HU192749B - Process for preparing pharmaceutical compositions for topical administration - Google Patents

Abstract

Field of the Invention The present invention relates to novel pharmaceutical compositions suitable for topical treatment that are capable of delivering active ingredients that are difficult to penetrate the skin's stratum corneum. According to the present invention, the pharmacologically active substance is converted into a microemulsion together with water and skin-compatible adjuvants, namely water-immiscible organic solvent, emulsifier and auxiliary emulsifier. 192749 -1-

Description

FIELD OF THE INVENTION The present invention relates to pharmaceutical compositions for topical use, in particular those containing a pharmacologically active agent which is difficult to penetrate the corneal layer of the skin.

The therapeutic efficacy of topical formulations depends inter alia on the absorption and penetration of the pharmacologically active agent. Before being applied topically, pharmacologically active agents must penetrate the stratum corneum at the appropriate site of action, either in the deeper layers of the skin below the cornea or elsewhere in the body. Penetration through the stratum corneum is a step in determining the rate of the entire percutaneous (dermal) process and is accomplished by the formation of a reserve of the pharmacologically active agent, i.e., the deposition of the pharmacologically active agent in this and this layer. In rare cases, the pharmacologically active agent is normally liquid and effectively passes through the skin layer; such as isosorbide dinitrate or glycerol trinitrate. In other cases, different methods must be used to properly penetrate the pharmacologically active agent through the cornea, especially the active ingredient, usually in solid form, can penetrate the corneal layer when applied normally to the skin, for example as a triglyceride or paraffin ointment, than 10 ^'9 mol ^{cm-2 h-1,} such as 10' ^{to 10 _2} mole cm h * ^1st Such pharmacologically active substances are hereinafter referred to as pharmacologically active substances which are difficult to penetrate through the skin.

One method of increasing the penetration rate is to dissolve the pharmacologically active agent, which is difficult to penetrate the skin, in a non-toxic solvent which is compatible with the skin, i.e., does not cause skin irritation over a prolonged period as in human skin or sensitive guinea pig skin. standard tests show. The solutions may be used in the form of macroemulsions, i.e. opaque oil-in-water or water-in-oil systems formed from water and water-immiscible organic solvents in the presence of an emulsifier.

Such a system has a number of disadvantages, particularly for pharmacologically active substances that are difficult to penetrate the skin.

It has been found that transdermal pharmaceutical formulations in the form of microemulsions have particularly beneficial properties with respect to pharmacologically active substances which are difficult to penetrate through the skin.

One of the most recent reports on microemulsions is described by M. Rosoff (Progress in Surface and Membrane Science 12, p. 405, 1978, Academic Press). Microemulsions are generally colored or colorless (oil-in-water or water-in-oil) emulsions in which the particles or droplets have a diameter of less than 150 nm, less than a quarter of the wavelength of light. Thus, they do not scatter light, for example, the diameter of the particles or droplets results from the presence of a small enough aggregate of colloidal molecules. The emulsion is thus transparent by optical microscopy. The emulsion may be isotropic or anisotropic. The anisotropic structure can be observed by X-ray technology. The particles in the microemulsion may be spherical but other structures, such as liquid crystals having a sheet, hexagonal or isotropic symmetry, are also possible.

Microemulsions generally an emulsifying agent (surfactant) and a segédemulgeálószerből (i.e., a co-surfactant, a polar additive, segédszolubilizálószerböl) is produced, which is .óla ja-water interfacial tension between phases reduces very small value (typically 10 ^-3 N / m, i.e. below 1 dynes / cm). In practice, microemulsions often form spontaneously and form a single, stable phase thermodynamically. In contrast, macroemulsions are thermodynamically unstable, two-phase systems and require energy storage in the form of heating or rapid mixing.

Microemulsions are well known in other fields, such as cosmetics, floor lights, paints or nutrition. However, the rules for microemulsions are to a certain extent empirical (see, for example, Microemulsion Theory and Practice, pp. 34-56, 1977, Ed. L. Prince) and so far no skin-permeable drug formulations have been prepared from skin-compatible carriers. for the systemic administration of penetrating pharmacologically active agents. J. · Ziegenmeyer and C. Fuhrer, Acta Pharmaceutica Technologica 26 (4) p. 273-275 (1980)] described a microemulsion formulation containing 1% tetracycline hydrochloride and decanol. However, the system is not able to exert all systemic therapeutic effects of tetracycline because the tetracycline concentration of the drug is too low. More importantly, decanol is not skin compatible. For example, in irritation tests on sensitive animal skin, mild irritation of guinea pig skin and severe irritation on rabbit skin have been observed (see, for example, Industrial Pediatrics, Vol. II, p. 1467, 1962, Interscience Publishers, John Wiley, New York and London). Serious irritation of the skin exposed to decanol for 24 hours has been observed in tests on less sensitive human skin [e.g., W. Kástner, J. Soc. Cosmet. Chemists, 28, p. 753 (741-754), 1974].

Furthermore, the recommended hydrocarbon solvents are not intended for use in humans.

It has been found that microemulsions containing pharmacologically active agents and skin compatible carriers can be prepared which have particularly advantageous penetration properties such that their penetration flux is sufficient to exert a therapeutic effect on the deeper layers of the skin or as systemically circulated as described below.

On the one hand, the present invention provides a skin permeable pharmaceutical composition comprising a skin penetrating pharmacologically active agent and wherein the composition is in the form of a microemulsion formed from skin compatible carriers.

In another aspect, the present invention provides a method of increasing the skin permeation of a pharmacologically active drug that penetrates the skin, comprising administering the active agent to the skin in the form of a microemulsion of skin compatible carriers.

In a further aspect, the present invention provides the use of a microemulsion of skin compatible carriers for percutaneous (percutaneous) administration of a transdermal pharmacologically active agent.

In yet another aspect, the present invention relates to a process for the preparation of pharmaceutical compositions which penetrate the skin. It consists of the formation of a microemulsion: water, a transdermal, pharmacologically active agent and boron compatible carriers which are capable of acting as a water immiscible organic solvent, and an emulsifier and auxiliary emulsifier.

Microemulsions may be formulated in conventional manner to formulate topical pharmaceutical compositions. The skin-compatible pharmacologically active agent, water immiscible organic solvent, water, emulsifier and co-emulsifier are suitably mixed at a maximum temperature of 100 ° C, for example at about 60 ° C to 95 ° C, and then cooled. It is not important that the microemulsion is formed above 32 °.

If the microemulsion is formed above 32 ° C, the phase transitions should preferably be reversible. Indeed, it is very common that at high temperatures, a milky macroemulsion is formed which passes through microemulsion phases alternating with one or more temporary turbid phases during cooling.

It is recommended that the microemulsion is formed in a range of about 20 ° C to 32 ° C, preferably about 15 ° C to 35 ° C.

The water immiscible organic solvent is, for example, a hydrocarbon or lipid.

An emulsifier is also required to form an oil-in-water 'or water-in-oil' emulsion in which the oil is a water immiscible organic solvent. The co-emulsifier aids in the formation and stability of the microemulsion.

The chemical structure or chain length of the co-emulsifier is a critical factor in controlling the size of the emulsion droplets or particles and must be consistent with the structure or chain length of the hydrocarbon moiety of the emulsifier. The co-emulsifier must be compatible with the water-immiscible organic solvent which forms the lipophilic phase. The organic solvent emulsifier and the co-emulsifier must also be compatible with the pharmacologically active agent.

It is, of course, possible for the same excipient to be a water immiscible organic solvent and a co-emulsifier at the same time. However, suitably, various carriers are used as organic solvents and co-emulsifiers.

The microemulsions may be colorless or colored, for example, yellow.

A suitable combination of an emulsifier and auxiliary emulsifier may be, for example, a combination of a water-soluble non-ionic emulsifier and a fatty alcohol of appropriate chain length. Another suitable combination may be a mixture of water soluble and water insoluble nonionic surfactants.

Suitably, at least two of the water-immiscible organic solvent, the co-emulsifier, and the emulsifier must have a chain length of from 12 to 20 carbon atoms.

For any particular system comprising a skin-compatible, pharmacologically active agent, a water immiscible organic solvent, water, emulsifier and auxiliary emulsifier, the relative amounts of the carriers may be varied and equilibrium diagrams may be drawn for the complete phase. Sometimes, it is more convenient to first form a microemulsion at any temperature, even above room temperature, from a series of carriers in order to demonstrate their compatibility, and then to modify the amounts slightly to form a suitable microemulsion at room temperature. Based on the following very sketchy guide, the microemulsion may contain:

a) 0.01-15% boron-coin-compatible, transdermal pharmacologically active agent;

b) 5-30%, e.g. 10-30%, of a biocompatible, water immiscible organic solvent;

c) 10-30% skin compatible emulsifier;

d) 4-30% of a skin compatible emulsifier and

e) 15-55% water.

-3192719

Where the same compound is present, for example, as a water immiscible organic solvent and at the same time as an auxiliary emulsifier, and especially when another auxiliary emulsifier or organic solvent is omitted, part of the concentration of the compound, together with any other water immiscible solvent present and the remainder, together with any other auxiliary emulsifier present, as an auxiliary emulsifier.

Where the same excipient is used as a water immiscible organic solvent, as an auxiliary emulsifier, and no excipient or organic solvent is present, this excipient may represent 9-60% of the composition.

The microemulsions of the present invention may be in the form of a liquid or preferably a gel which is semi-viscous and contains less water. Some microgels, due to their good viscoelastic properties, can form elastic gels.

For any vehicle mentioned below, any aliphatic carboxylic acid may be straight-chain or branched and saturated or unsaturated, preferably with one or two double bonds. Any aliphatic alcohol is a monovalent alcohol, unless otherwise noted, and is preferably secondary or, more particularly, primary alcohol. They are branched or preferably straight-chained and unsaturated, preferably with one or two double bonds, or more saturated. Any glycerol ether or ester is prime etherified or esterified at one or both of the terminal glycerol hydroxyl groups.

Suitable skin-compatible carriers include:

1) esters of a C3-C18 aliphatic alcohol and a C10-C22 aliphatic carboxylic acid; or

2) a straight chain hydrocarbon having from 12 to 32 carbon atoms having from 6 to 16 methyl groups as substituents and containing up to six double bonds.

The above may be suitable organic solvents immiscible with water.

Examples of group 1) include isopropyl laurate, hexyl laurate, decyl laurate, isopropyl myristate and lauryl myristate.

Particularly suitable examples are isopropyl laurate, hexyl laurate and isopropyl myristate, especially hexyl laurate.

Examples of Group 2 include terpenes such as polymethyl butanes and polymethyl butenes such as 2,6,10,15,19,23-hexamethyl-2,6,10, 14,18,22-tetracosahexane, known as squalene C30H50, and its perhydro analogue, pskalane. Squalane is a particularly suitable example.

Skin-compatible carriers selected from the following group:

3) mono-ester of ethylene glycol or propylene glycol and a C 6 -C 22 aliphatic carboxylic acid;

4) an ester of an aliphatic alcohol and lactic acid having from 12 to 22 carbon atoms, or

5) a mono- or di-ester of glycerol and a C 6 -C 22 aliphatic carboxylic acid, suitable as water immiscible organic solvents and / or as co-emulsifiers.

When the carrier of any one of groups 3), 4) or 5) is the organic solvent, the same or different excipients may be used as co-emulsifiers.

An example of group 3) is propylene glycol monolaurate and propylene glycol mono myristate, preferably propylene glycol monolaurate. An example of group 4) is myristyl or more particularly lauryl lactate and group 5) is glycerol caprolate.

Any skin-compatible carrier selected from the group consisting of:

6) a poly (27) -ethylene glycol glycerol ether having at least one free hydroxyl group - and an ester of a C 6 -C 22 aliphatic carboxylic acid, which may be suitably used as a water-immiscible solvent or co-emulsifier.

Some of these groups may be miscible with water, for example, if the poly (ethylene glycol) moiety is of low molecular weight, it may not be suitable as an organic solvent, but may be used as an auxiliary emulsifier. An example of this is poly (17) -ethylene glycol glycerol cocoate.

If the carrier is a transesterification product of a vegetable triglyceride oil and a polyethylene glycol of molecular weight 200-400, as disclosed in U.S. Patent 3,288,824, the contents of which are incorporated by reference in their entirety, and may be suitably used as water. immiscible organic solvents.

Skin-compatible carriers selected from:

7) an aliphatic alcohol having from 12 to 22 carbon atoms; or

8) esters of poly (2,10) -glycerol with at least one hydroxyl group and an aliphatic carboxylic acid having from 6 to 22 carbon atoms, also suitable co-emulsifiers.

Examples of group 7 include dodecanol, tetradecanol, oleyl alcohol, 2-hexyldecanol and 2-octyldecanol.

A particularly suitable example is letradekatud and especially dodecanol.

Preferably, the alcohol is liquid at 32 ° C.

Skin-compatible carriers selected from the following group:

9) a monomer of polyethylene glycol and a C 12 -C 18 aliphatic alcohol having an HLB of 10 to 18 or

10) an ester of a C 6 -C 22 aliphatic carboxylic acid

a) polyethylene glycol,

(b) sucrose,

(c) sorbitan; or

d) polyethylene glycol sorbitan ether; if the HLB of the ester is between 10 and 18, suitable emulsifiers may be used.

The emulsifiers preferably have an HLB of between 12 and 15. (HLB values are indicators of hydrophilic-lipophilic equilibrium in the emulsifier. The subject is discussed in detail in the literature, for example, Pharm. Act. Helv. 44.9, 1969. and HP Fiedler, Lexikon d. Hilfsstoffe f. 2nd Edition, 1981, Editio Cantor AG, BRD).

A preferred example of group 9 is the commercially available polyoxyethylene (10) oleate ether.

The water-immiscible organic solvents of the microemulsions are preferably selected from the group consisting of group 1) or group 2), but preferably group 1), the co-emulsifiers group 7) and the emulsifiers group 9).

The correct choice of organic solvent, emulsifier and co-emulsifier will depend, among other things, on the pharmacologically active agent used.

The pharmacologically active agent may be any compound which is capable of penetrating the corneal layer of the skin, for example up to 3000 molecular weights, although higher molecular weight compounds may be used.

In general, the weight of the pharmacologically active agent is preferably less than 1000. Suitably, the active ingredient has a hydrophilic-lipophilic balance. For example, the active ingredient molecule may be suitably structurally solid, may have aromatic groups, and may not contain many reactive groups such as hydroxyl.

The microemulsions of the present invention are capable of containing a very large amount of active ingredient, for example 5 to 15%, even air, and more than 20% of the total weight.

When systemic activity is desired, the pharmacologically active agent should be effective to produce a systemic therapeutic effect, that is quite active in the skin 10 ^-8 mole must penetrálnia cm ^_1 h ^-z magnitude. For a local effect in the deeper layers of the skin, a penetration flux of 10 ' ⁹ moles cm' ² h ' ¹ may be sufficient. Suitable active compounds are those having an oral daily dose of about 0.1 to about 20 mg, preferably no more than 1 mg.

The microemulsions of the present invention are alkaline to the systemic administration of any active ingredient. Suitable for use as prophylactic (prophylactic) and myotonolytic (muscle tension releasing) agents. The microemulsions of the present invention can be used to deliver active ingredients under the cornea, such as anti-acne or antifungal agents.

Examples of active ingredients include:

(E) -methyl-6,6-dimethyl-N- (naphthylmethyl) hept-2-en-4-ynyl-1-amine, i.e., proquazone;

(E) -N-methyl-N- (1-naphthylmethyl) -3-phenylpropen-2-ylamine, hereinafter naphthphin;

4- (1-Methyl-4-piperidylidene) -4H-benzene (4,5) cyclohepta (1,2-b) thiophen-10 (9H) -one - hereinafter called ketotifen

4- (1-methyl-4-piperidylidene) -9,10-dihydro-4H-benzo (4,5) cyclohepta (1,2-b) thiophene, hereinafter referred to as pizotifen;

griseofulvin; fluocinolone acetonide; triamcinolone acetonide;

14-O- (5- (2-Amino-1,3,4-triazol-yl) -thioacetyl] -dihydro-mutilin and preferably (+) - 1-methyl-2- [2 - {(-) - methyl p-chloro-diphenylmethoxy-ethyl) -pyrrolidine (hereinafter clemastine) and in particular

5-Chloro-4- (2-imidazolin-2-ylamino) -2,1,3-benzothiadiazole, hereinafter referred to as tizanidine

For clemastine, the microemulsion preferably contains the ingredients in one of the following concentrations:

5-15% clemastin,

5-30% water-immiscible organic solvent

15-25% emulsifier,

5-25% co-emulsifier,

10-45% viz.

More preferably, the microemulsion contains the ingredients in one of the following concentrations:

7.5 to 12.5% clemastin,

7.5 to 28.5% water-immiscible organic solvent,

19.5-22% emulsifier,

7.5 - 22.5% co-emulsifier,

13-42% water.

Most preferably, clemastine microemulsion contains the following ingredients in the concentrations ^tr alamelyikében:

8-12% clemastin,

8-27% water immiscible solvent,

20-21% emulsifier,

15-40% water.

The organic solvents are preferably selected from group 1) as defined above,

As defined above, group 3 carriers may be present as organic solvents or as co-emulsifiers, in particular propylene glycol monolaurethane. The auxiliary emulsifier may also be a carrier of group 6) according to the above classification, in particular poly (7) -ethylene glycol glycine 510 cerine cocoate or propylene glycol myristate. The preferred emulsifier, as defined above, is in group 9), in particular polyoxyethylene (10) -oleyl ether having an HLB of about 12-13.

Clemastin can produce micro-gels with a high concentration of clemastine, while stable macroemulsions with such a high concentration of clemastine are difficult to produce.

In the case of tizanidine, the microemulsion preferably contains the ingredients in one of the following concentrations:

6-10% tizanidine,

15-25% water-immiscible organic solvent,

15-25% emulsifier,

5-10% co-emulsifier,

30-35% water.

Preferably, the microemulsion contains the ingredients in one of the following concentrations:

7.5 to 8.5% tizanidine,

19.5-21.5 organic solvent immiscible with water,

19 to 22% emulsifier,

5.5-21.5% co-emulsifier,

32-42% water,

More specifically, when the emulsion contains the ingredients in one of the following concentrations:

8-8.4% tizanidine,

20-21% water-immiscible organic solvent,

20-21% emulsifier,

6.2-8.4% auxiliary emulsifier,

33-42% water.

Of course, the choice of the water-immiscible organic solvent for the microemulsion system emulsifier and co-emulsifier will vary depending on the individual pharmacologically active agent, so that in some cases one carrier may be appropriate in one system, e.g. for example as a co-emulsifier.

The pH of the pharmaceutical composition may be adjusted to a skin-compatible pH with suitable acids or bases, preferably weak acids or bases such as lactic acid or acetic acid. Preferably, the pharmacologically active agent is at least partially in free form, for example in the form of a free base, as it may increase the penetration through the skin. Suitably, the pH of the microemulsion is slightly acidic.

Other skin-compatible active ingredients may be included, such as water-immiscible solvents such as propylene glycol, ethanol and isopropanol, or water-soluble film-forming agents used in cosmetic compositions, such as partially hydrolyzed collagen-derived, medium molecular weight polypeptides that reduce the solvent evaporation after rubbing into the skin.

Of course, the microemulsion should consist of boron compatible ingredients. The components must be non-toxic, non-allergenic and well-tolerated by the skin tissue. Such ingredients can be selected based on standard acute and chronic tests.

The tests may be performed on human skin or on more sensitive animal species such as guinea pig boron.

The microemulsions of the present invention may be used for transdermal administration of pharmacologically active agents, due to their skin penetration enhancing effect and their ability to contain large amounts of pharmacologically active agents.

The skin penetration enhancer may be tested in standard in vitro and in vivo tests, for example using human skin.

One in vitro test is a well-known diffusion test that can be performed according to the principles described by H. Schaeffer et al., Using isolated human skin [H. Schaffer et al., Adv. Pharmacol. Ther. (Proc. 7tH Int. Congr. Pharmacol) 9, 223-235, 1978. ed. by Y. Cohen, Pergamon, Oxford, 1979; H. Schaeffer et al., Current Problems in Dermatclogy 7, 80-94, Ed. Simon et al., Karger, Basel, 1978; J.M. Franz et al., Arch. Dermatol. Gap. 271, 275-282, 1981.]

Microenulsions containing the radioactive, labeled form of the pharmacologically active compounds are applied to approximately 2 cm (2 cm) of isolated human abdominal skin in an amount of about 5 to 10 mg of microemulsion per square centimeter. The skin is maintained at 32 ° C between an upper chamber and a physiological saline solution placed in a lower chamber. After 100, 300 and 1000 minutes, the skin is fastened at 32 ° C. Remove the residue from the skin surface using a cotton cloth and measure the radioactivity. The stratum corneum is peeled off and the radioactivity is determined for each portion removed. The remaining skin is frozen and cut into sections of about 20-40p using a microtome. The radioactivity is determined in different sections. Radioactivity is also measured in an aqueous saline solution in contact with the lower layer of the skin.

Since, in general, the passage of the pharmacologically active agent through the cornea is the rate-determining step, the amount of pharmacologically active agent that passes through the cornea is important for systemic activity. This part of the pharmacologically active substance contained in the various layers of the skin, i.e., the epidermis, the upper, approximately 800 μm thick and the lower, approximately 1000 μ thick subcutaneous tissue, and the approximately 1500 μ thick subcutaneous connective tissue, live in the capillary system.

-612 delivers it to the bloodstream and thereby to the general circulation.

Suitably, the portion of the pharmacologically active agent that penetrates the cornea and the deeper skin layers within 16 hours is calculated and calculated from the average number of tests (n) by the mean percutaneous penetration flux (F) and the percutaneous re-absorption ratio. (RQ) as a percentage of the dose administered.

The results obtained are as follows:

The number of the example F (0-16 hours) .10 ⁸ mól.cm ^'2 h' ¹ n RQ (%) First 2.6 ± 0.5 8 24 Third 1.4 ± 0.3 20 14 4th approx. 1.6 4 13 5th approx. 2.6 4 21 ' 13th 1.3 + 0.01 12 12 14th 1.7 ± 0.7 8 12 17th approx. 1.2 4 15 18th approx. 1.7 4 25 20th approx. 1.3 4 12 25th 1.6 ± 0.6 8 1 ......... 13

* The examples are listed below.

In vivo studies may also be performed, e.g., cross-over studies comparing oral and percutaneous administration of the pharmacologically active agent in healthy subjects.

In one study, 480 mg of tizanidine as an active ingredient, the gel-like microemulsion of Example 1 was placed behind the ear or a 4 mg tizanidine tablet was administered orally.

Urine was collected for 72 hours and the amount of unchanged active substance and the corresponding two metabolites were measured separately.

The results obtained are as follows:

Time elapsed after administration (h)

Unchanged drug after oral administration (p / h)

Unchanged drug after percutaneous administration (p / h)

0-2 3:08 0:03 2-4 1.61 1:01 4-6 0:53 1.81 6-8 0:24 1:33 8-12 0:04 3:36 12-24 - 4:16 24-36 - 2:54 36-48 - 1:57 48-60 - 1:10 60-72 1:07 Cumulative percentage absorption oral percutaneous tizanidine . 0.28% 0:37% .A 'metabolites 2.5% 0.4% , B 'metabolites 1.1% 0:16%

The above results confirm the significant percutaneous (dermal) absorption observed in in vitro tests and suggest the effect of sustained release of the agent.

Furthermore, the relatively small amount of metabolites found has a significantly lower first pass effect. 60

100 mg of the clemastine formulation of Example 3 containing 10 mg of clemastine is placed behind the ears of 2 or 3, 18- to 38-year-old subjects. This corresponds to 10 mg of the active substance clemastine. The amount of active ingredient in urine was determined according to the principles described in the literature [R. Thain. Awl. Frosch. 28 (1), 1017, 1978],

-714

Time elapsed after transmission (h) Active ingredients in it g in urine (pg / h) The girls 0-6 - 3 6-8 0486 i 0164 3 8-12 0890 ± 0384 3 12-24 1042 + 0621 3 24-36 1101 ± 0422 3 36-48 1469 ± 0455 3 48-60 0504 + 0211 2 60-72 0231 ± 0:05 2

The percentage cumulative excretion of unchanged agent was 0.664 ± 0.183.

In comparison, oral clemastine (2 mg) delivered unchanged 7.1% ± 0.46% after 72 hours.

The results show an excellent effect, the maximum concentration 36 hours after the displayed broadcast in the urine, and the local clemastine újrafelszívódási air ratio ^20, approximately 10%.

As shown by the above results, the microemulsions of the present invention can produce systemic effects of pharmacologically active agents. In a special way, it has been surprisingly found that topical administration of tizanidine is also possible.

Accordingly, the present invention provides a topical pharmaceutical composition comprising tizanidine as an active ingredient. In another aspect, the invention provides a method of topical administration of tizanidine to individuals in need of such treatment. ^ 5

The observed penetration rate thus at least 1-3 x 10 ⁸ mol ^cm-2 h 'to be ^{1, such} that the systemic effect is undesirable, to achieve a local effect cm deeper skin layers and 1 x 10 * ⁹ M' ² h ¹ required . The concentration of the pharmacologically active agent in the microemulsion can be selected accordingly.

The amount of pharmacologically active agent to be administered in the microemulsion of the present invention depends, among other things, on the rate of penetration of the pharmacologically active agent, as measured by in vitro and in vivo assays, the size of the skin area treated with the microemulsion. Generally, the appropriate daily dose is 5-20 times the effective oral or topical dose, and this dose may be increased to achieve an effect greater than one day. 55

Generally, a suitable area of application is between about 1 and 4 square centimeters.

The microemulsions of the invention may be used in the usual manner.

In the case of liquid preparations, the microemulsion 60 may be administered, for example, from a plexiglas container which may be in contact with, for example, an upper arm or, for example, by means of a microemulsion impregnated patch placed behind the ear. Semi-solid microgels can be rubbed into the skin.

For tizanidine and clemastine, for example, the appropriate single dose is between 10 and 50 mg, and can be administered for up to 3 days.

The microemulsions of the present invention may be used for the same purposes as other forms of the pharmacologically active agent, such as clemastine as an antihistamine, tizanidine as a myotonolytic agent, anti-depressant, or minor tranquillant.

The microemulsions of the present invention may increase the permeation of the pharmacologically active agent accumulated in the epidermis. This may result in a so-called depot effect, whereby the pharmacologically active agent is slowly introduced into the systemic circulation without being inactivated in the liver, thereby maintaining the active substance concentration in the blood for a long time (delayed effect). Unlike oral administration, the blood concentration achieved through the skin is characterized by the absence of an initial peak concentration of the drug in the blood. Side effects can be minimized. In addition, the pharmacologically active substance accumulated in the stratum corneum, if locally active, may produce local effects.

The microemulsions of the invention generally have other significant advantages over macroemulsions. For example, microemulsions are generally thermodynamically stable and have little or no reactivity. In general, microemulsions spread well on the skin surface. Usually they do not stick to the skin, but I can easily rub into the skin. They cause little greasy after-effect and can be washed with water if desired. The skin does not dehydrate significantly (dries out on the net) as the only water-containing phase is easily accessible to the skin.

The invention will now be illustrated by the following examples:

For example, polyoxyethylene (10) -oleyl ether can be obtained as either BRIJ 97 with an Hb of 12.4, Atlas

-818

Example Active ingredient Organic solvent Auxiliary emulsifier Emulsifier Dist. Other additives

number% the) % b) % c) % water,% % 9th 1 1.0 isopropyl 20.0 dodecanol 7.0 polyoxyethylene 18.0 53.7 90% 0.3 laurate ethylene-10- lactic acid -oleiléter **THE 10th 6. 0.5 2,6,10,15,19, 21.0 dodecanol 6.5 polyoxyethylene 21.0 26.0 polyethylene 25.0 23-hexamethyldisilazane ethylene-10- air glycol 400 tetracosene -oleiléter 11th 7. 0.2 2,6,10,15,19 - 20.5 dodecanol 8.8 polyoxyethylene 20.5 50.0 23 hexamethyl ethylene-10- -tetrakozán oleyl ether ^: B ** 12th 8 0.1 isopropyl 22.5 dodecanol 8.0 polyoxyethylene 22.5 46.9 laurate ethylene-10- -oleiléter **THE 13th 3. 8.2 2,6,10,15,19- 20.5 dodecanol 6.5 polyoxyethylene 20.5 41.0 90% 3.3 F = 1.3-10 * ⁸ 23 hexamethyl ethylene-10- lactic acid -tetrakozán -oleiléter 14th 3. 8.2 isopropyl 20.5 dodecanol 6.5 polyoxyethylene 20.5 41.0 90% 3.3 F = 1.7-10-8 laurate ethylene-10- lactic acid -oleiléter B ** 15th 3. 8.2 laurilacetát 20.5 tetradecanol 6.5 polyoxyethylene 20.5 41.0 90% 3.3 ethylene-10- lactic acid -oleiléter B ** obsession THE 16th 3. 8.2 myristyl 20.5 tetradecanol 8.0 polyoxyethylene 20.5 39.5 90% 3.3 acetate ethylene-10- lactic acid -oleiléter **THE 17th 4. 8.3 isopropyl 20.5 dodecanol 6.5 polyoxyethylene 20.5 41.3 90% 2.9 F = 1.2-10-8 laurate ethylene-10- lactic acid -oleiléter 18th 5. 8.3 isopropyl 20.6 dodecanol 6.6 polyoxyethylene 20.6 41.2 90% 2.7 F = 1.7-10-8 laurate ethylene-10- lactic acid -oleiléter B ** 19th 2. 10 isopropyl 20.5 propylene 10 polyoxyethylene 20.5 35.6 90% 3.4 myristate glycol mono ethylene-10- lactic acid laurate-oleyl ether B ** 20th 3. 8.2 polyethylene 20.5 dodecanol 6.5 polyoxyethylene 20.5 41.0 90% 3.3 F = 1.3-10-8 glycol glycolic ethylene-10- lactic acid ceryl fatty acid -oleiléter B ** ester ** D 21st 9. 4.0 hexillaurót 13.0 poly (7) ethylene 26.0 polyoxyethylene 10.0 16.0 propylene 6.0 glycol-glycolic ethylene-10- glycol cerilkokoát -oleiléter **THE isopropanol 25.0 C ** 22nd 2. 10 propylene 13.0 poly (7 jetylene 26 polyoxyethylene 20 31 -glikol- glycol-glycolic ethylene-10- monolaurate cerilkokoát -oleiléter **THE C ** 23 '. 2. 10 propylene 13.0 poly (7 Ethylene) 26 polyoxyethylene 20 16.0 96% glycol glycol glycolic ethylene-10- alcohol monolaurate cerilkokoát -oleiléter **THE c ** 24th 3. 8.2 isopropyl 20.5 dodecanol 8 polyoxyethylene 20.5 39.1 90% 3.7 myristate ethylene-10- lactic acid -oleiléter 25th 3. 8.2 2,6,10,15,19 - 20.5 dodecanol 6.5 polyoxyethylene 20.5 41 90% 3.3 F - 1.6-10-8 23 hexamethyl ethylene-10- lactic acid tetracosene -oleiléter **THE

List of active substances

1. (E) -N-Methyl-N- (1-naphthylmethyl) -3-phenylpropen-2-ylamine, 65

2. (+) - 1-methyl] -2- [2- (α-ethyl-p-chlorodiphenylmethoxy) ethyl] pyrrolidine,

3. 5-chloro-4- (2-imidazolin-2-ylamino) -2,1,3-benzothiadiazole,

-920

4. 4- (1-methyl-4-piperidylidene) -4H-benzo (4,5) cyclohepta (1,2-b) thiophene-10- (9H) -one,

5 4- (l-methyl-4-n piperidylidene) - 9,10-dihydro-4H-benzo (4,5) cyclohepta (l, 2-b) thiophene _I

6. griseofulvin,

7. fluocinolone acetonide,

8. triamcinolone acetonide,

9. 14-O- [5- (2-Amino-1,3,4-triazolyl) thioacetyl] dihydro-mutilin, which is 14 - [(5-amino-4H-1,2,4-triazol-3) Also known as thioacetoxy] -14-deoxy-19,20-dihydro-mutilin.

** Commercial Product Table

The Brij 97 HLB value is 12.4 (Atlas)

B Volpo 10 HLB Value 12.4 (Croda)

C Cetiol HE (Henkel)

D Labrafil 1944S (Gattefosse)

Colladerm 350: Zinc salt solution of high purity cosmetic polypeptide of collagen (Stephan Chemical Company).

Further pharmacological tests were performed to determine the skin-corrosive activity of the pharmacologically active 5-chloro-4- (2-imidazolin-2-ylamino) -2,1,3-benzothiadiazole (tizanidine) using an amount that is systemic throughout the body, i.e., to induce a pharmaceutically acceptable plasma level.

Tizanidine is a centrally acting myotonolytic agent, for example, for the systemic treatment of local muscle spasms. For the treatment of muscle spasms, systemic exposure can be achieved with a daily dose of about 6-12 mg.

Generally, with a penetration flux of 1.10 to ⁸ moles / cm ^{2 of} boron per hour, a therapeutically effective plasma level can be maintained when tizanidine is applied to a few cm ^{2 of} skin. When applied to a larger area of skin, for example, a penetration flux of at least 1.10 to ⁹ moles / cm ² per hour is also suitable for 10-20 cm ² .

Penetration flux was determined in vitro.

Radioactive labeled tizanidine formulations were applied to one side of the cornea layer on approximately 2 cm of intact human skin. The other side of the skin was in contact with physiological saline. Samples were stored at 32 ° C for 16 hours and radioactivity was determined in the remainder, the peeled cornea, the various skin sections microscopically separated by freezing and in the aqueous receptor phase. Transdermal flux was calculated from the concentrations measured in each layer of the skin, except for the stratum corneum, and the aqueous receptor phase concentration.

Tizanidine was applied topically in the following formulations:

organic, aqueous lead; organic, aqueous microemulsion and semi-solid, anhydrous, hydrophobic ointment.

1. Organic, aqueous solution

(a) Composition:

tizanidine 15 t% arginine-glu witness buffer page. (pH = 7.6) 35 1% ethanol 39 t% lauric 11 t%

Dosage: 5.00 mg / 2.0 cm ² Skin surface Penetration flux: 8.54.10 ⁹ mol / cm ² / hour

(b) Composition:

tizanidine 10 t% ethanol 40 t% water 40 t% N-lauroyl sarcosine 10 t%

Dosage: 5.00 mg / 2.0 cm ^{2 of} skin surface

Penetration Flux: 1.11.10 to ⁸ mol / cm ² / hour

Ingredients: tizanidine 15 t% ethanol (6%) 35 t% arginine-glutamine aqueous buffer solution (pH = 7.6) 30 t% lactic acid 5 t% lauryl dimethylamide 15 t%

Dosage: 5.00 mg / 2.0 cm ² boron surface Penetration flux: 3.93.10 ^_8 moles / cm ² / h

2. Microemulsion

Ingredients:

tizanidine 8.2 t% water 41.0 t% Isopropyl laurate 20.5 t% polioxie tile η— (10) - -oleiléter 20.5 t% dodecanol 6.5 t% lactic acid 3.3 t%

Dosage: 11.33 mg / 2.0 cm ² skin area

Penetration Flux: 2,61.10 ~ ^s mol / cm ² / hour.

3. Semi-solid ointment

Ingredients:

tizanidine 10% silicone paste 90%

Dosage: 23.25 mg / cm ² skin to 1.0 Penetration Flux: l 40.10 ^'9 mol / cm ² / hour. Formulations 1a) -c) contain tizanidine in an organic solvent with and without a surfactant. Surprisingly, these formulations above 10 ^'9 mol / cm ² / h, a highly satisfactory penetration flux is achieved.

Microemulsion composition 2 provides very advantageous penetration flux. Semi-solid composition 3 is acceptable for penetration flux.

The results show that the active ingredient tizanidine is surprisingly able to penetrate the skin and produce systemic effects in a number of topical formulations.

Claims (34)

PATENT CLAIMS 1. A method for topical administration to the skin, at least 10 ^"9 moles / ^cm2 / hr penetration flux preparation of pharmaceutical compositions in the form of a microemulsion pharmacologically active substance, a water-immiscible organic solvent, emulsifying agent, emulsifier, water and optionally with other auxiliary materials, characterized in that the active ingredient is (E) -N-methyl-N- (1-naphthylmethyl) -3-phenylpropen-2-ylamine, or (E) -N-methyl-6,6-dimethyl-N- ( naphthylmethyl) hept-2-en-4-yl-1-amine, or (+) - 1-methyl-2- [2- (α-methyl-p-chlorodiphenylmethoxy) - ethyl] pyrrolidine or 5-chloro-4- (2-imidazolin-2-ylamino) -2,1,3-benzothiadiazole, or 4- (1-methyl-4-piperidylidene) -4H-benzo (4,5) cyclohepta (1,2-b) thiophen-10 (9H) -one, or 4- (1-methyl-4-piperidylidene) - 9,10-dihydro-4H-benzo (4,5) cyclohepta (1,2-b) thiophene or (2S-trans) -7-chloro-2 ', 4,6-trimethoxy-6'-methyl-spiro [benzofuran-2 (3H), 1 '- (2) cyclohexene] -3,4'-dione, or 6oc, 9-difluoro-11 S, 21-dihydroxy-16o, 17 - [(1-methylethylidene) bis (oxy)] pregna-1,4-diene-3,20-dione, or 9-fluoro-11β, 21-dihydroxy-16oc, 17 - [(1-methylethylidene) bis (oxy)] pregna-1,4-diene-3,20-dione, or 14-0- [5- (2-Amino-1,3,4-triazolyl) -thioacetyl] -dihydro-mutilin is mixed with the above excipients at a concentration of 0.01-15% by weight at a temperature up to 100 ° C. (Priority: 04/05/1982) 2. A process according to claim 1, wherein the water-immiscible, skin-compatible solvent is used in an amount of 5 to 30% by weight. (Priority: 04/04/1982) The process according to claim 1 or 2, wherein the emulsifier is compatible with 4-30% by weight of the skin. (Priority: 04/04/1982) 4. A process according to any one of claims 1 to 4, wherein a skin-compatible auxiliary emulsifier is used in an amount of 10-30% by weight. (Priority: 04/04/1982). 5. A process according to any one of claims 1 to 4, wherein 15 to 55% by weight of water is used. (Priority: 04/04/1982) 6. A process according to any one of claims 1 to 5, wherein 0.01 to 15% by weight of the pharmacologically active agent penetrating the skin is used. (Priority: 04/04/1982) 7. The method of claim 6 wherein 5 to 15% by weight of a pharmacologically active agent that penetrates the skin is used. (Priority: 04/05/1982) 8. A process according to any one of claims 1 to 3, wherein the skin compatible ester of a C 3 -C 18 aliphatic alcohol with a C 10 -C 22 aliphatic carboxylic acid is used. (Priority: 04/04/1982) 9. A process according to claim 8 wherein the ester is selected from the group consisting of isopropyl laurate, hexyl laurate, decyl laurate, isopropyl nrristate and lauryl myristate. (Priority: 04/04/1982) 10. The process of claim 9 wherein the ester is selected from the group consisting of isopropyl laurate, hexyl laurate and isopropyl myristate. (Priority: 04/04/1982) 11. A process according to claim 10 wherein the ester is hexyl laurate. (Priority: 04/04/1982) 12. A 1-11. A process according to any one of claims 1 to 6 wherein the straight chained hydrocarbon having from 12 to 32 carbon atoms substituted with 6 to 16 methyl groups and having up to 6 double bonds is used. (Priority: 04/04/1982) 13. A process according to claim 12 wherein 2,6,10,15,19,23-hexamethyltetracosan is used. (Priority: 04/04/1982) 14. A process according to any one of claims 1 to 6, wherein the skin compatible monoester of ethylene glycol or propylene glycol with a C 6 -C 22 aliphatic carboxylic acid is used. (Priority: 04/04/1982) 15. The process of claim 14 wherein the ester is propylene glycol monolaurate or propylene glycol monoyristate. (Priority: 04/04/1982) 16. A process according to any one of claims 1 to 3, wherein the skin-compatible ester of a C 12 -C 22 aliphatic alcohol is lactic acid. (Priority: 04/04/1982) 17. The process of claim 16 wherein the ester is myristyl lactate or lauryl lactate. (Priority: 04/04/1982) 18. A process according to any one of claims 1 to 3, wherein the C 12 -C 22 aliphatic alcohol is used. (Priority: 04/04/1982) 19. The process of claim 18 wherein the alcohol is dodecanol, tetradecanol, oleyl alcohol, 2-hexyldecanol or 2-octyldecanol. (Priority: 04/04/1982) 20. The process of claim 19 wherein the alcohol is dodecanol. (Priority: 04/04/1982) 21. A process according to any one of claims 1 to 3, wherein the poly (2-7) ethylene glycol glyceryl ether containing at least one free hydroxyl group and A skin-compatible ester of a C 6 -C 22 aliphatic carboxylic acid is used. (Priority: 04/04/1982) -1 124 22. A process according to claim 21 wherein the ester is poly (7) ethylene glycol glyceryl cocoate. (Priority: 04/04/1982) 23. A process according to any one of claims 1 to 3, wherein the skin is mono or diester of glycerol with a C 6 -C 22 aliphatic carboxylic acid. (Priority: 04/04/1982) 24. A process according to any one of claims 1 to 3, wherein the skin is an ester of a poly (2-10) glycerol with at least four hydroxyl groups of a C 6 -C 22 aliphatic carboxylic acid. (Priority: 04/04/1982) 25. A process according to any one of claims 1 to 4, wherein the skin is a monoether of polyethylene glycol with a C12-C18 aliphatic alcohol having a HLB of 10-18. (Priority: 04/04/1982) 26. A process according to claim 25 wherein the monoether is polyoxyethylene (10) oleyl ether. (Priority: 04/04/1982) 27. A process according to any one of claims 1 to 6, wherein the C 6 -C 22 aliphatic carboxylic acid is dermalized with (a) polyethylene glycol, (b) sucrose, (c) sorbitan or (d) polyethylene glycol sorbitan ether having an HLB of 10-18. compatible ester. (Priority: 04/04/1982) 28. A process according to any one of claims 1 to 3 wherein the active ingredient is (+) - 1-methyl-2- [2- (N-methyl-p-chlorodiphenylmethoxy) ethyl] pyrrolidine. (Priority: 04/04/1982) 29. Process according to any one of claims 1 to 3, characterized in that the active ingredient is 5-chloro-4- (2-imidazolin-2-yl-amino) -2,1,3-benzothiadiazole. (Priority: 04/04/1982) 30. Process according to any one of claims 1 to 3, characterized in that the active ingredient is 14-0- [5- (2-amino-1,3,4-triazolyl) thioacetyl] dihydro-mutilin. employed. (Priority: 04/04/1982) 31. A process according to claim 28 or 30 wherein hexyl laurate, poly (7) ethylene glycol glyceryl cocoate and polyoxyethylene (10) oleyl ether are used. (Priority 04.04.1981) 32. The process of claim 29, wherein 6-10% by weight of 5-chloro-4- (2-imidazolin-2-ylamino) -2,1,3-benzothiadiazole, 15-25% by weight of a water immiscible organic solvent, 15-25% by weight of emulsifier, 5-10% by weight of auxiliary emulsifier and 30-35% by weight of water, characterized in that the ingredients are mixed at a temperature of up to 100 ° C. (Priority: April 22, 1981) 33. The process of claim 32 wherein isopropyl laurate, polyoxyethylene (10) oleyl ether and dodecanol are used. (Priority: April 22, 1981) 34. A method for topical administration to the skin, pharmacological least 10 ^"9 moles / ^cm2 / hr penetration flux preparation of a medicament active ingredient in an organic solvent - preferably in a lower alkanol, preferably ethanol - water and optionally other auxiliary material - preferably the buffer or 5-15% by weight of 5-chloro-4- (2-imidazolin-2-ylamino) -2,1,3-benzothiadiazole as a pharmacologically active ingredient. (Priority: April 22, 1981)