CH653550A5 - PHARMACEUTICAL COMPOSITION FOR DELAYED RELEASE OF A MEDICINE IN THE ORAL AREA. - Google Patents

Description

The invention relates to a pharmaceutical composition for the delayed release of a medicament for use in the mouth, as defined in claim 1.

Delayed release pharmaceutical compositions are designed to allow steady and continuous release of the drug over a long period of time, thereby avoiding the need for frequent drug administration. Certain delayed release pharmaceutical compositions which are capable of adhering to the oral mucosa are already known. The drug, if it is systemically effective, penetrates directly through the mucous membrane of the mouth into the bloodstream. On the other hand, the drug can also be locally active against diseases in the mouth area. A proposed strip strip in the mouth area is equipped for use so that it has a reservoir for the active ingredient and a pressure-sensitive adhesive layer which sticks the strip to the surface of the mucous membrane of the mouth or the gums. The container contains the active ingredient, for example an oxytoxic drug in microencapsulated form in a film made of a polymer such as polyvinyl acetate, which is completely insoluble and does not become permeable in contact with the mucus, but which is permeable to the medicament, if the adhesive strip is attached to the inside of the mouth, there is.

However, these pharmaceutical compositions are complicated in their structure, they often do not release the active ingredient satisfactorily and the bioavailability characteristics are inadequate for many pharmaceuticals. In addition, the drug containers have a tendency to release only a small proportion of the drug in the film.

Recently published European Patent Application No. 20,777 and U.S. Patent No. 4,292,999 describe sustained release pharmaceutical compositions in the form of compressed tablets with flat top and bottom surfaces that have two layers, one of which is a non-stick layer which is either water-soluble or decomposable in water, adheres to a surface of the mucous membrane and which swells when in contact with water.

Such compositions can have disadvantages. For example, the tablets cannot adhere securely to the mucous membrane, especially if they are of sufficient size to accommodate large proportions of a medicament that allow satisfactory delayed release over a longer period. The tablets can also cause discomfort if they stick to the lining of the mouth. Furthermore, there is no possibility to visually distinguish between a non-adhesive and an adhesive layer, which can be cumbersome in practice.

After exhaustively examining many systems for administering medication in the mouth, we have created a pharmaceutical composition that has interesting release properties, simple construction and a wide range of uses.

The present invention consists of a pharmaceutical composition for delayed release of a medicament in the mouth area and contains i) a non-adhesive, water-soluble or water-decomposable layer,

ii) an adhesive layer which is suitable for adhering to the mucous membrane of the mouth, and iii) a medicament in at least one of these layers, and is characterized in that the outer upper compartments of the adhesive layer conform to the shape of the mucous membrane of the mouth which of the compositions is to be applied, adapted or adapted.

The outer surface of the adhesive layer is expediently shaped such that it is concave on the inside in order to match the outer surface of the gums. The outer surface of the non-adhesive layer is preferably convex on the outside.

The exact radius of curvature depends on the shape of the mucous membrane to which the pharmaceutical composition according to the present invention is applied. Preferably, the pharmaceutical compositions according to the present invention are applied to the inner surface of the gums in the vicinity of the upper large molar tooth. The adhesive layer is expediently characterized by a different color than the non-adhesive layer.

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The preparation of the pharmaceutical composition can, as in the European. Patent application no. 20 777 and US Pat. No. 4,292,999 are described, the individual components being incorporated as described therein. The pharmaceutical compositions are preferably produced by compressing a granulate in a form such that tablets with correspondingly curved surfaces are obtained. Another preferred form of the pharmaceutical composition is a flexible film strip.

The pharmaceutical composition for administering a medication in the mouth area is preferably in the form of a film strip. This is conveniently called the buccal stripe.

This film strip consists of i) a non-adherent polymer film which becomes porous on contact with and is wettable through the mucous membrane of the mouth,

ii) an adhesive layer capable of adhering to the inside of the mouth, and iii) a medicament dissolved or dispersed in at least one of these layers.

The constituents of the non-adhesive layer, in particular the polymer, should be chosen so that they dissolve slowly, care being taken to ensure that the dissolution rate is not too rapid, since on the other hand a satisfactory delayed release is not achieved. It is desirable that the non-stick layer dissolve for 5-24 hours.

The non-stick layer can be made of any suitable polymer, for example an acrylic acid polymer and co-polymer, hydrophilic vinyl polymer, polysaccharides, etc.

Suitable non-adhesive layers can consist of cellulose derivatives which form corresponding permeable films which can be formed by conventional physical means such as e.g. B. Electro-microscopy, can be determined. Cellulose derivatives that come into question include methyl cellulose (e.g. with the brand name Methocel), ethyl cellulose (e.g. with the brand name Ethocel) and preferably hydroxypropyl cellulose (e.g. with the brand name Klu-cel).

Preferred hydroxypropyl cellulose polymers are those obtained by reacting alkali cellulose with propylene oxide, as described, for example, on page 307 and following in Encyclopedia of Polymer Science and Technology, Vol. 15, Supplement 1973, and which have a bookfield viscosity from 4000 to 6500 in a 2% aqueous solution.

If desired, the film may also contain a plasticizer, for example a hydrophilic plasticizer in concentrations of 5-30% by weight, to give the film sufficient flexibility and foldability to easily conform to the bulges of the mouth and a satisfactory release of the drug allowed. A preferred plasticizer is polyethylene glycol (molecular weight 100-500) or glycerol triacetate such as triacetin.

Of course, other polymers and excipients can also be incorporated into the pharmaceutical composition according to the invention, as long as the composition obtained is decomposable, soluble or porous on contact and can be moistened by the mucus of the mouth.

Any adhesive can be used in the adhesive layer. A suitable adhesive is a water-soluble cellulose gum, such as sodium carboxymethyl cellulose.

Any medication is necessary for the administration of the pharmaceutical composition according to the invention

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suitable. Preferred drugs are used in the form in which they are sufficiently stable in the oral mucosa. It has been found, for example, that for use in the pharmaceutical composition according to the present invention, the medicament should be stable under weakly acidic conditions, for example pH 5.8.

The medicament is preferably sufficiently active that the pharmaceutical composition according to the present invention can be of a reasonable size in order to release sufficient amounts of the active ingredient over a long period of time.

For the pharmaceutical composition according to the present invention, the medicament is preferably in a form that is acceptable in terms of taste or is completely tasteless. The pharmaceutical compositions according to the present invention are particularly indicated for the local administration of drugs which are effective against oral diseases.

On the other hand, the pharmaceutical composition according to the invention is also suitable for the administration of medicaments which cannot be administered orally satisfactorily, for example because of poor absorption from the gastrointestinal tract or because of a high first-pass effect.

Typical drugs that can be used in the pharmaceutical composition according to the present invention are vasoconstrictors, vasodilators, beta-blockers, calcium antagonists, attention-increasing agents, migraine agents, analgesics, antipyretics, local anesthetics, anti-parkinson drugs, anti-obesity agents, sympathomimetics, Diuretics, antihistamines, analeptics, antihypertensives, antibiotics, anti-inflammatory agents, myotonolytics, CNS stimulants, antidepressants, neuroleptics, tranquilizers, antiagressants, antiasthmatics, antidiabetics, anticonvulsants, prolactoneinhibitors. The drugs can be local or systemic. The drug can also be a vasodilatory nitrate, for example. The pharmaceutical compositions according to the present invention show interesting and surprising release and bioavailability characteristics when the medicament is an ergot alkaloid, for example a cyclic ergot peptide alkaloid, in which the Lyserg-45 acid part is optionally hydrogenated in the 9.10 position. A preferred ergot alkaloid is codergocrin. On the other hand, however, it can be ergotamine, dihydroergotamine, bromergocryptin, methyllysergide or methylergobasin. Preference is given to using beta blockers as medicaments, such as, for example, pindolol, mepindolol, or in particular other preferred medications, such as, for example, Dihydropyridine, calcium antagonists, such as, for example, 4- (2,1,3-benzoxadiazol-4-yl) -1,4-dihydro-2,6-dimethylpyridin-3,5-carboxylic acid diethyl ester or 55 4- (2,1, 3-benzoxadiazol-4-yl) -1,4-dihydro-5-methoxy-carbonyl-2,6-dimethyl-3-pyridinecarboxylic acid isopropyl or

4- (2,1,3) -benzothiadiazol-4-yl-1,4-dihydro-2,6-dimethylpyridin-3,5-carboxylic acid methyl ester.

In another variant, the medicament is preferably N (1,6-dimethylergolin-8a-yl) -N ', N'-dimethylsulfamide. The medicament is preferably micronized. If desired, the medicament can be in the form of a pharmaceutically acceptable acid addition salt. 65 The pharmaceutical composition according to the invention can also contain other hydrophilic pharmaceutical additives, for example flavors, sweeteners and other agents for covering an undesirable substance.

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taste of the drug, preservatives, etc.

The pharmaceutical composition according to the present invention can have any desired thickness. It is preferred to use a non-adhesive layer approximately 0.1 to 5 mm thick, particularly 0.2 to 1.7 mm thick, and an adhesive layer approximately 0.05 to approximately 0.5 mm thick , in particular approximately 0.08 mm thick. The single pharmaceutical composition according to the invention can be of any desired shape and dimension. It is preferred to use a rectangular film strip approximately 1 cm x approximately 3 cm in size with rounded corners.

Pharmaceutical compositions according to the invention can be prepared as described in European patent application 20 777 and US patent 4,292,999.

The pharmaceutical composition according to the present invention, which is in the form of a strip, can be produced in a manner known per se in a continuous drawing, melting, dissolving or spraying process or in a corresponding non-continuous process. The layers can be built up in several stages. If desired, the non-stick layer can also be built up in different stages. The adhesive layer is then added in the final stage.

Another manufacturing method can be to first make the adhesive layer and build the non-adhesive film layers on top of that adhesive layer. The process for producing individual layers can be carried out in a manner analogous to that described in British Patent 1,510,999, which describes the production of single-layer films for oral or vaginal administration.

In a simple, non-continuous process, the components of the film layer can be dissolved or suspended in a volatile solvent, giving a highly viscous liquid which is then poured onto a smooth surface, for example a siliconized glass plate. The solvent should of course be selected so that any residue thereof is pharmaceutically acceptable. Suitable solvents are acetone and ethanol. The solvents should be able to escape at room temperature or at a slightly elevated temperature. If desired, the film layer can be built up in several stages. The constituents of the adhesive layer can be sprayed onto the surface of the film layer in a suitable solvent, for example water, and the solvent can then be evaporated.

The remaining film is then removed, for example with a spatula, optionally after previously treating the film with dry ice to facilitate removal. The film is then cut into strips. Each strip can be packed in a flexible protective container, which is made of aluminum foil, for example.

The preferred proportion and the concentration of the medicament in a special pharmaceutical composition according to the invention will in particular include depend on the release characteristics of the pharmaceutical composition, the size of the pharmaceutical composition and the strength and characteristics of the medicament and the period of time in which the pharmaceutical is to be used.

In general, a once-daily pharmaceutical composition suitable for buccal use is said to be about 0.1 to 10, especially 1

up to 10 times the daily dose of the drug. The proportion of the medicament is preferably less than 50 per pharmaceutical composition, in particular less than 20 mg. A suitable dose is from 1 to 10 mg if an ergot alkaloid of the class described above is used. The drug suitably comprises from 0.1 to 5% of the total film weight. The medicament is preferably in the non-adhesive layer.

If the medicament is distributed in the pharmaceutical composition according to the invention, the particle size of the medicament should expediently be less than 50 microns.

For use, the pharmaceutical composition according to the invention is glued to the outside or inside of the gums, in particular in the vicinity of the molar with the help of the adhesive layer. It has been found that the pharmaceutical composition according to the invention usually remains in place and causes a minimum of nuisance even while smoking, drinking and eating.

The following examples illustrate the invention. The following should be noted in the examples:

1) Codergocrine mesylate is micronized; the particle size is smaller than 50 μm in diameter. Pindolol is micronized in the same way.

2) HPC = hydroxypropyl cellulose, trademark Klucel LF, available from Hercules, USA,

3) triacetin = glycerol triacetate,

4) NaCMC = sodium carboxymethyl cellulose, trademark 7MF from Hercules, USA,

5) the lemon taste is Tetrarome aroma (liquid),

6) Ethyl cellulose has the brand name Ethocel from Dow, USA.

More information about the additives is available in H.P. Fiedler, Lexicon of auxiliaries for pharmacy, cosmetics and related areas, Editio Cantor, Aulendorf, West Germany, 2nd edition, 1981, as well as from the manufacturers described above, for example Klucel, brochure on chemical and physical properties, 1976 by Hercules.

Example 1:

Co-dergocrine film strips

Composition of the film

Components per strip per batch

(1x3 cm) mg g

Film layer

Co-dergocrine mesylate "4.5 3.19

HPC2 '186.9 156.76

Triacetin3 '60 50,174

FD + C Blue No. 2 (color) 0.24 0.21

Adhesive layer

NaCMC4 '47.9 40

299.54 250.434

Manufacturing

A batch of the components of the film layer is stirred in 600 ml of an acetone / methanol (1: 1) mixture to give a highly viscous mixture. The mixture is poured onto a glass plate, the surface of which has been siliconized by treatment with dimethylpolysiloxane and o-xylene (1:10), then heated to 240 ° C. for 5 hours and finally cooled. In order to obtain a flat layer, an appropriate device 3 mm s

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moved above the surface of the glass plate. The mixture is then dried at room temperature for 48 hours, a film layer (of approximately 0.291 mm thickness) being obtained.

40 g of sodium carboxymethyl cellulose is dissolved in 1 liter of water. The liquid is applied to the film layer and dried to give an adhesive layer approximately 0.082 mm thick. The remaining film is treated with dry ice, being cooled and then removed with a spatula.

The film is cut into strips of 1 cm x 3 cm (approx. 300 mg weight), the corners being rounded. For use, the buccal strip is glued to the outer side of the upper gums of the mouth.

The buccal strip composition was administered to 6 healthy subjects, the results obtained are:

Time (hrs)

Blood plasma (ng / liter)

Urine (% of dose)

2nd

0.09 (+ 0.03)

-

4th

0.26 (+ 0.06)

0.09 (+0.03)

6

0.33 (+0.08)

-

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0.32 (+ 0.06)

0.35 (+0.06)

24th

0.07 (+0.02)

0.69 (+0.11)

48

-

0.82 (+0.13)

The figures show a significant delay in the release of the drug.

Example 2:

Pindolon film strips Analogously to Example 1, 300 mg of buccal strips containing pindolol are produced with the following composition:

Components

Proportion per strip in mg a) b)

Film layer pindolol (free base)

HPC2 »

Ethyl cellulose6 »

PEG 200

Saccharin sodium lemon flavor

Adhesive layer NaCMC4 »

Tartrazine (FD + C No. 5)

Sodium saccharine

Lemon taste

5.6 232.9

1.5

59.7 0.3

7.74

75.81

94.82 18.97

1.27 1.27

101.15 0.07 0.64 1.26

Example 3:

Co-dergocrin film strips The following compositions are made:

Components

Per strip Per batch ms g

Adhesive layer

NaCMC4 »32.6

Tartrazine (F D + C Yellow 5) 0.16

Film layer

HPC2) 381.64

Co-dergocrine mesylate "4.5

80 0.4

936.3 11

Manufacturing

The batch of adhesive layer components is dissolved in 200 ml of 40% ethanol. Half of this mixture is sprayed onto a glass plate which has been prepared in accordance with Example 15, a flat, dry layer analogous to that described in Example 1 being obtained. The process is repeated with the rest of the mixture to increase the thickness of the adhesive film layer, which is then allowed to dry.

io A batch of the film layer components (first with Co-dergocrin and then with HPCL) is dissolved in acetone / ethanol (1: 1 4200 ml). A quarter of this mixture is then sprayed over the adhesive layer, a film layer being obtained in an analogous manner to that described in Example 1 and drying overnight. This is repeated 3 times, using up the rest of the mixture and increasing the thickness of the film. The film is finally dried for 2 days.

The film layer is cut into strips of 3 cm which are suitable for use in the mouth area, each weighing 418.9 mg and having a thickness of 1.1625 mm.

Release share of the active ingredient 25 6 strips are immersed in 5 ml of an aqueous stirred phosphate buffer solution at pH 5.1 and the amount of the active ingredient which is released into the buffer solution is measured spectrophotometrically.

30th

Time min.

Release%

Standard deviation%

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4.6 6.4 11.4 19.8 29.2 36.8 45.8 54.1

0.8 0.8 1.5

3.5

3.6

6.0

6.1 8.4

As can be seen from the figures, approx. 45 10% of the active ingredient are released per hour.

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Example 4 Pindolol film strips

Components

Mg per strip

Per batch

Adhesive layer NaCMC4 »indie carmine (FD + C Blue No. 2)

60 film layer HPC2 '

Pindolol (base)

32.6 0.16

381.64 15

80 0.4

936.3 38.0

65 In the same manner as described in Example 3, strips for use in the mouth area are produced with a weight of 418.9 mg and a thickness of 1.625 mm.

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Released portion of the active ingredient (analogous to example 3)

Time min.

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Release%

10.9 13.9 19.3

27.8

35.9

44.8

51.9 59.6

Standard deviation%

0.6 0.9 1.4

2.2

2.8

3.9

5.3 6.7

The batch of film layer components is dissolved in acetone, ethanol (1: 1.4200 ml) with vigorous stirring. A quarter of the mixture is added to the adherent layer to give a layer 1.3 mm thick (if wet). The new layer is dried at 40 ° C. for 24 hours. The process is repeated 3 times using the rest of the mixture to increase the thickness of the film. The remaining two-layer film is removed from the plate and cut into oval strips of 3 cm with a thickness of 1.58 mm and an average weight of 383.8 mg.

The remaining buccal strips are then sealed separately in an aluminum foil.

A constant release of approximately 10% of the active ingredient per hour is observed.

Clinical examination An examination is carried out on 6 healthy patients, using a 15 mg strip for oral use and a 15 mg normal tablet. With the buccal strip there was a delay of 1-2 hours until pindolol could be detected in the blood plasma. In addition, the maximum proportion of the active ingredient in the plasma was reached significantly later than with the normal tablet. The bioavailability of the buccal strip is indicated by the AUC (area under the curve) of the proportion of the active substance in the plasma, which is approximately 65% of the proportion in the normal tablet.

Example 5:

Pindolol film strip composition

Components

Per strip

Per batch

(1x3 cm) mg g

Film layer

Pindolol (free base form)

15

38

HPC2>

371.95

936.3

Adhesive layer

NaCMC4 »

31.8

80

FD + C Blue No. 2

0.15

0.4

Manufacturing

In an analogous manner to that described in Example 3, the batch of the constituents of the adhesive layer is dissolved in 3000 ml of a 40% strength ethanol. Half of this batch is used to form a film layer approximately 1.3 mm thick (if wet) on a 10 x 20 cm glass plate. The plate is dried at 40 ° C, then the remaining half of the dose is sprayed and the film layer is recently dried at 40 ° C.

The release rate of the active ingredient in vitro This was measured analogously to the method described in Example 3.

20th

Time min.

Release %

30 60 120 180 240 300 360

13.6 20.2

30.5

38.6

46.1

54.2 61.6

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35

40

Clinical examination An examination was carried out on 4 healthy volunteers. Two tablets of 5 mg each or buccal strips containing an average of 13 mg of pindolol (as determined by analysis) were attached to the inside of the mouth on the gums near the large molar tooth. Blood samples were taken from V *, Vi, 1.1 Vi, 2,3,4, 6, 8,11 and 24 hours after administration and analyzed for the amount of pindolol. Urine is collected up to 72 hours after administration.

The results obtained were:

Tablets

Buccal stripes

")

Cmax (ng "11 45 Tmax (h)

AUC 0-24 (ngmI_1)% urine excretion

47.2 ± 7.7 0.63 ± 0.13 276.3 ± 47.3 35.90+ 5.73

(AUC = area under the curve)

30.1 ± 3.7 4.25 ± 0.63 275.0 +52.6 24.07+ 4.03

A comparable total absorption of pindolol was found for both tablets and buccal strips. However, the buccal streak caused a delay in pindo-lol release.

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Claims (10)

653 550 2nd PATENT CLAIMS 1. A pharmaceutical composition for the delayed release of a medicament in the mouth area comprising i) a non-adhesive water-soluble or water-decomposable layer, ii) an adhesive layer which is suitable for adhering to the mucous membrane of the mouth, and iii) a medicament in at least one of these layers, characterized in that the outer surface of the adhesive layer conforms to the shape of the mucosal surface of the mouth to which the The composition is to be applied, adapted or adapted. 2. A pharmaceutical composition according to claim 1, wherein the outer surface of the adhesive layer is shaped so that it is concave on the inside to match the outer surface of the gums. 3. A pharmaceutical composition according to claims 1 and 2, wherein the outer surface of the non-stick layer on the outer side is convex. 4. A pharmaceutical composition according to any one of claims 1-3 characterized by a labeling measure in or on the layer and / or the non-stick layer. 5. A pharmaceutical composition according to any one of claims 1-4, wherein the adhesive layer is colored differently than the non-adhesive layer. 6. A pharmaceutical composition according to any one of claims 1-5, wherein the pharmaceutical composition is in the form of a flexible strip. A pharmaceutical composition according to claim 6, wherein the flexible strip is in the form of a film strip. 8. A pharmaceutical composition according to any one of claims 1-5, wherein the pharmaceutical composition is in the form of a compressed tablet. 9. A pharmaceutical composition according to claim 6 in the form of a film strip, comprising i) a non-adhesive polymer film layer which becomes porous on contact with and is wettable by the mucus of the mouth, ii) an adhesive layer suitable for adhering to the inside of the mouth, and iii) a medicament which is dissolved or dispersed in at least one of these layers. 10. A pharmaceutical composition according to any one of the preceding claims, wherein the non-stick layer dissolves in the mouth for 5-24 hours.