was that it was also used to protect the operating personnel the processing machines a considerable technical effort had to be driven, since the carbocromene hydrochloride with external impact, skin-irritating and too

509822/0341

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Has allergy-leading properties. So are z. ϊ>. in the production of the coated tablets, which are made using an alcohol wet granulation process special dust protection, explosion protection and environmental protection measures necessary.

When administering the previous oral dosage forms the carbochromene hydrochloride was absorbed of the active ingredient in the upper and middle sections of the small intestine.

There was therefore a need for a process by which carbocromene hydrochloride could be solidified in a simple manner Preparations can be processed which remain stable even when exposed to moisture and heat and which are suitable for the Therapy have optimal properties.

The invention relates to a method for producing solid preparations containing carbocromene-I hydrochloride.

The inventive method is characterized in that carbocromene hydrochloride and

1-30% by weight filler

1-20% by weight swelling and disintegrating agents

1-10% by weight flow and loosening agent 10-50% by weight melting aid

$ 09822/0941

be heated under niches until the softening or Melting range of the melting additive is the mass of granules forms.

Are preferred in the method according to the invention 2-20% by weight fillers, 2-10% by weight swelling and disintegrating agents, 2-8% by weight flow and loosening agents and / or 15-30% by weight of melting aids used.

If desired, the granules formed are broken up and administered as a dosage form or orally solid dosage forms, for example capsules, tablets or dragees, processed. The division is expediently carried out, in the still plastically deformable state. The granules can still be warm while cooling down are located or have already cooled down. During this division, the individual granulate particles become themselves not crushed, but larger particles made up of several sticking together at the points of contact Granulate particles exist, v / are divided into the individual granulate particles. Such a division of each other agglomerated or adhering granules. .can e.g. B. be done on shaking or oscillating sieves. If desired, this division can be followed by a classification or linked to the division •will. However, the classification is usually not

509822/0941 bad oföginal

- 4 - Ref. 29 ·· 33

necessary because the individual granules are of the same size when they are broken up.

A division of agglomerated granules is not necessary if care is taken during the production of the granules that the granules formed do not agglomerate into large particles. This can be done, for example, by terminating the mixing preparation and / or the supply of heat in good time. The granules produced can be administered directly or, if appropriate, after the granule agirlomerates have been divided and classified, as solid oral administration forms of carbocromene hydrochloride. However, the granules can also be used in other solid dosage forms, e.g. B. capsules, tablets or coated tablets are processed. It is generally expedient to add 1-10% by weight, preferably 2-5% by weight of swelling and disintegrating agent and / or 1-15 % by weight, preferably 2-10% by weight of flow and loosening agent or Add mold release agents and lubricants. This f'ischunjr can then z. B. filled in capsules or tablets z. B. to single-layer, multi-layer or coated tablets, or to cores for film tablets or coated tablets.

S09822 / 0941

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In the process according to the invention, it is not necessary for the mixture to be granulated from carbocromene hydrochloride, filler, swelling and Disintegrants, flow and loosening agents as well as melting auxiliaries are heated so high that the .melting aid or even the entire mixture has melted. It is a characteristic of the method according to the invention, that the mass is only heated while mixing until the melting aid, which does not have a narrow melting point, but has a softening or melting range, comes into this softening or melting range.

The melting aid is used to form the granules and to control the hydrophilic-lipophilic properties of the finished products. Softening ranges between 40 ° C and 100 ° C, preferably between 55 ° C and 85 ° C. Suitable melting aids are, for. For example: hydrogenated oils such as hydrogenated castor oil, hydrogenated coconut oil, hydrogenated peanut oil; "IRST, in particular mono-, di- and TrigL ^ rceride of fatty acids, such as BV Glycer inrnonostear atpalmi did Gl ycerintristearatpalmitat, self-emulsifying Glycerinmonoöistearat, Glycerinmonoditristearatpalmitat, esters of purified montan wax acids, Z ₀ B ₀ Hoechst Wax E;. Or higher fat V / axic acids, Z ₀ B ₀ stearic acid, palmitic acid, behenic acid, miristic acid, purified montan wax acids,

ζ. B. Hoechst ¥ ax S; higher fatty alcohols, e.g. Lauryl alcohol, 12-hydroxystearyl alcohol, cetyl, stearyl, M3 ^r ristyl-, myricyl, arachyl, Carnaubj'l-, ceryl alcohol; natural, semi-synthetic and synthetic! 'axis, such as B, beeswax, carnauba wax, paraffin wax, vaseline wax, Ozokeri't, Ceresin, Walrat, solid polyethylene glycols, polyethylene with a low softening point, z. E. Hoechst wax PA 250.

The following are preferably used as melting aids: purified montan wax esters, e.g. B. Hoechst wax E, purified montan wax acids, e.g. B. Hoechst wax S, carnauba wax, hydrogenated castor oil, glycerol monoditristearate palmitate and polyethylene glycols with mean molecular weights of 4,000-2O,000.

The fillers used are substances which serve to increase the weight and which can also be used to influence the dissolution behavior and the pH and ionization conditions of the finished preparations. Suitable fillers are e.g. E.g .: Cplcium hydrogen phosphate dihydrate, tetr. Calcium phosphate, calcium sulfate dihydrate, sodium carbonate, sodium hydrogen carbonate, calcium carbonate, magnesium carbonate, ammonium chloride , citric acid, tartaric acid, lactose, cane sugar, mannitol, koalin, diatomaceous earth, cellulose, microcrystalline cellulose. Calcium hydroxide phosphate dihydrate, calcium sulfate dihydrate or lactose are preferably used as fillers.

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The swelling and disintegrating agents are used to control the disintegration of the finished preparations. Examples of suitable swelling and disintegrating agents are:

Various types of starch (rice, corn, potato starch, etc.), Sodium amylopectin glycolate (ultraamylopectin), MethyX-celluloses, Isopropylmethyl celluloses, methyl hydroxyethyl celluloses, Hyniroxypropylcellulosen, Hydroxyäthylcellulosen, Hydroxypropylmethyl celluloses, carboxymethyl celluloses, their salts and esters, alginic acids, their Salts and esters, polyacrylic acids, their salts and esters, Guar gum, carrageenan, carboxymethyldextrans, sodium arboxymethyl starch, Preferred versions are used as puelling and disintegrating agents various types of starch, sodium amylopectin glycolate (ultraamylopectin) and methylhydroxyethyl celluloses and Sodium carboxymethyl celluloses with a viscosity of 500 - 1500 cP, sodium carboxymethyl starch and cross-linked Polyvinylpyrrolidone used.

The flow and loosening agents are used to control the miscibility of the masses during the granulation process and to control the porosity of the granules. Examples for suitable flow and loosening agents sd.nd colloidal silica, e.g. B. Aerosil 200, colloidal disperse hydrophobic silica, e.g. B. Aerosil R 972, amorphous silicas, e.g. B. Syloid types. Preferably used as Flow and loosening agents colloid-disperse silica or colloid-disperse hydrophobic silica are used.

- 8 - Ref. 2983

Mold release agents and lubricants may possibly be used in the further processing of the granules obtained Flow and loosening agents of the type already mentioned used. Suitable mold release agents and lubricants are, for. B. Magnesium stearate, calcium stearate, zinc stearate, Aluminum stearate, calcium behenate, talc, silicone oil. The preferred mold release agent and lubricant is magnesium stearate used.

The active ingredient carbocromene hydrochloride can also be used other pharmaceutically active substances, e.g. B. with digoxin, cC-methyldigoxin, cymarin, nifenalol, hydroxazine, Nicotinic acid, its salts and esters, ciofibric acid, its salts and esters, xanthines and xanthine derivatives, pyridine-3 carbinol, dihydroergotamine tartrate, potassium chloride, rauwolfia alkaloids, thiabutazide, clofenamide, hydralazine theopb ^ llinat, Phenobarbital, prenylamine, dipyridamole, nitroglycerin,

Pentaerythrol tetranitrate, chlordiazepoxide hydrochloride be combined.

As auxiliary materials, namely as fillers, swelling and disintegrating agents, Flow and loosening agents, melting aids, mold release agents and lubricants are used by the health authorities Approved substances are used.

509822/0941

- 9 -t ■■■ "■■ - ■ -". ■■ Ref. '■■ 2983

In general, not just a single melting aid, instead a mixture of two or more melting aids is used. Also with the other groups of auxiliary substances can mixtures, e.g. B. a mixture of different swelling and disintegrating agents or a mixture of different Flow and loosening agents are used.

The percentages given relate to the total mixture present in each case.

Through a suitable qualitative and quantitative selection in the hydrophilic-lipophilic composition of the melting aids, together with a suitable qualitative and quantitative selection of the filling, swelling and blasting, flowing and loosening, mold release and lubricating agents can be the Availability of the active ingredient in the gastrointestinal tract can be controlled in a way that is optimal for the therapy. a melting aid or a mixture of melting aids with predominantly lipophilic properties is used, then the release of the active ingredient is delayed while when using a melting aid or mixture of Melting aids with predominantly hydrophilic properties the release of the active ingredient takes place more quickly.

- 10 - Ref. 2983

A suitable qualitative and quantitative selection of the loosening agents can reduce the porosity of the resulting Granulate grains can be controlled and the penetration of liquid ■ accelerated or delayed.

Through a suitable qualitative and quantitative selection of the swelling and disintegrating agents used in the acidic areas of the gastrointestinal tract can swell and burst more slowly than in areas with higher pH values be delayed in acidic areas.

The ionization ratios in the gastrointestinal canal can be determined by a suitable qualitative and quantitative selection of the fillers to be influenced.

With a suitable implementation of the invention Method, in particular through a suitable selection of the auxiliaries, the availability of the active ingredient can be determined Carbocromene hydrochloride both accelerate and accelerate compared to the previous commercial form of soft gelatin capsules also delay.

Dosage forms with accelerated release of the active ingredient can be obtained if melting aids with predominantly hydrophilic properties, ζ. B. polyethylene glycols,

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and / or colloid-dispersed as flow and loosening agents "Silica or amorphous silica and / or as swelling and Disintegrants starch (rice, corn, potato starch etc.), sodium amylopectic glycolate, sodium carboxymethyl starch or cross-linked polyvinylpyrrolidone can be used.

Dosage forms with delayed release of the active ingredient can be obtained if melting aids with predominantly lipophilic properties, e.g. B. montan wax acids, montan wax acid esters, carnauba wax, glycerol monoditristearate palmitate, and / or as a flow and loosening agent colloidal hydrophobic silica and / or sodium carboxymethyl cellulose as swelling and disintegrating agent, Methyl cellulose, methyl hydroxyethyl cellulose, hydroxypropylmethyl cellulose be used.

Due to the possibilities shown, the resorption of the active ingredient can be controlled in the various sections of the gastrointestinal tract.

The manufactured and assembled according to the invention Granules containing carbocromene hydrochloride, mixtures thereof and the dosage forms produced therefrom compared to the previous ones. Process manufactured Products have the advantage that the unpleasant Eijjen-

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businesses have disappeared to the point that processing becomes possible without special precautionary measures.

A dust development can be in contrast to the usual Production methods of dry granulation and wet granulation Avoid to a large extent with subsequent drying, especially if the granules are possibly in the still plastically deformable state divided or classified will.

Surprisingly, it is also in those produced according to the invention Preparations of the active ingredient carbocromene hydrochloride against moisture and heat hydrolytic decomposition, so that preparations for the tropics can be packed in normal tropical packs.

Example 1

Carbocromene hydrochloride 1,500 kg

Polyethylene glycol 6000 x 0.332 kg

HOECHST wax E 0.168 kg

Calcium hydrogen phosphate 0.140 kg

Aerosil 200 0.066 kg

Methylhydrox37ethylcellulose 1000 cP 0.066 kg

were in a high-speed, closed mixer (HENSCPEL-FLUID mixer FM 10 L with one-storey Variant Tool) is heated by mixing at 3600 revolutions / minute due to the resulting friction, until at about + 70 ⁰ C a granulate of about 0, 5-2 mm grain size. The cooling granulate was broken up on a vibrating sieve machine while it was still plastically deformable.

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The cooled granules were

Sodium amylopectic glycolate. . 0.082 kg Aerosil 200 _: 0.008. kg

Magnesium stearate ■■ - "0.033 kg .-" ■ - ■

mixed in. This mixture was packed in hard gelatin capsules filled or compressed into tablets or cores for film tablets or coated tablets.

The in vitro dissolution characteristics (dissolution model SAYTORIUS) for 1 hard gelatine capsule a 150 mg Garböcroraen-iTydrochlOrid and 1 dragee a 150 mg carbocromene hydrochloride are in Table 1 in comparison with the soft gelatine capsules customary up to now shown.

The stability under tropical pollution is compared to the Previously customary dosage forms are given in Table 1.

Example 2

Carbocromene hydrochloride 45Og

Hoechst Wax E '- "... ISO ^g;,

Calcium hydrogen phosphate - 130 g

Hydrogenated castor oil 5Cg

Aerosil 200 <5 g

Methyl hydroxyethyl cellulose 100 cP 5 g

509821/0941

were in a slow-running compulsory mixer with jacket heating (LÖDIGE mixer MG 5 / jacket temperature approx. + 90 ° C) until a granulate with a grain size of 0.5 - 2 mm has formed.

The cooling granules became on an oscillating

Divided sieve. There were

Magnesium stearate 10 g

mixed in and compressed oblong tablets of 8OO mg weight, which have been coated with a snow-soluble, flavored film varnish.

The in vitro dissolution characteristics (SARTORIUS dissolution model) for 1 film-coated tablet each is 450 mg carbocromene hydrochloride in Table 2 in comparison to the soft gelatin capsules customary up to now shown.

The stability under exposure to tropical conditions is given in Table 1 in comparison to the dosage forms customary up to now.

Example 3

Carbocromene hydrochloride 9,000 kg

Hoechst Wax E, 3.667 kg

Calcium hydrogen phosphate 2.500 kg

Polyethylene glycol 6000 0.333 kg

Aerosil 200 0.100 kg

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Sodium carboxymethyl cellulose 1000 cP 0.100kg

were in a sniffing, closed mixer (HENSCHEL FLÜID mixer FM 75 L with two-tier Väriant tool) heated by mixing as a result of the resulting friction, up to approx. + 70 C a granulate of a grain size of approx. 0.5-2 mm. The cooling one Granules were broken up on a vibrating sieve.

The cooled granules were

Aerosil 200 0.100 kg

Magnesium stearate 0.200 kg

mixed in and pressed Obiong tablets of 800 mg weight with a quick-dissolving, flavored Paint film were coated. . "

The in vitro dissolution characteristics (dissolution model SARTORIUS) for 1 film-coated tablet of 450 mg carbocromene hydrochloride is shown in Table 2. -'-'-

Example 4 ■.

Carbocromene hydrochloride 750.0 g

Nifenalol HCl 500.0 g

Hydroxycin 2 HCl - 50.0 g

Polyethylene glycol 6000 250.0 g

S098 22/09:41

HOECHST wax E 125.0 g

Calcium hydrogen phosphate 75.0 g

Aerosil 200 50.0 g

Methyl hydroxyethyl cellulose 1000 cP 50.0 g

were mixed in a slow-running, closed planetary mixer with scrapers and jacket heating (MULTIBOMO MH 10 C / jacket temperature approx. + 90 ° C) until a granulate with a grain size of approx. 0.5-2 mm formed at approx. 70 ° C of the product .

The cooling granules were placed on a vibrating sieve divided. There were

Corn starch 54, above

Aerosil 200 25, supra

Sodium amylopectic glycolate 8.5 g

Magnesium stearate 62.5 g

mixed in and pressed into tablet cores.

Example 5

The homogeneous mixture of the trituration of

Digoxin 0.050 kg with

Calcium hydrogen phosphate 0.950 kg

was with

- 17 - Ref. 2933

Polyethylene glycol 6000 6.640 kg ^;

HOECHST wax E 3.360 kg

Calcium hydrogen phosphate; -1, SOO kg ■ - ■■ "

Aerosil 200 '' 1.320 kg

Sodium carboxymethyl cellulose 1000 cP 1.320 kg

was with

Carbocromene hydrochloride 30,000 kg

• mixed in a low-speed, closed mixer with jacket heating and scrapers (DRAIS planetary FII 165 / jacket temperature ca, ⁰ + 90 C) until a granulate of 0.5-2 mm Korhgrösse formed.

The cooling granules were placed on a vibrating sieve divided. There were

Sodium carboxymethyl starch 1.640 kg

Aerosil 200. . - 0.160 kg

Magnesium stearate 0.760 kg

mixed in and pressed into tablet cores.

Example 6 . ·

Composition and working methods correspond to Example 5, but instead of HOECHST wax E the same amounts
of carnauba wax or hydrogenated: castor oil or glycerin monoditristearate palmitate were used. The resulting granules with a grain size of 0.5-2 mm were without distribution
reused .;

Example 7

Compositions and working methods correspond to the examples 1-6, but instead of calcium hydrogen phosphate triturations of the active ingredients

Digoxin,

oC-methyldigoxine

Dihydroergotamine tartrate with calcium hydrogen phosphate

were used.

The SARTORIUS solution model is described in Pharm. Ind. 31,794-799 and Pharm. Ind. 33,446-454.

509822/0941

Table 1
Stability (8 months of storage under tropical conditions, 40 ° C and 90% relative humidity)

Dosage form

Exceptions

% Hydrolysis product (resulting from hydrolysis Acid)

crt O ίο

Carbocromene hydrochloride "Soft gelatin capsules

Carbocronene hydrochloride Dragee / alcohol granules

spoiled

spoiled

5 - 10

5 - 10

Example dragee

stable

example

Film-coated tablet

stable

Tabel

Release of active ingredients (SARTORIUS solution model)

(in minutes)

% Active substance, 10 '' 15 · released after 45 ' 60 ' • 120 ' 180 ' 240 ' 300 ' 360 ' Dosage form 5 ' 66 99 30 ' Carbocromene hydrochloride
Soft gelatin capsules 4th 95 example 1
Hard gelatin capsules 29 20th 44 98 example 1
dragee 4th 81 28 33 52 66 76 87 96 Example 2
Film-coated tablets 11 21. 26th 32 66 .87 98 Example 3
Film-coated tablet 19th

Claims (1)

are heated with mixing, h ± s in the softening or melting range of the skin auxiliaries forms the cash granules. .., '- " 2. The method according to claim 1 _T, characterized in that-2 - 20 wt. %. Filler is used «; . 3. The method according to claims 1 and 2, characterized in that that 2 - 10% by weight of source and disintegrant is used. 4. The method according to claims 1 to 3, characterized;! Characterized, that 2-8% by weight flow and loosening agent is used" ' 5ο Method according to claims 1 to 4 _f, characterized in that 15-30% by weight of melting aids are used. ·. is turned. """*" -. BATH 235751 - 22 - Ref. 2933 6 »Method according to claims 1 to 5, characterized in that that the heating by frictional heat in a high-speed mixer. 7. The method according to claims 1 to 5, characterized in that that the heating takes place through a heated surface in a slow-running mixer. 8. The method according to claims 1 to 7, characterized in that that the granules are broken up. 9 »The method of claims 1 to S, characterized in that the granules leavening agent 1-15 wt.% Flow and on and / or Formtrenn.- and lubricant are admixed. 10. The method according to .Ansprüche 1 to 9, characterized / re characterized in that the granules 2-10 wt.% Flow and Loosening agents and / or mold release agents and lubricants are mixed in. 11. The method according to claims 1 to 10, characterized .q-e, that as .Melting aid a polyethylene glycol is used. $ 09822/0941 - 23 - Ref. 2983 12. The method according to claims 1 to 11, characterized in that that as a flow and loosening agent a colloidal or amorphous silica is used will. 13. The method according to claims 1 to 12, characterized in that that as swelling and disintegrating agents starch, sodium amylopectic glycolate, sodium carboxymethyl starch, cross-linked polyvinylpyrollidone is used. 14. ^N method according to claims 1 to 10, characterized in that - one indicates that as a melting aid / flönt wax acid, a mohtan wax ester, carnaupa wax, Glycerol monoditristearate palmitate is used. . 15. The method according to claims 1 to 10, characterized in that the flow and loosening agent colloidal hydrophobic silica is used, 16. The method according to claims 1 to.10, characterized in that a swelling and disintegrating agent Fatriunicarboxymethyl cellulose, methyl cellulose, Methylliyöroxyäthylcellulose or Eydroxypropylmethyrcellulose is used. ■■ * ■■ BATH 509-8227 0S4-1 - ■.