DE3135917A1 - CARRIER FOR ONE OR MORE MEDICINAL PRODUCTS AND METHOD FOR THE PRODUCTION AND USE THEREOF - Google Patents

Description

HOFFMANN · EITLE

PAT E N TANWAETE DR. ING. E. HOFFMANN (1930-1976) Dl PL.-I NG. W. EITLE DR.RER. NAT. K.HOFFMAN N DIPL.-I NG. W. LEH N

DIPL.-ING. K. FDCHSLE ■ DR. RER. NAT. B. HANSEN ARABELLASTRASSE 4 D-8000 MO NCH EN 8V. TELEPHONE (089) 911087. TELEX 05-29S19 (PATHE)

35 568 m / wa

JOHAN ALFRED OLOF JOHANSSON, OLOFSTRÖM / SWEDEN

Carrier for one or more medicaments, as well as processes for their production and their use

The invention relates to a solid or semi-solid carrier which comprises one or more medicaments, a method for producing the same and its use.
5

In the treatment of various stages of the disease Difficulties generally arise in maintaining a steady and uninterrupted Drug concentration. Often, with intermittent dosing, either to high or low concentrations with respect to the

3 * 0 β C) «β A 0 β β Ci

ο 6 β ρ ü t <■ «« β g ο ι-

get ideal treatment concentration.

If desired, an adequate minimum concentration for a specified time, e.g., during treatment infection, this results in an overdose in connection with or immediately after the intermittent dose.

This often leads to side effects of differentiated Difficulty levels.

There is therefore a great need for a drug preparation, which over a long period of time drugs in therapeutically desirable concentrations releases. ,

U.S. Patent 3,867,519 has attempted to address this need Use of a device or a carrier in the form of a film to correspond. In this case it will the carrier is made of a polyelectrolyte, which with a divalent or polyvalent metal ion is cross-linked. The carrier contains one or more drugs. These drugs can e.g. Microcapsules may be included, which in turn are incorporated into the carrier. The microcapsules are made in the usual way by coating the drug with a thin layer of polymer.

However, the known carrier and the manufacture thereof have a number of disadvantages. So must ZoB. the carrier after the crosslinking reaction

O ΙΟϋΟ

be washed carefully. In this way there are great losses of the drug.

In addition, the carrier has poor flexibility in terms of the release mechanism of the drug.

After the crosslinking reaction, the polymer contains toxic Heavy metals such as cadmium or barium. These metals are used in the bioerosion of the polymer when using the carrier, e.g. released into the eye.

The object of the present invention is to overcome the disadvantages that arise according to the prior art, to overcome. Surprisingly, it has been shown that the need for a medicament preparation, which the medicament for a long period of time releases in therapeutically desired concentrations can be satisfied.

. - ■ The above object is achieved according to the invention by a solid or semi-solid support, e.g. in the form a membrane, an envelope or a film, solved in that particles of one or more cross-linked Gelchromatografischer materials are incorporated into the carrier, said gelchromatograf ical materials "contain one or more drugs, and that the carrier is made of a polymer was prepared without adding a crosslinking agent.

■ According to a preferred embodiment according to

* (vagitory), which contains one or more drugs and is made of a polymer, such as _ q _ Consists of agar, agarose or a derivative thereof,

χ \

«6 * ft * α φ ι

* · B 4 d - »« θ 6

Β> α β Λ

~ 9 -

In accordance with the invention, the carrier is made from at least one of the following polymers: agar, agarose or a derivative one of the same, manufactured. Particularly good results are obtained when the polymer is made up alone Consists of agarose.

According to a further preferred embodiment according to the invention, the carrier is produced from a mixture of at least one of the polymers agar, agarose or a derivative of one of these and at least one other polymer. In this case, the other polymer suitably has hydroxyl groups . ■ ■

Examples of such polymers containing hydroxyl groups are: starch, dextran, cellulose, Agaropectin or a derivative of one of the same. Other polymers containing OH groups can also be used. The carrier can have functional groups such as anionic or cationic groups. The anionic Groups can represent, for example, carboxyl groups, sulfonic acid groups or phosphoric acid groups, while the cationic groups e.g. diethylaminoethyl groups, ß-morpholinoethyl groups or di- (hydroxyethyl) aminoethyl groups can represent.

According to the invention, particles are made up of one or more cross-linked gel chromatographic materials incorporated into the carrier as described above. The said gel chromatographic material should consist of a crosslinked polymer which may have hydroxyl groups, such as a crosslinked one

- 10 -

Polyvinyl alcohol or a crosslinked carbohydrate or a crosslinked derivative of one of these polymers. Examples of suitable carbohydrates are: crosslinked dextrin, starch, dextran, cellulose or a derivative of one of the same. -

Other gel chromatographic materials, such as cross-linked polyacrylamide or polyvinylpyrrolidone, can be used. In certain cases these polymers can also contain hydroxyl groups.

The gel chromatographic material can be anionic or include cationic groups. The anionic groups can be, for example, carboxyl groups, sulfonic acid groups or represent phosphoric acid groups.

On the other hand, the cationic groups, e.g. diethylaminoethyl groups, can be β-morpholinoethyl groups or represent di (hydroxyethyl) aminoethyl groups.

The aforementioned gel chromatographic materials are known per se. In this regard, reference is made to the publication "Gelchromatography" · νοη Determann (1967), GB-PS 854 715 and 974 054, US-PS 3,277,025 and 3,275,576 and SE-PS 209 015 and 222 291 pointed out.

It is preferred that the gel-chromatographic material μΐη an average particle size of 10 to 1000 \ im, more preferably from 20 to 500, comprising. ·

- 11 -

- 11 -

The particles of the gel chromatographic material can preferably into the carrier by mixing it with the polymer which is used for the preparation of the Carrier is used to be incorporated. As stated above, the carrier has the shape a film, a casing or a jacket or a membrane. The carrier or the Device can be made, for example, by molding.

The particles of the gel chromatographic material should comprise one or more different drugs. These drugs can be incorporated into the gel chromatographic material in a number of ways e.g. by absorption / adsorption, ionic bonding, complex bonding or chemical bonding. The method of incorporation is chosen according to the physical and chemical properties of the drugs of the drug, but also depending on how quickly the drug is used should be released.

In general it is possible to use gel chromatography Adapt material to suit the properties of the medicinal product in a suitable manner.

According to the invention, separate gel chromatographic materials can be used for each drug, if so desired.
30th

According to one embodiment according to the invention contains

- 12 -

O I O O O i /

- 12 -

not only the gel chromatographic material, but also the carrier itself, one or more drugs. These drugs can be incorporated into the material of the carrier in the same manner as in connection with above the incorporation of "drugs" into the gel chromatographic Material described, incorporated.

In general, the carrier contains 75 to 99% by weight of water in the water-swollen state. In the treatment

It is special for skin, wounds and mucous membranes it is preferred that the carrier swell in water or in a physiologically acceptable sodium chloride solution will. In this state, the wearer is so accepted by the tissue that it is even in the The orbit and releases the drugs there, such as antibiotics or intraocular pressure reducing agents such as pilocarpine. Examples of other drugs incorporated into the carrier are listed in US Pat. No. 3,867,519.

In addition, the carrier can contain spermicides, enzymes or prostacyclines. "- ·

When particles of a gel chromatographic material are incorporated in the support according to the invention the rate of release of the drug can be regulated in a satisfactory manner. -

In this embodiment according to the invention must namely, the drugs first traverse the gel chromatographic material and then the carrier until they finally, ζ e.g. pass into the mucous membrane.

- 13 -

β · Ο

By choice of gel chromatographic materials A suitable impermeability and the associated diffusion properties can increase the speed the release of the drug can be regulated. In addition, it is in the manufacture of a carrier, which comprises several different drugs, possibly, as mentioned above, a specific one to incorporate gel chromatographic material for each drug. In this case, the different gel chromatographic materials have the same or different opacity as well have the associated diffusion properties. In this way it is possible to produce combination preparations produce in which the different drugs with the same or with a different Speed to be released. Of course, the proportion of drugs in the gelchromatograf ical material can be varied widely, depending on the type of drug and on the Type of gel chromatographic material.

According to the invention, it is possible to make extraordinary Regulation options with regard to the speed of the release as well as the proportioning of the To create a medicinal product.

When the drug is anionic or cationic groups contains, it is possible to further improve the binding ability of the carrier and later one to release larger amounts of medicinal product on the condition that the gel chromatographic material has counterions,

\ J I

such as corresponding cationic and anionic ions.

The rate of release of such ionically bound drugs can be compared to the above further embodiments described can be regulated to a greater extent. In this case be namely, the drug is only released after an ion exchange process, with the main thing being Sodium ions in a wound or mucosal fluid first in and through the wearer and then in the particles of the gel chromatographic material migrate have to. The drug itself must diffuse through the gel chromatographic material and the carrier, until it finally enters a mucous membrane, for example. ■

The time it takes for the drug to diffuse required from the particles of the crosslinked gel chromatographic material can also be extended thereby that the particles are covered with a thin sealing layer of a suitable material such as e.g. polyvinylpyrrolidone.

According to one embodiment according to the invention the carrier advantageously by dissolving or suspending agar and / or agarose and / or a Derivative of one of these polymers in an aqueous solvent, optionally together with one or several other polymers, whereupon particles of one or more cross-linked gel chromatography

- 15 -

Materials containing one or more drugs with the appropriate solution or suspension be mixed. The mixture obtained in this way then becomes a solid or semi-solid Carrier or a corresponding device converted, e.g. in the form of a film, a cover or Encapsulation, or a membrane, by applying it to a surface or introducing it into a mold whereupon it is quenched or slowly cooled.

This solution or suspension of the above polymers is generally prepared with heating.

As mentioned above, the carrier can be made of, for example, a film, envelope or membrane. exist, which in turn can be shaped to the desired size, e.g. by cutting. It is Of course, it is very efficient to manufacture the film, the shell or the membrane by molding or casting, there in this way a continuous manufacturing process can be carried out. The division of the film or membrane into smaller parts can also be done according to a rational process.

According to the invention, it is also possible to use the carrier in other forms, as foils, envelopes or membranes, to manufacture. However, the above forms have a very wide field of application.

The carriers according to the invention generally contain

- 16 -

ο ι \; vj j

75 to 99% by weight of water in the water-swollen state. They often provide direct evidence of this water content. their manufacture on. In general, a film according to the invention, which has this water content, soft, flexible and slippery. It is often transparent. Under the microscope it can easily be seen that the particles of gel chromatography Material in the polymer material, which is the film itself, are embedded. 10

The invention is described in more detail below by means of exemplary embodiments. Example 1 describes the production of a membrane in which gel chromatographic particles are embedded. The particles contain the medicine pilocarpine. Example 2 also relates to the production of a membrane "in which gel-chromatographic particles are embedded. In this case the particles contain complex-bound iodine.
20th

Example 3 shows the production of a cylindrical support or a device in which gel chromatographic Particles containing prostaglandin are incorporated. Example 4 relates to manufacture a combination preparation in the form of a membrane, in which particles of two different gel chromatographic Materials are incorporated. The former are gel chromatographic Particles contain a local anesthetic while the others contain an anti-inflammatory drug contain. In addition, the material of the wearer itself contains a local anesthetic. In the end

-17

Example 5 relates to the production of a membrane in which gel chromatographic particles containing a Antibiotic are incorporated.

example 1

A gel chromatographic material consisting of the sodium salt of carboxymethyldextrin, which had been prepared from dextrin according to US Pat. No. 3,277,025 and 3,275,576, had a gel bed volume of 6.5 ml / g and an ion exchange capacity of 0 .4 mekv / g in terms of carboxymethyl groups. . · ■

40 g of this gel material were placed on a suction filter and treated with 400 ml of 0.16N hydrochloric acid in an aqueous solution which contained 50% ethanol and 50% distilled water.
20th

The gel was then distilled to a neutral reaction with 400 ml of a mixture of 50% ethanol and 50% Water washed,

The gel was sucked dry and then on the suction filter with a solution of 10 g pilocarpine hydrochloride (Merck) in 200 ml of a mixture of 50% ethanol and 50% distilled water.

The gel was then distilled to neutral reaction with a solution of 75% ethanol and 25%

- 18 -

OIOO U I /

Washed water and then shrink in 99.5% ethanol calmly.

After drying in a drying chamber for 5 hours at 75 ^° C., 38 g of a dry powder with a nitrogen content of 0.34% were obtained.

A solution of 4 g of agarose (AGAROSE A 37, INDUBIOSE®, Pharmindustrie) in 100 g of water was obtained by heating on a boiling water bath. The solution was then chilled to 60 ⁰ C, followed by 5 g of the powder of the above gelchromatografischen ma- •. terials, which contained ionically bound pilocarpine, added.

· ■

The suspension obtained in this way was in a 3 mm thick layer applied * to a glass plate. "The suspension is allowed to cool to room temperature. Then the support was obtained in the form of a transparent, soft, flexible and slippery membrane. It could be cut into pieces of the desired shape and size will. Under the microscope it was found that the gel chromatographic particles, which contain the ionically bound pilocarpine, were embedded in the membrane. '

The membrane produced in this way is suitable for the treatment of the eye disease glaucoma. This will be a part of the membrane of a suitable size is placed under the upper eyelid, where the pilocarpine gradually becomes is released to the mucous membrane of the eye.

- 19 -

Example 2

A cross-linked gel chromatographic material containing iodine, which was made from sugar according to SE-PS 405 680, had an iodine content of 1.11%, an ion exchange capacity of 0.92 mekv / g with respect to on the carboxymethyl groups in acid form, a gel bed volume of 7.3 ml / g and an average particle size of 70 μm.

3 g of this gel material became a solution having a temperature of 45 ° C. and a content with stirring 6 g of agarose (agarose A 37, Kebo 1.7539) in 100 ml of distilled water are added. Once the homogenization was reached, the viscous suspension was applied to a glass plate in a 2 mm thick, flat layer. The suspension is allowed to cool to 22 ° C. This was then solidified into a membrane, which e.g. suitable for disinfecting skin and wound surfaces.

Example 3

A prostaglandin-containing cross-linked gel chromatographic material made from hydroxyethyl cellulose according to British patent application 8001176 had a gel bed volume of 5.3 ml / g and contained 0.35% prostaglandin (PGE ₀ ).

- 20 -

J I J D 3 I /

7 g of this gel material was added with stirring to a solution having a temperature of 44 ⁰ C and a content von.1,06 g agarose (agarose A 37, Indubiose ^, Pharm Industry) and 0.53 g of hydroxyethyl cellulose (hydroxyethyl cellulose, type 822068, Merck ) added in 50 ml of distilled water.

• "" The suspension obtained in this way was added to the Form of cylindrical shells with a diameter of 15 mm and a length of 30 mm by cooling in brought to a form. In this way 10 casings were obtained. Of these, 5 were obtained in a manner known per se freeze-dried.

All vagitories, regardless of whether whether or not they were freeze-dried, were for intravaginal use, possibly after one Radiation sterilization provided. They were used to speed up the completion of a pregnancy or for termination of pregnancy in connection with legal abortion.

25. Example 4 ■

0.2 g lidocaine (lidocaine, chloride, anhydrous) were in 1 ml of water · dissolved, whereupon the pH value to 6.5 by Addition of sodium hydroxide was stopped. · 'The solution obtained in this way was with 2 g

- 21 -

Λ · ■ *

- 21 -

commercially available gel chromatographic material (Sephadex ^, G-25, Pharmacia Fine Chemicals) with a particle size of 20 to 80 μm and a gel bed Volume of 4.8 ml / g mixed in water. The solution is left in the gel chromatographic material Diffuse stirring, whereupon the product obtained was dried.

5 g of the anti-inflammatory drug (Betnovat 0.1% solution, Glaxo Laboratories Ltd.) was mixed with 2.5 g of a commercially available gel chromatography . ^ v ^ wv, ^ * «. ^^, - ^ w ^« ^ .. LH-20, Pharmacia Fine Chemicals) with an average particle size of 60 μm and a gel bed volume of 4.1 ml / g mixed in water.

The solution is left with stirring in the gel chromatographic Diffuse material, whereupon the product obtained is dried.

A solution of 0.6 g of agarose (Agarose A 37, Indubiose ^ Pharmindustrie) in 20 ml of water was prepared by heating on a boiling water bath with stirring. The resulting solution was abgesehreckt at 45 ⁰ C, were stirred and then the above-prepared two products in the solution.

A solution of 0.2 g of lidocaine (lidocaine chloride, anhydrous) in 1 ml of distilled water was added. The pH of this solution was increased by adding adjusted to 6.5 by sodium hydroxide. The on

- 22 -

The suspension obtained in this way was applied to a glass plate in a 2 mm thick layer. Man
lets cool to 20 ^{0 C.} The membrane obtained could be cut into pieces and was suitable, for example, for the treatment of painful and infected wounds.

Example 5
. ~ ^ -, w ——- ....., j , Parke-Davis, USA) were dissolved in 8 ml of distilled water. The solution obtained in this way was added with stirring to 2.0 g of gel chromatographic polyacrylamide gel (Biogel P-6, Bio-Rad Laboratories, USA) with a
average particle size of 60 μΐη added. The product obtained in this way was freeze-dried in a manner known per se.

. ·

A solution of 0.5 g of agarose (Agarose A 37, "Indubiose ^, Pharmindustrie) in 20 ml of distilled
Water by warming it on a boiling water bath
produced with stirring. ■■

The solution obtained in this way was ^{quenched to 46 °} C., whereupon the above product was mixed with the solution.

The suspension thus obtained wuijde in a 2.5 ml thick Layer applied to a glass plate. One lets up.

- 23 -

20 ⁰ C to cool. The solidified membrane could be cut to the desired dimensions for the treatment of wound infections and eye infections, for example.

Claims (22)

HOFFMANN · EITLE. & ^ I PATENT LAWYERS DR. ING. E. HOFFMANN (1930-1976) ■ Dl Pl.-t NG. W. EITLE DR.RER. NAT. K. HOFFMANN. DIPL.-ING.W. LEAN DIPL.-ING. K. FOCHSLE DR. RER. NAT. B. HANSEN ARABELLASTRASSE 4 ■ D-8000 MO NCHEN 81. TELEPHONE (089) 911087. TELEX 05-2J619 (PATHE) 35 568 m / wa JOHAN ALFRED OLOF JOHANSSON, OLOFSTRÖM / SWEDEN Carrier for one or more medicaments / as well as processes for its production and its use PATENT CLAIMS Solid or semi-solid support, e.g. in the form of a membrane / envelope or a film, which comprises one or more medicaments, this carrier consisting of a polymer "from the group agar, Agarose and a derivative of one of these polymers is produced, characterized in that that particles of one or more cross-linked gel chromatographic materials in the carrier are incorporated, said gel chromatographic materials being a or contain several drugs, and that the carrier was made from a polymer without the addition of a crosslinking agent. 1 O O O I / 2. Carrier according to claim 1, characterized in that the gel chromatographic Both the material and the carrier itself contain one or more drugs. 3. Carrier according to claims 1 or 2, characterized in that it consists of a Mixture of agar and / or agardse and / or a derivative of one of these polymers and at least another polymer is made. 4. Carrier according to claim 3 ", characterized in that it consists of agar and / or Agarose and / or a derivative of one of these polymers and at least one other hydroxyl group-containing polymer. 5. Carrier according to claim 4, characterized in that the hydroxyl groups contain Tending polymers is starch, dextran, cellulose, agaropectin or a derivative of one of these polymers. ■ 6. Carrier according to claims 1 or 2, characterized · Indicated that it is made from agarose or a derivative thereof. 7. Carrier according to one or more of claims 1 to 6, characterized in that that it contains functional groups such as anionic or cationic groups. 8. Carrier according to claim 7, characterized in that the anionic groups e.g. represent carboxyl groups, sulfonic acid groups or phosphoric acid groups. 9. Carrier according to claim 7, characterized in that the cationic groups e.g. diethylaminoethyl groups, ß-morpholinoethyl groups or di (hydroxyethyl) aminoethyl groups represent. 10. Carrier according to one or more of claims 1 to 9, characterized in that that the gel chromatographic material is a cross-linked Polymer represents. 11. Carrier according to claim 10, characterized in that the gel chromatographic Material is a cross-linked, hydroxyl group-containing Polymer such as a carbohydrate or a derivative thereof. 12. Carrier according to claim 11, characterized in that the gel chromatographic Material e.g. a cross-linked compound from the group dextrin, starch, dextran, cellulose, or a derivative of one of these polymers. 13. Carrier according to claim 10, characterized in that g e k e η η, that the gel chromatographic material is a cross-linked compound of the • Polyvinyl alcohol, polyacrylamide or polyvinylpyrrolidone group represents. 14. Carrier according to one or more of claims 1 to 13, characterized in that that the gel chromatographic material contains anionic or cationic groups. 15. Carrier according to claim 14, characterized in that g e k e η η, that the anionic groups e.g. carboxyl groups, sulfonic acid groups or Represent phosphoric acid groups. . 16. Carrier. According to claim 14, characterized in that g e k e η η, that the cationic groups e.g. diethylaminoethyl groups, ß-morpholinor represent ethyl groups or di (hydroxyethyl) aminoethyl groups. 17. Carrier according to one or more of the claims 1 to 16, characterized in, that the gel chromatographic material has an average particle size of 10 to ΙΟΟΟμίη, preferably 20 to 500 μm. " 18. Carrier according to one or more of claims 1 to 17, characterized in that that the particles of the gel chromatographic material are embedded in the support. · 19. Carrier according to one or more of the claims α 4 »iii e m ύ · ή * -a α α - ■ 5 1 to 18, characterized in that that this contains 75 to 99% by weight of water in the water-swollen state. 20. Use of the carrier according to one or more of claims 1 to 19 for application on wounds, on the skin or on the mucous membranes. 21. · Process for the production of a carrier according to one or more of claims 1 to 19, characterized in that agar and / or agarose and / or a derivative of one of these polymers, optionally together with one or several other polymers, dissolved or suspended in an aqueous solvent, whereupon particles of one or more cross-linked gel chromatographic materials, which contain one or more drugs, mixed with the appropriate solution or suspension the mixture thus obtained on a solid or a semi-solid support, e.g. in the form of a film, an envelope or a membrane, by applying the same to a surface or is transformed by means of a form, whereupon this is quenched or slowly cooled = 22. The method according to claim 21, characterized in that the solution or suspension is formed with the application of heat. 30th - 6 -