DE1617527A1 - Medicinal preparations and their manufacture - Google Patents

Description

RAH 4008/101

F. HofFmann-La Roche & Co. Aktiengesellschaft, Basel / Switzerland

Medicinal preparations and their manufacture

The invention relates generally to new pharmaceutical preparations and a method for their production. In particular The invention relates to pharmaceutical preparations which. the therapeutically valuable Hydrochlorld of T-Chlor-S ^ -dihydr Contains l-methyl-S-phenyl-lH-lj ^ -benzodiazepine as an active ingredient.

T-chloro-SiJ-dihydro-1-methyl-S-phenyl-1H-1 ^ -benzodiazepine is a therapeutically active ingredient that is used as a muscle relaxant, sedative and as an anticonvulsant. At first glance, the processing of this compound into a suitable, orally applicable, liquid appears dosable application form to be unproblematic, since the

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Hydrochloride salt of this compound is water soluble. This However, like the free base, water-soluble hydrochloride salt has a characteristic bitter and astringent character Taste. Even after dilution, e.g. with a syrup solution, the salt temporarily causes an unpleasant biting Irritation of the mucosa of the mouth. So far, a palatable xind orally administrable dosage form of this active ingredient has not been possible getting produced. It is therefore the purpose of the present invention to create such a metered application form.

Correspondingly, in its broadest embodiment, the invention relates to dosage forms of application that cover the whole therapeutic value of Y-chloro-l ^ -dihydro-l-methyl-S-phenyllH-l, 4-benzodiazepine hydrochloride accentuate and at the same time eliminate the unpleasant taste, which usually have common drug forms of this salt.

In particular, the invention relates to stable, debittered and irritant-free suspensions which contain the hydrochloride of 7-chloro-1,2-dihydro-1-methyl-5-phenyl-1H-1,4-benzodiazepine contained as an active ingredient.

It has been found that when you mix the water-soluble T-chloro-l ^ -dihydro-l-methyl-S-phenyl-lH-l ^ -benzodiazepine hydrochlorides at room temperature or at elevated temperature with an inorganic hydrophilic colloid that is characterized in more detail below, a water-insoluble one

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The product contains the entire therapeutic activity of 7-chloro-l _> 2-dihydro-l-raethyl-5-phenyl-lH-l, ² J-benzodiazepine hydrochloride, but no longer has the undesirable taste characteristics of this compound.

The present invention thus relates to a pharmaceutical preparation, characterized by a reaction mixture containing the hydrochloride salt of 7-chloro-1,2-dihydro-1-methyl-5-phenyl-1H-1,4-benzodiazepine and an inorganic hydrophilic colloid in contrast to water, wherein in the reaction mixture a ratio of at least about 9 * 0 parts by weight of inorganic hydrophilic colloid per part by weight of the 1,4-benzodiazepine compound is present.

In practicing the present invention, it is preferred as the inorganic hydrophilic colloid either an aluminum silicate or a magnesium aluminum silicate used. The aluminum silicate used is a purified product obtained from montmorillonite. An aluminosilicate of this type is from Georgia Kaolin Company, USA, under the trade name "Albagel". Magnesium aluminum silicates, which are used as inorganic hydrophilic Colloids can also find use are the purified complex magnesium aluminum silicates, as they are made from obtained from natural sources and from the R.T. Vanderbilt Co., USA, under the name Veegum ".

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However, since the present invention with particular reference to the use of "Veegum" and "Albagel" as inorganic When describing hydrophilic colloids, it must be emphasized that the invention works in exactly the same way with others Aluminum or magnesium aluminum silicates the comparable Properties like Albagel "and Veegum have performed.

The reaction mixtures according to the invention can be prepared quickly and safely. In a preferred embodiment, the water-soluble 7-chloro-1,2-dihydro-1-methyl-5-phenyl-1H-1,4-benzodiazepine hydrochloride is first dissolved in water. This is done by adding the compound to distilled water and Stir the mixture at room temperature or at an elevated temperature. In a particularly preferred embodiment of the invention, the aqueous solution of the 1,4-benzodiazepine hydrochloride by adding and mixing the therapeutically active salt to water which is heated to a temperature range of about 70-85 ⁰ C is "manufactured. The so solution is used in the second step of the process. in this second step, the inorganic hydrophilic colloid is added to the aqueous solution and stirred in. Here, the reaction mixture is maintained at a temperature between about 70 and ungefähr.85 ⁰ and es'wird until the end of Reaction Stirred Continuously Numerous factors affect the time it takes to complete the desired reaction, however, it has been found that

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a product with the desired characteristics is obtained, when the reactants are at a temperature between about and 85 ° .mixed., and for one hour at this temperature be left.

The ratio of inorganic hydrophilic colloid to 7- "ChIOr-I, a-dihydro-l-methyl-S-phenyl-lH-l, 4-behzodiazepine hydrochloride, as it is for the production of the Drug preparation is used, is critical to a certain extent, but still variable within certain limits. In general, at least 9 weights parts of the inorganic hydrophilic colloid per part by weight of the hydrochloride of ^ -Chlor-ljS-dihydro-l-methyl-S-phenyl-IH-1,4-benzodiazepine used. Obviously let yourself however, if desired, also use larger amounts of inorganic hydrophilic colloid. However, there is no special one Advantage when using more than 60 parts by weight of inorganic hydrophilic colloid per part by weight of hydrochloride Find Benzodiazepine Salt. More preferred when manufacturing

Get pharmaceutical preparations according to the present invention 12 to about 33 parts by weight of hydrophilic colloid per Part by weight ^ -ehlor-lia-dihydro-1-methyl-S-phenyl-1H-i ^ diazepine hydrochloride for use.

The amount of water specified in the "above preferred embodiment used is not particularly critical. Obviously, however, a sufficient

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Amount of water necessary to completely dissolve the therapeutic active salt is sufficient to be used. In addition, should The amount of water in the system can be chosen so that after adding the inorganic hydrophilic colloid a free-flowing easily stirrable reaction mixture is obtained. This is achieved by using the described preparation in the first step! Using the technique, about 2.5 to about 15 parts by weight Water per part by weight of hydrophilic colloid, which in the second Step is used.

The aqueous reaction mixture described above may be a preservative or a mixture, if desired Contains additional preservatives. The preservative or mixture of preservatives can be added to the water either before or after dissolution of the 7-chloro-1,2-dihydro-l-methyl-5-phenyl-IH-I, 4-benzodiazepine hydroehlorides can be added. Alternatively, the preservative can be used or the mixture of preservatives at a point in time after the formation of the water-insoluble reaction ■ Product is to be incorporated into the system. In general any water-soluble non-ionic preservative can be used which, under the reaction conditions stable and suitable for pharmaceutical purposes. In a preferred embodiment of the invention, the hydrochloride salt of .7-chloro-l, 2-dihydro-l-methyl-: 5-phenyl-lH-l, 4-benzodiazepine added to the water and dissolved in it, the already effective amounts of the preservatives p-hydroxy-benzoe-

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contains methyl acid ester and propyl p-hydroxy-benzoate.

- ■ -, E) Ie aqueous reaction mixtures in the preferred Embodiment according to the present invention are obtained let 'are allowed directly, i.e. without removing the water processed liquid dosage forms, e.g. aqueous suspensions for oral application. The way in which the products are used for this purpose familiar to the person skilled in the art * In general, the liquid ones are meterable Usage forms produced by the customary processes corresponding to the prior art, in the auxiliaries and exeipients as they normally are in the manufacture of dosable pharmaceutical preparations are used for use reach. For example, the liquid, meterable Preparations according to the present invention as auxiliaries. suitable suspending agents, such as, for example, polyoxyethylene sorbitan fatty acid esters ζ.B. Polyoxyethylene sorbitan monooleate, Polyoxyethylene sorbitan monolaurate etc-j poryoxyethylene ester of fatty acids such as polyoxyethylene-8-stearate, Polyoxyethylene 4o stearate, etc; Preservatives such as Benzoic acid, methyl p-hydroxy-benzoate, propyl p-hydroxy-benzoate, Sorbic acid, etc., buffers such as lactic acid, citric acid, etc., sweeteners such as sugar or. artificial sweeteners, anti-foaming agents, coloring agents, flavorings etc. included. Specific and detailed descriptions of the production of stable, debittered, non-

Astringent tasting and non-irritating pharmaceutical Find suspensions -:; : -

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in the following examples. The amount of active ingredient in the suspension according to the invention can vary within a wide range, but contain the suspensions according to the preferred embodiment, about 5 to about 25 mg of the 1,4-benzodiazepine per 5 ml.

The aqueous suspensions produced using the reaction mixture obtainable according to the invention are remarkable in several ways. First of all, these sus- pensions have a completely sufficient character of stability eristika. If sedimentation occurs after a long period of storage, the suspension can be removed by simply shaking the container, i.e. the bottle before use, restored will. This is of considerable importance because it requires the application of the active ingredient in the correct, safer and more specific manner Lot. However, it is even more important that the suspensions, as they are produced from the reaction which can be prepared according to the invention mixtures obtained are completely tasteless. They do not irritate and they have no unpleasant taste how the numerous oral forms of administration including liquid pharmaceutical preparations of 7-chloro-2,3-dihydro-l-methyl-S-phenyl-lH-lj ^ -benzodiazepine hydrochlorides characterized. This is important insofar as it enables the patient to take the therapeutically valuable drug is guaranteed.

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In the foregoing, a preferred embodiment was developed for the manufacture of the appropriate products and the use of these products for. Description of the distribution of liquid medicinal products * It goes without saying that the reaction mixtures can also be prepared according to a different embodiment or method ^Λ and independently _: '■ "" were generated / these can be incorporated into meterable application forms or other liquid meterable preparations. For example, a water-insoluble ent.bittertes nonirritating product can be prepared by mixing the water-soluble T-Ghlor-S / ^ - dihydrö-l-methyl-5-phenyl-lH-l _J% -benzödiazepin-hydroehlorides with an inorganic hydrophilic colloid in the presence of an amount of water obtained which is considerably less than that which is used in the preferred embodiment of the invention. In a single operation, you get- /. a completely satisfactory reaction product by simply mixing the active ingredient and the colloid in the presence: an amount of water sufficient to obtain a just moist homogeneous mixture. The reaction mixture obtained in this way can be used directly, ie * without prior drying> for the production of an aqueous suspension, or alternatively it can be dried and then added to a liquid orally administrable medicinal product preparation, for example a suspension, or into a solid orally administrable preparation ^

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IB IfIP

Spielsweisö tablets, capsules, etc. be incorporated. .

For a better understanding of the present invention demonstrated on the examples below.

example 1

0.105 g T-

Benzodiazepine hydrochloride dissolved in 25 ml of distilled water. Before the active ingredient was dissolved, there was 0.09 g of methyl p-hydroxybenzoate and 0.02 g of p-hydroxybenzoic acid propyl ester has been dissolved in the water. The solution is applied to a

. Temperature between about 8o ° and 85 ° heated and at this Temperature left. While stirring are in this temperature range 2.5 g of magnesium aluminum silicate were added Magnesium aluminum silicate is sold under the name "Veegum Neutral". The reaction mixture is in the temperature range stirred between 80-85 ° for 1 hour.

To the aqueous reaction mixture, prepared as described above, 0.5 g of Myrj 45 (polyoxyethylene 8-stearate, commercially available from Atlas Chemical Industries, Inc.) and 40 g Given sucrose. To the aqueous reaction product thus obtained becomes a solution consisting of 4 ml of distilled water, 0.01 g Ethylenediamine tetraacetic acid disodium salt dihydrate, 0.15 g Sodium hydroxide, 0.25 g benzoic acid, 0.10 g sodium cyclamate,

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-XX-

1 & Ί7527

Added 0.01 g sodium sacharin, 21.0 g sorbitol and 1.1 g lactic acid. Then a mixture of 12.5 g glycerine, 0.4 g tragacanth and 8.0 ml distilled water is added. Finally, a dispersion containing 0.003 g of Antifoam C (a silicone type antifoam agent with a silicone content of J) O ⁰ J) and marketed by Dow Corning Corporation) and 0.1 ml of water ^ are added. The pH of the product is then adjusted to a range between 3.7 to 4.0 with sodium hydroxide. If necessary, flavorings are added to the suspension and it is then diluted to 100 ml with distilled water. The suspension is then homogenized and deaerated. ·

The suspension prepared in this way contains 5 mg / 5 ml of 7-chlorine ^^ - dihydro-l-methyl - ^ - phenyl-lH-l, 4-benzodiazepine hydrochloride. It is extremely tasty, appeals to the mueosa of the mouth and it lacks every bitter astringent Taste, of normally suspensions, the 7-ChIOr ^, 3-dihydro-l-methyl-5-phenyl-lH ~ l, 4-benzodiazepine hydrochloride contain, characterized. Furthermore, the suspension is excellent Stability characteristics when viewed at room temperature lets stand. ■

Example 2

0> 09 g of methyl p-hydroxybenzoate and 0.02 g

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Propyl p-hydroxybenzoate is dissolved in 25 ml of distilled water. There are 0.105 g T-Chloro ^^ - dihydro-l-methyl-5-phenyl "-lH-l, 4-benzodiazepine hydrochloride was added and dissolved therein, the solution thus obtained is heated to a temperature range between 80 to 85 ⁰ C. At this temperature, 6.0 g of magnesium aluminum silicate (“Veegum Neutral”) are added with stirring, and the reaction mixture is stirred for about 1 hour at a temperature between 80-85 °.

To the aqueous reaction mixture prepared as above Section described, 55.0 g of sugar are added. A solution that-3.0 ml of distilled water, 0.13 g of sodium hydroxide, 0.25 g benzoic acid, 0.01 g ethylenediaminetetraacetic acid disodium salt dihydrate, 21.0 g of sorbitol, 12.5 g of glycerin and 1.25 S of lactic acid are added. Thereafter becomes a dispersion containing 0.0033 g of Antifoam C and 0.1 ml contains distilled water, added. If necessary Flavors are added and then the pH of the solution is adjusted to about 3 * 7 with sodium hydroxide. The reaction mixture is made up to a volume of 100 ml with distilled water filled up. The suspension is then homogenized and deaerated.

The result is a stable, tasty, i.e. debittered one and the mucosa of the mouth non-irritating suspension, the 5 7-chloro-2,3-dihydro-1-methyl-5-phenyl-1H-1,4-benzodiazepine hydrochloride contains per 5 ml of solution.

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. ■ "■■ - ■■ V" -. Bsi game ^ -, ■■. '■ -.' ■ - ' ^; '■ "-

0.09 g of methyl hydroxybenzoate and 0.02 g of p-hydroxybenzoic acid are dissolved in 25 ml of distilled water «Pb _! enyl «lH« l, # wb§n ^ odiai§epin added and dissolved in this solution, the mixture becomes thin. heated to a temperature between 80 and 8 ° and then 3 * 0 g of aluminum silicate are added with stirring. The Äluminiumsilieat used is a commercial product with the ^{M-Hafldglsnahmen} Albagel "The reaction mixture for about 1 hour is at a temperature between ungefathr 8Q and ^e imgefähr 85 ° ■, stirred, ^'.'; ''.

2 to the aqueous reaction mixture, prepared - as above « First, 55 * 0 g of sugar and then a solution * that includes the following components in the contains specified amounts, added; , *

Distilled water '3.0ml Sodium hydroxide ''. 0.13 g

Benzoic acid 0.25 g

Ethylenediamine tetraacetic acid ^ disodium salt dihydrate,,. 0.01 g

Sorbitol -. , _.

Glycerin. 12.5 S.

Lactic acid 1.25 g

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After that, a dispersion will be the Q ₄ OOj? g "Antifoam: contains C ^M and 0 * 1 ml of distilled water * added ,. Where necessary be incorporated Geschmaekstoffe The pH of the mixture to sodium hydroxide about%, set f with a corresponding amount of distilled water, the reaction product to 1 volume... 100 ml. The suspension obtained in this way is homogenized and deaerated.

A stable aqueous suspension with a content of 5 mg 7-chloro-.aι3 '· dihydro-l' · methyl-5 ^ phen3Γl-lίl '»l _ί 4-ben2iodia25epin per 5 ml of solution is obtained. The suspension is extremely tasty, it does not irritate the muoosa of the mouth and it lacks any bitter, astringent taste that the usual aqueous suspensions of J-chlorine - ^^ - dihydrQ-l-methyl-5-phenyl-lH-l, 4-benzodiazepine hydrochloride characterized.

Example 4

.0.09 g of methyl p-hydroxybenzoate and 0.02 g of propyl p-hydroxybenzoate are dissolved in 28 ml of distilled water. 0.525 g of 7-chloro-2,3-dihydro-1-methyl-5-phenyl-1H-1,4-benzodiazepine hydrochloride are added to this solution and dissolved therein. The solution is heated to a temperature range between about 80 ° and about 85 °, and then 10.5 g of magnesium aluminum silicate CVeegum Neutral ") 'are added with stirring. The reaction mixture

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is / -then about 1 hour, stirred within a temperature interval between approx ^^^^ and about 85 ⁰ C.

To the aqueous reaction mixture, prepared as above described, 0.75 g of polyoxyethylene-8-stearate (a commercial product with the commercial name Myrj 45), 55.0 g Sucrose and 12.5 g of glycerin were added. Then the following substances are added in the specified amounts:

^. ".... distilled water 1.5

Sodium Hydroxide 0.11 g '

Benzoic acid: 0.25 g

Ethylenediamine-tetraacetic acid-. disodium salt dihydrate 0.01 g

Sorbitol 21.0 g

Lactic acid: 1.15 g

It becomes a dispersion that contains 0.0033 g of Antifoam C "and ^ 0.1 ml contains distilled water, added. The suspension is adjusted to a pH of 3.7 with sodium hydroxide. Thereafter is distilled with an appropriate amount of Ti water Mixture made up to a volume of 100 ml. The suspension obtained in this way is homogenized and deaerated.

A stable aqueous suspension is obtained with a Content of 25 / mg 7-chloro-2,3-dihydro-1-methyl-5-phenyl-1H-1,4-benzodiazepine hydrochloride per 5 ml of solution. The suspension is

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extremely tasty. It irritates the mucosa of the mouth. not bitter and has no astringent taste, which the ordinary Suspensionen'von _r 7-chloro 2,3-dihydro-l-methyl-S-phenyl-lH-l / ^ - benzodiazepine hydrochloride characterized.

Example 5

The purpose of this example is to provide an alternative method

for the production of a tasty product that contains 7-chloro ^ -dihydro-l-methyl-S-phenyl-lH-l, ² ! · - benzodiazepine hydrochloride.

A. 0.105 g of T-benzodiazepine hydrochloride is mixed with 2.10 g of magnesium aluminum silicate ("Veegum") mixed. There is so much water in the dry Mixture stirred in that a moist homogeneous mixture is obtained. This mixture is at a temperature of about 45 ° C dried and then pulverized.

This gives a dry, powdery product that is essentially tasteless. This product is under Addition of the usual excipients and auxiliaries used in the manufacture of tablets compressed into tablets that are pronounced are tasty, i.e. the tablets do not have any bitter astringent taste and irritate the mucosa des Mouth. Suspensions resulting from the dry product

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are placed, are similarly sneaky ».

B. The rule given under A. is repeated by adding instead of magnesium aluminum silicate 2.1 g aluminum silicate ("Albagel") are used.

The dry product thus obtained is used for manufacture orally administrable pharmaceutical preparations, i.e. tablets and suspensions used * Each of the preparations is extremely tasty and has no bitter astringent properties The taste of the mouth still irritates the muoosa of the mouth.

ι ·

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Claims (1)

Claims 1. Pharmaceutical preparation, characterized by a reaction mixture which contains the hydrochloride salt of 7-chloro-1,2-dihydro-1-methyl-5-phenyl-1H-1,4-benzodiazepine and contains an inorganic hydrophilic colloid in the presence of water, wherein in the reaction mixture a ratio of at least about 9 * 0 parts by weight of inorganic hydrophilic colloid per gel • A substantial part of the 1,4-benzodiazepine compound is present. 2. Medicinal preparation according to claim 1, characterized by a ratio of about 12 to about 35 parts by weight Aluminum silicate as a hydrophilic colloid per part by weight 1,4-benzodiazepine compound and a ratio of about 2.5 to about 15 parts by weight of water per part by weight of said hydrophilic colloid. 5 »Medicinal preparation according to claim 1, marked · is characterized by a ratio of about 12 to about '55. Parts by weight of magnesium aluminum silicate as a hydrophilic colloid per part by weight of 1,4-benzodiazepine compound and a ratio from about 2.5 to about 15 parts by weight of water per Part by weight of said hydrophilic colloid. ι ■ 4. Pharmaceutical preparation naoh claim 2, marked Λ. by mixing the raactants in a temperature 109815/1831 rich between about 70 ° and about 85 ° C * with the reaction mixture additionally p-hydroxybenzoic acid methyl ester and
p-Hydroxybenzoic acid propyl ester contains _v 5. Pharmaceutical preparation according to claim J, characterized by mixing the reactants in a temperature range between approximately 70 ° un, d approximately 85 ⁰ C, wherein the
Reaction mixture additionally p-hydroxybenzoic acid methyl ester
and p-hydroxybenzoic acid propyl ester. .. "- .. '".". ■ ■■■ "■■ -'. Ί '' ■ ■ j 6 .. A stable and tasty pharmaceutical preparation \ device in suspension form for oral administration according to claim 1, j characterized by a content of 1. water, 2. a Re- j "■■ - ■ ■ - ■ -! action mixture made by mixing an inorganic hydrophilic colloid with the hydrochloride salt of 7-chloro, 2-dihydro-l-methyl * 5-phenyl-lH-l, 4-benzodiazepine ' in the presence of water in a ratio of at least un-! risk 9.0 parts by weight of the inorganic hydrophilic colloid per part by weight of 1,4-benzodiazepine compound, and 3.
inert pharmaceutical excipients. _y 7 · Medicinal preparation according to claim 6, marked.; net by a content of about 5.0 mg to about 25.0 mg
of 7-chloro-1,2-dihydro-1-methyl-5-phenyl-1H: -1, 4-benzodiazepine hydrochloride per 5 ml of suspension. 109815/1831 8. Process for the production of a pharmaceutical preparation, characterized in that the hydrochloride salt is used of T-chloro-l ^ -dihydro-l-methyl-S-phenyl-lH-l ^ -benzodiazepine mixed with an inorganic hydrophilic colloid in the presence of water by making a ratio of at least about 9 * 0 parts by weight of inorganic hydrophilic colloid used per part by weight of the 1,4-benzodiazepine compound. 9. The method according to claim 8, characterized in that that one has a ratio of about 12 to about 33 parts by weight Aluminum silicate as a hydrophilic colloid per part by weight of 1,4-behzodiazepine compound and a ratio of about 2.5 to about 15 parts by weight of water per weight. part of said hydrophilic colloid is used. 10. The method according to claim 8, characterized in that there is a ratio of about 12 to about 33 parts by weight Magheslum aluminum silicate as a hydrophilic colloid per part by weight of 1,4-benzodiazepine compound and a ratio from about 2.5 to about 15 parts by weight of water per part by weight of said hydrophilic colloid. 11. The method according to claim 9, characterized in that the reactances are ^{mixed in a temperature range between about 70 ° and about 85 0} C and the reaction mixture is additionally methyl p-hydroxybenzoate and p-hydroxy 10 98 IS / 183 tons Propyl benzoate added. · «-. ■ 12. A method according to Änspruoh 10, characterized in that mixing the reactants in a temperature range between about 70 ⁰ C and about 85 ⁰ C and the addition Beaktiönsgemiseh p-hydroxybenzoic acid-methylester, and p-hydroxybenzoic acid propyl ester are added. "- ■ 13. The method according to claim 8 for producing a stable and tasty medicament formulation in suspension form for oral application, characterized in that that 1, water, 2. a reaction mixture is prepared by Mixing an inorganic hydrophilic colloid with the hydrochloride salt of T-chloro-l ^ -dihydro-l-methyl-S-phenyl-lIi-1,4-benzodiazepine In the presence of water in a ratio of at least about 9 * 0 parts by weight of the inorganic hydrophilic colloid per part by weight of JL, 4-benzodiazepine compound and 5 · Inert pharmaceuticals before exe ipi en ti en ti s. 14. The method according to Änspruoh I3, characterized in ", that about 5.0 mg to about 25.0 mg of 7 ~ chloro-1,2-dlhydrol-methyl-S-phenyl-1H-l ^ -benzodiazepine hydrochloride used per 5 ml of suspension solution. 109815/1831