HU183053B - Process for heatstabilizing and form-stabilizing soft gelatine capsules containing active agents inside the envelope utilizable perlingual and buccal application - Google Patents

Abstract

The invention relates to a process for the thermal stabilization and improvement of the shape stability of the pharmaceutical active ingredient in the softgelatine capsules containing the capsule in which the capsules are provided with a film coating of a film-forming, water-soluble or swellable and soluble in solvents Loeslichen polymers. This improves the properties of the soft gelatin capsules while preserving their other advantageous properties. For example, the soft gelatin capsules obtained are temperature resistant and less susceptible to moisture and they do not stick together in the storage container even after prolonged storage.

Description

BACKGROUND OF THE INVENTION The present invention relates to a novel process for thermally stabilizing and improving the durability of soft gelatine capsules for perlingual and buccal use containing the drug in a capsule. The process according to the invention is carried out by using a 2-5% alcohol solution of a cellulose ester, preferably hydroxypropylmethyl cellulose having a molecular weight of 50,000-1,250,000 or polyvinylpyrrolidone 10,000360,000, The film is coated with a film thickness of 93.3 mg'cm ^{2 with} a film thickness between 8 and 3 µπι.

Gelatin capsules have proven to be effective for many years for safely packing a variety of drugs. They have the advantage of uniform quality and the same shape, size and shelf life.

A distinction is made between hard gelatin capsules and soft gelatin capsules. The difference is, on the one hand, in the material of the gelatin mass employed and, on the other hand, in the filling of the active ingredient.

For the preparation of hard gelatine capsules, the empty capsule is first prepared and then filled with the active ingredient using special capsule filling machines. The capsule is then resealed. For the preparation of hard gelatine capsules, only pure gelatin may be used, which may contain a small amount of coloring and / or opacifying agent. Generally, the gelatin used in the preparation of cumin gelatine capsules does not contain any plasticizer.

In contrast, soft gelatine capsules are manufactured in a single process, i.e., forming the capsule shell and filling the capsule in a single process. Gelatin used to make soft gelatine capsules contains higher amounts of plasticizers, such as glycerol and / or sorbitol. Due to the higher moisture content of the soft gelatin capsule shell, a preservative should also be added to the gelatin. If necessary, colorants and opacifying agents may be added to the gelatin. The use of soft gelatine capsules allows the administration of easily suppressed or liquid active ingredients such as vitamins, oily active ingredients, etc. dosage unit form in a stable form.

The preparation and use of hard and soft gelatine capsules are described, for example, in "The Theory and Practice of Industrial Pharmacy" by Lea and Febiger, Philadelphia, 389-420. page 1976.

Further, soft gelatine capsules are disclosed in U.S. Pat. German Federal Publication Document. For example, a gelatin capsule is formed from a gelatin mass which is softened with 8-15% by weight of glycerol and 12.5-15% by weight of sorbitol.

More recently, soft gelatine capsules have been commercially available which, unlike conventional hard gelatine capsules and soft gelatine capsules, contain the active ingredient not in the capsule shell but in the gelatin shell itself. In this type of soft gelatin capsule, the effective ingredients are embedded in the gel gel and the capsules contain a small core of air which gives them some flexibility. The gelatin mass used for this purpose is substantially the same as that used to make conventional soft gelatin capsules. The composition of the gelatin paste is generally chosen so that the capsule releases the active ingredient uniformly for about 15 minutes when chewed or sucked. Thus, this dosage form is particularly advantageous in the case of active ingredients which must be absorbed perlingually or orally (e.g., cardiac glycosides, steroids, etc.). They can also be used in oral care, cosmetics and throat disinfectants. Due to its high mechanical strength, premature disintegration of the capsule does not occur. The time required for dissolution is significantly longer than for conventional soft gelatin capsules or hard gelatin capsules, which have not been post-treated to prolong disintegration.

However, in addition to the benefits listed above, these soft gelatine capsules have the following disadvantages:

1. Because of the large amount of plasticizer needed, the capsules are highly hygroscopic. As a result, the capsules in the bulk mass next to each other will adhere to a semi-solid or solid solid after a short time. The compressible capsules absorb moisture and soften.

2. The very low thermal stability of soft gelatine capsules also leads to significant transport and download difficulties. As early as 40 ° C, irreversible deformation of the soft gelatin capsule begins and the tendency to adhere increases. The soft gelatin capsule is completely melted at 50 ° C so that exposure to such a temperature cannot be exposed even for a short time.

Due to these disadvantages, the known soft gelatin capsules do not provide satisfactory results in all respects.

Soft gelatine capsules containing the active ingredient in the gelatin envelope constitute a special case; when the capsule is cut and sucked, the active ingredient is released and absorbed from the mouth. It follows that the coating of the capsule plays a very important role. The present invention ensures that, while providing favorable properties (improved thermal stability, mechanical strength), the active ingredient passes unobstructed through the capsule wall. The known solutions could not provide this advantageous effect. According to the state of the art, it was not expected that the coated capsules of the invention would release the active ingredient in the mouth, but, on the contrary, it would have been expected in the literature to inhibit the release of the active ingredient. Therefore, the results obtained by the process according to the invention are very surprising.

It is an object of the present invention to overcome the drawbacks of known soft gelatin capsules containing the active ingredient in capsule shells, and in particular to provide soft gelatin capsules that are mechanically and thermally stabilized.

The present invention therefore relates to a process for thermostabilizing and improving the stability of soft gelatine capsules containing a drug substance in a capsule shell. The process according to the invention is characterized in that the capsules are film-coated using a water-soluble or swellable solvent-soluble film-forming polymer.

Examples of film-forming, water-soluble or swellable, solvent-soluble polymers are pharmaceutically acceptable cellulose esters, cellulose ethers and / or polyvinylpyrrolidone. Other suitable film-forming polymers or copolymers that meet the above requirements are, for example, esters of acrylic and methacrylic acids, polyethylene glycols, and proteins such as zein, which is the major protein component of corn adhesive.

Table I below lists some of the substances suitable for this purpose.

Table I

Suitable materials for the film coating process

Chemical sign IU Trade name Hydroxypropylcellulose, molecular weight 50,000-1,250,000 Klucel Hydroxypropyl methylcellulose, Pharmacoat, 15 19-30% methoxy and 3-12% Methof P, containing hydroxypropyl Methocel E Premium, mixed cellulose ether Viscontran Methyl cellulose, 25-30% methyl Methocel, Tylose, content, average degree of polymerization 200-1000 Viscontran 20 Polyvinylpyrrolidone, Molecular Kollidon.RTM, weight 10,000-360,000 Plasdone Vinylpyrrolidone / vinyl acetate 60:40 copolymer, molecular weight 40,000-90,000 Kollidon VA 64 25 Dimethylaminomethacrylic acid and copolymerization of neutral methacrylic acid esters is soluble in acidic media Eudragit E 30 Ethyl acrylic acid and methacrylic acid methyl ester was copolymerized to 70:30 Eudragit E 30D 35 Polyethylene glycol, molecular weight Polyglykol, 6,000-20,000 Polywachs Zein, protein, molecular weight 35,000-40,000 - 40

Further details on the materials listed in Table I and descriptions of the preparation of the corresponding film coatings can be found, for example, in "Theory and Practice of Industrial Pharmacy", Lea and 45 Febiger, Philadelphia, 368, 1976.

It is surprising to those skilled in the art that film-forming materials that are highly soluble in water and, for example, unsuitable for protection from moisture, significantly increase the mechanical strength of the film coating without adversely affecting the time required to dissolve the capsules (cf. 1). Comparative Example #. The shape stability of soft gelatine capsules is substantially increased by the coatings applied according to the invention (cf. Comparative Example 2). 55

The film coating is applied in a manner known per se, such as that described in the literature above. Preferably, the film coatings are formed by spraying a solution of liquid in a fluidizer or dragee drum onto the surface. 60

An average amount of 0.9-3.3 gm / cm ² , preferably 1.1-2.2 mg / cm ^2, is applied from the film-forming material.

The film thickness achieved with this amount is 8-30 micrometers, preferably 10-20 micrometers.

For example, the coating process is as follows:

Prepare a lacquer solution with the following composition:

2-4% 0.2-0.5% 0.4-0.8% 94.8-97.4% film-forming material polishing agent plasticizer solvent

The polishing agent used is, for example, polyethylene (e.g., having a molecular weight of 20,000), beeswax, carnauba wax or solid paraffin. The plasticizer is, for example, 1,2-propanediol, diethyl phthalate, dibutyl phthalate, glycerol or sorbitol. Suitable solvents are, for example, ethanol-dichloromethane (e.g. 2: 3 by volume), methanol, trichlorethylene, carbon tetrachloride or isopropanol.

Additional substances such as coloring agents or flavoring agents such as sweetening and flavoring agents may be added to the lacquer solution if desired.

The lacquer solution thus prepared is then applied to the soft gelatin capsule at elevated temperature, for example 30 ° C, in a fluidizing device or dragee drum. The capsules are then dried, for example, at 50 ° C.

The film coating thus formed adheres well to the capsule and is transparent when used with clear film-forming solutions, so that it does not alter the appearance of the capsule and has high strength.

The advantageous properties of the known soft gelatine capsules remain unchanged, however, according to the invention, the disadvantages mentioned above are overcome:

Capsules with the coating of the invention:

1. They are less sensitive to moisture.

2. They do not stick together in the storage container even after prolonged storage.

3. Resistant to temperature. Even in 70 Con, the capsule shape remains unchanged and the capsules do not stick together. Thus, it is possible to fully test stability.

4. There is no difficulty in filling the capsules into packaging. Both of the aforementioned forms of packaging are possible: bulk storage and compression packaging.

5. The solubility, elasticity and dissolution of the capsule in the mouth remain unchanged.

The invention is illustrated in detail by the following examples:

Example 1

Film coating for soft gelatine capsules

consists of the following components: Hydroxypropyl methylcellulose (viscosity 20-28 cP in 2% aqueous solution) 3g Polyethylene glycol, molecular weight 20,000 0.3 g 1,2-Propanediol 0.6 g Solvent mixture, 2 parts ethanol and 3 parts dichloromethane 96.1 g

Preparation of varnish solution:

The solvent mixture is prepared by dissolving hydroxypropylmethylcellulose and polyethylene glycol in succession. The 1,2-propanediol is then added with stirring.

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sputtering:

In a WSLD Type 5 smooth fluidizer equipped with nozzles of 0.8 mm diameter, a total of 1.35 kg of lacquer solution was sprayed onto 2.5 kg of softened gelatin core at a pressure of 80, 100 g / min and a spray temperature of 30 ° C. Coating is performed continuously, and when complete, the capsules are dried for 4 minutes at 50 ° C.

Example 2

Film coating for soft gelatine capsules

consists of the following components: Hydroxypropylcellulose, molecular weight about 100,000 ³ g Polyethylene glycol, molecular weight 20,000 0.2 g 1,2-Propanediol 0.4 g Solvent mixture, 2 parts ethanol and 3 parts dichloromethane 96.4 g

Preparation of the varnish solution:

The solvent mixture is reconstituted and sequentially dissolved in hydroxypropyl cellulose and polyethylene glycol. To the resulting solution, 1,2-propanediol is added with stirring.

pulverization

In a WSLD Type 5 fluidization apparatus equipped with nozzles of 0.8 mm diameter, a total of 1.35 kg of lacquer solution was sprayed onto 2.5 kg of gelatin core at a pressure of 2 and at a spray rate of 80-100 g / min at 30 ° C. After continuous spraying, the capsules were dried for 4 minutes at 50 ° C.

Example 3

The film coating for soft gelatine capsules consists of the following components:

Etherified methylcellulose (viscosity of 2% aqueous solution approximately 220 cP) 3.0 g

Polyethylene glycol, molecular weight 20,000 0.2 g

1,2-Propanediol 0.4 g

Solvent mixture, 2 parts ethanol and 3 parts dichloromethane 96.4 g

Preparation of varnish solution:

The solvent mixture is prepared by sequentially dissolving etherified methylcellulose and polyethylene glycol. The 1,2-propanediol is then added with stirring.

sputtering:

In a WSLD 5 fluidization apparatus equipped with nozzles of 0.8 mm diameter, a total of 1.35 kg of lacquer solution was continuously sprayed onto 2.5 kg of gelatin core; spray pressure 2 µm, spray rate 80-100 g / min, spray temperature 30 ° C. The capsules are then dried for 4 minutes at 50 ° C.

Example 4

The film coating for soft gelatine capsules consists of the following ingredients: Methyl hydroxyethyl cellulose, molecular weight 3.0 g, about 100,000

Polyethylene glycol, molecular weight 20,000 0.2 g

1,2-Propanediol 0.4 g

Solvent mixture, 2 parts ethanol and 3 parts 96.4 g dichloromethane

Preparation of varnish solution:

The solvent mixture is prepared by dissolving methyl hydroxyethyl cellulose and polyethylene glycol sequentially and adding 1,2-propanediol to the solution while stirring.

sputtering:

In a WSLD Type 5 fluidization apparatus equipped with nozzles 0.8 mm in diameter, a total of 1.35 kg of lacquer solution was continuously sprayed onto 2.5 g of gelatin at a pressure of 80-100 g / min at 30 ° C. The capsules are then dried for 4 minutes at 50 ° C.

Example 5

The film coating for the soft gelatine capsules, including the dye, consists of the following components:

Polyvinylpyrrolidone, molecular weight 5.0 g, about 40,000

Polyethylene glycol, molecular weight 20,000 0.5 g

Cochenillerot The dye is 0.05 g

Dichloromethane 40.0 g

Ethanol, denatured 54.5 g

Preparation of varnish solution:

Prepare the solvent mixture and sequentially dissolve the polyvinylpyrrolidone, polyethylene glycol and dye. To the resulting solution was added 1,2-propenediol with stirring.

sputtering:

In a WSLD type 5 fluidization apparatus equipped with nozzles of 0.8 mm diameter, 1.35 kg of lacquer solution was continuously sprayed onto 2.5 kg of gelatin core at a pressure of 80 at 100 g / min at 30 ° C. The capsules are then dried for 4 minutes at 50 ° C.

Example 6

Sweetener for soft gelatine capsules

Film coatings containing the following components: Polyvinylpyrrolidone, molecular weight about 40,000 4.5 g zein 0.5 g Polyethylene glycol, molecular weight 20,000 0.5 g Saccharin sodium 0.005 g dichloromethane 40.0 g Ethanol denatured 54.5 g

Preparation of varnish solution:

Prepare the solvent mixture and sequentially add polyvinylpyrrolidone, zein, saccharin, and polyethylene glycol. To the resulting solution was added 1,2-propanediol with stirring.

sputtering:

In a WSLD type 5 fluidization apparatus equipped with nozzles of 0.8 mm diameter, 1.35 kg of lacquer solution was continuously sprayed onto 2.5 kg of gelatin core at a pressure of 80 at 100 g / min at 30 ° C. The capsules are then dried for 4 minutes at 50 ° C.

183,053

Example 7

III. spreadsheet

Flavoring agent for soft gelatine capsules

i.s. film-coating consists of the following components: Polyvinylpyrrolidone, molecular weight 3.0 g 5 about 40,000 cellulose 2.0 g Silicone oil, type AK 350 0.5 g Menthol (quality according to DAB 7) 0.005 g dichloromethane 40.0 g 10 Ethanol denatured 54.5 g

Preparation of varnish solution:

The solvent mixture is prepared by sequentially dissolving polyvinylpyrrolidone, menthol, ethylcellulose and polyethylene glycol. To the resulting solution was added silicone oil with stirring.

sputtering:

In a WSLD type 5 fluidization apparatus equipped with nozzles of 0.8 mm diameter, a total of 1.35 kg of 20 lacquer solution was continuously sprayed onto 2.5 kg of gelatin core at a spray rate of 80-100 g / min at 30 ° C. The capsules are then dried for 4 minutes at 50 ° C.

Comparative Example 1

To compare the dissolution times, film-free capsules and the capsules of Example 1 were tested in an Erweka disintegration tester using water at 37 ° C (cf. Deutsches Arzneibuch, 7th edition, 1968. Wissenschaftliche Verlag GmbH, Stuttgart, Germany). Govi-Verlag GmbH, Frankfurt, page 75/96). The results of the study are shown in Table II. are summarized in Table. 35

II. spreadsheet

Experiment number

Time to dissolve in minutes with film-coated capsules without film-coating

- ₄₅

22

22

23

Comparative Example 2

For the purpose of determining durability, the film-free soft gelatin capsules of the film-coated 55 film-coated capsules of the present invention were stored at 60 ° C for 24 hours. Some of the soft gelatine capsules used in the experiments contained an extract of the active ingredient which is respiratory tract catarrh, bronchitis, cough, nicotine cough, influenza qq infections, and so on. (Solubifix). The other part of the capsules contained the active substance chlorhexidine digluconate.

The results obtained are summarized in Table 111.

preparation examined kapszu- house number The shape is unchanged Slightly Strong distorted Capsules containing an antitussive active ingredient 1) film coating without 100 100 (b) film-coated 100 100 - - chlorhexidine digluconate with capsules (a) without film coating 100 100 (b) film-coated 100 98 2

Example 8

The film coating consists of the following components:

Methocel E 5 Premium 2.3 g Methocel E 15 Premium 2.3 g Glycerol 0.9g Polyethylene glycol, molecular weight 20,000 0.45 g Ethanol denatured 56.6g Water, desalted 37.5g

Preparation of varnish solution:

The ethanol and water are mixed, the polyethylene glycol dissolved, and the Methocel E5 and Methocel E15 components are added with stirring. Glycerol was then added to the solution and stirred for 5 minutes.

sputtering:

WSLD 5 type fluidizing apparatus, which has nozzles with a diameter of 1.2 mm, 11.9 kg of gelatin continuously spraying the above composition varnish was 2816 kg in total, 4 atmospheres gauge pressure, 100 g / min spray rate of 35 to 40 ^c C. The capsules are then dried for 4 minutes at 38-43 ° C.

Claims (4)

CLAIMS 1. A method for thermally stabilizing and improving the durability of soft gelatine capsules for perlingual and buccal use, comprising the cellulose ester, preferably hydroxypropylmethylcellulose, having a molecular weight of 50,000 to 1,250,000, or 10,000 to 10,000. It is coated with a film thickness of 0.9 to 3.3 mg / cm ² using a 2-5% solution in alcohol. in addition, the film thickness is between 8-30 pm. 2. The process of claim 1, wherein the capsules are coated with a 3% alcohol solution of hydroxypropylmethylcellulose having a molecular weight of about 100,000. 183,053 3. The process of claim 1 wherein the capsules are coated with an alcoholic solution of polyvinylpyrrolidone having a molecular weight of about 40,000. .4. The process of claim 1, wherein the film coating is formed in a fluidizing device or a dragee drum.