CH658993A5 - PREPARATION FOR PERCUTANEOUS ADMINISTRATION OF PHYSIOLOGICALLY ACTIVE AGENTS TO HUMANS AND MAMMALS. - Google Patents

Description

The present invention relates to a preparation aimed at accelerating the percutaneous absorption of physiologically active agents, often referred to below as "active agent" for the sake of simplicity.

Active agents are usually administered to the skin or mucosal tissues to treat local diseases, and systemic agents are generally administered by taking pills or by injections. However, efforts have recently been made to achieve systemic administration of active agents through topical applications to skin or mucosal tissue. Such topical means 55 for achieving systemic administration has the advantage that desired blood concentrations can be easily achieved and maintained, so that the duration of the therapy can be easily controlled. Side effects due to overdosing of the active agent can thus be avoided. Metabolism due to a first passage through the liver and digestive organs, which is characteristic of certain drugs, such as indomethacin when administered orally, can also be switched off.

However, normal skin is relatively impermeable to most therapeutic agents so that the desired therapeutic agent blood levels cannot be achieved by percutaneous absorption. Percutaneous

Absorption of therapeutic agents can, however, be increased by additives or penetration enhancers.

One of the best known penetration aids of this type is dimethyl sulfoxide, the use of which is explained in detail in US Pat. No. 3,551,554, the use of dimethyl sulfoxide as a penetration aid for psychopharmacological drugs, such as benzodiazole derivatives, being highly recommended.

GB-PS 1 504 302 is concerned with sedative methods and preparations and discloses the administration of sedatives by applying a soothing amount of one or more soothing compounds in various penetration aids such as hydrocarbons, e.g. aromatic hydrocarbons or paraffins, halogenated aliphatic hydrocarbons, ketones, esters, ethers, alcohols, amides or sulfones, on the skin of animals. It is pointed out in detail here that one or more of the abovementioned liquids can be used in combination, although only carbon tetrachloride and only dimethylformamide for amides are given as examples for halogenated aliphatic hydrocarbons.

JP-OS 52-148 614 discloses the use of sulfones as by-products of the refining of petroleum as a solvent for increasing the effectiveness of drugs against skin diseases and as drug penetration enhancers without supporting data or substantial explanations.

US Pat. No. 4,202,888 discloses absorbable pharmaceutical preparations which contain at least one glycoside cardiac agent which is distributed in a vehicle which contains an absorption-increasing amount of at least one partial glyceride of a medium-chain fatty acid.

U.S. Patent 3,472,931 relates to percutaneous absorption using lower alkyl amides and exemplifies binary systems containing dimethylacetamide and ethanol, dimethylacetamide and isopropyl alcohol and dimethylacetamide and isopropyl palmitate. However, the combination of dimethylacetamide with higher molecular alcohols or with low molecular esters is not explained or disclosed.

US Pat. No. 4,017,641 deals with skin-moistening preparations which contain 2-pyrrolidones and can be used with appropriate oils and waxes, including aliphatic, straight-chain fatty acids and alcohols with 10-20 C atoms. However, percutaneous administration of physiologically active agents is not dealt with here.

In EP patent application 0 043 738, binary percutaneous administration systems are disclosed which contain a monoglyceride, a diol or a diol ether, in combination with a second component, such as an alcohol, ester, amide or the like.

The present invention relates to multicomponent carrier systems for percutaneous administration of physiologically active agents which differ from the prior art systems described above.

It has been found that certain multicomponent carrier systems enable improved and controllable percutaneous administration of physiologically active agents.

The invention thus relates to the preparation defined in claim 1.

The invention is explained below, for example:

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The auxiliaries of the preparations according to the invention are selected from optionally halogen-substituted aliphatic hydrocarbons, alcohol esters of aliphatic carboxylic acids, mono- or diethers, ketones, higher aliphatic monoalcohols, or mixtures of these substances. These aids expediently have a melting point below 38 C.

The solvents of the preparation according to the invention are selected from thioglycerols, lactic acids and lactic acid esters, cyclic ureas, compounds of the formula R1R2NCONR3R4, compounds of the pyrrolidone type, amides, lactones, or mixtures of these substances.

According to the invention, physiologically active agents can be administered percutaneously by mixing them with a combination of component A, component B and a diol as a moderator and applying the mixture obtained to the skin.

The preparation described can be used as the basis for medical preparations which contain active agents which can be applied to the outer skin.

One of the objects of the invention is to provide a basic preparation in the form of a percutaneous absorption-increasing combination of component A, component B and a diol as moderator, which is often abbreviated to “PAEC” (Percutaneous Absorption Enhancing Combination) for medical preparations for external use, which increases the permeability of active agents through the skin and percutaneous absorption of the active agent.

In a preferred embodiment, the preparation described, which increases percutaneous absorption, contains one or more members from the group of certain pyrrolidone-type compounds, amides and mixtures of such compounds, one or more members from the group of certain alkyl halides, fatty acid esters, higher aliphatic monoalcohols, Hydrocarbons and mixtures of such substances, as well as one or more diol (s) as moderator (s).

Another object of the invention is to provide PAEC embodiments which ensure rapid and controlled transepidermal delivery of physiologically active agents to humans or mammals and which result in blood concentrations in the therapeutically effective range for the treatment of humans and mammals.

Another object of the invention is to provide relatively constant blood concentrations in the therapeutic range by transepidermal delivery at appropriately set rates, so that the side effects and reduced therapeutic efficacy that can result from wide, time-dependent fluctuations in blood concentrations are avoided.

In the following preferred embodiments of the invention are explained with reference to the drawing. The drawing is a diagrammatic representation of the time-dependent flow of diazepam with different compositions of the preparation according to the invention and a comparison composition.

Component A can contain, for example, the following compounds:

1) Optionally with one or more halogen (s) substituted, straight or branched chain or cyclic aliphatic hydrocarbons with 5 - 24 carbon atoms, bromine and chlorine being preferred as halogen substituents.

Straight or branched chain hydrocarbons with 5-24, preferably 6-18, carbon atoms can be used, which can be saturated or unsaturated, preferably with 1-2 unsaturated bonds. From cyclic carbon

3rd

5

10th

15

20th

25th

30th

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Hydrogen oils are preferred to be 6-10 membered mono- or "10-12 membered dicyclic hydrocarbons containing those having saturated or unsaturated alkyl groups

1-4 carbon atoms, such as methyl, butyl, isopropenyl, etc., can be substituted.

Specific examples are n-pentane, n-hexane, n-heptane, n-octane, n-nonane, n-decane, n-undecane, n-dodecane, n-tetradecane, n-hexadecane, n-octadecane, 2-methylpentane , 2-methylhexane, 2,3-dimethylhexane, 2-methylnonane, 2,6-dimethyloctane, 2,2,4,4,6,8,8-heptamethylnonane, pristan, limonene, hydrogenated limonene dimer, cyclohexane, 1, 3-dimethylcyclohexane, cyclooctane, isobutyl-cyclohexane, cyclododecane, methyldecalin, decalin, octyl chloride, decyl chloride, dodecyl chloride, hexadecyl chloride, dodecyl bromide, dichlorododecane, etc.

2) Alcohol esters of aliphatic carboxylic acids with a total of 7-18, preferably 7-17, carbon atoms:

Monovalent alcohols with 1-6 C atoms, such as

Methyl alcohol, ethyl alcohol, n-propyl alcohol, isopropyl alcohol, n-butyl alcohol, isobutyl alcohol, sec-butyl alcohol, t-butyl alcohol, n-amyl alcohol, isoamyl alcohol, n-hexyl alcohol, etc.

prefers. Furthermore, fatty acids with 6 to 16 carbon atoms are preferred as the carboxylic acid part, in particular saturated fatty acids with 8 to 14 carbon atoms. Specific examples of such esters are

Methyl laurate, ethyl laurate, butyl laurate,

Isopropyl myristate, etc.

3) Mono- or diether with 10-18 carbon atoms:

Specific are alkyl monoethers such as

Dihexyl ether, dioctyl ether, methoxydodecane, ethoxydodecane, etc.,

Ethers with an alicyclic group, such as 1,8-cineol, etc., alkyl di-ethers, such as ethylene glycol dibutyl ether, ethylene glycol dioctyl ether, etc.

4) Ketones with 10-18 C atoms:

Aliphatic ketones are preferred, for example

2-undecanon, 3-undecanon, 4-undecanon, 5-undecanon,

6-undecanone, 2-dodecanone, 4-dodecanone, 5-dodecanone,

7-tridecanone, etc.

5) Higher aliphatic monoalcohols with 10-26 carbon atoms, which can be straight or branched, saturated, unsaturated or cyclic and primary, secondary or tertiary.

Component B includes, for example, the compounds:

1) Thioglycerins:

Any mono-, di- and trithioglycerol can be used, for example a-monothioglycerol.

2) Lactic acids and lactic acid esters:

Monovalent aliphatic alcohols having 1 to 4 carbon atoms are preferred as the alcohol part of the esters. Specific examples are lactic acid, methyl lactate, ethyl lactate, butyl lactate, etc.

3) Cyclic ureas:

5- and 6-membered rings are preferred. Specific examples are ethylene urea, N, N-dimethyl ethylene urea and the corresponding propylene ureas, etc.

4) Compounds of the formula

N -

0

II c

- N

r;

/

\

where R 1, R 2, R 3 and R 4 each represent hydrogen, lower alkyl having 1 to 4 carbon atoms, such as methyl, ethyl, n-propyl, isopropyl, n-butyl, etc., or acyl having 1 to 2 carbon atoms:

Specific examples are urea, N-methyl urea, N-ethyl urea, N-butyl urea, 1,1-dimethyl urea, 1,3-dimethyl urea, 1,1,3,3-tetramethyl urea, N-acetyl-N'-methyl urea, etc.

5) Compounds of the formula

0

II

c,

15

R -N

D

V

(CH.) Z n

20th

where R5 is hydrogen or lower alkyl with 1.4 C atoms, such as methyl, ethyl, n-propyl, isopropyl, etc., and n is an integer from 3-5:

: Specific examples are 2-pyrrolidone, N-methylpyrro-lidone, N-methylpiperidone, caprolactam, N-methylcapro-lactam, etc.

6) Compounds of the formula

30th

35

—CON

O

\

8th

wherein R6 is hydrogen or alkyl with 1 to 3 carbon atoms, such as 40 methyl, ethyl, n-propyl, etc., and R7 and R8 each alkyl with 1 to 3 carbon atoms with the proviso that R6, R7 and Rs have a total of at least 3 carbon atoms.

Specific examples are N, N-diethylformamide, N, N-dimethylacetamide, 45 N, N-diethylacetamide, N, N-dimethylpropionamide, N, N-diethylpropionamide, etc.

7) Lactones with 4-6 C atoms:

Specific examples are y-butyrolactone, 5-valerolactone, etc.

As already stated, a diol is used as a moderator in the preparation according to the invention together with the active agent and components A and B. This diol can be straight or branched chain and is preferably a diol with 3-8 C-atoms, in particular 55 3-6 C-atoms, e.g. an aliphatic diol such as 1,2-propanediol, 1,3-butanediol, 2,3-butanediol, 1,5-pentanediol, 1,6-He-xanediol. However, other diols can also be used.

The proportion of diol as a moderator is not necessarily restricted, but is typically in the range of 10-400% by weight, preferably 25-200% by weight, based on the weight of the solvent component B. The resulting combination of materials must of course be fluid.

65 The diol as moderator reduces the effectiveness of components A and B in the preparation described and creates a possibility for further control of the absorption rate of the active agent.

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Larger proportions of the diol as moderator reduce the flow rate of the active agent, while smaller proportions compared to larger ones increase the flow rate of the active agent.

It should be noted that the diol as a moderator does not increase the percutaneous absorption of the preparation described and its rate decreases in all proportions, which is surprising to the person skilled in the art.

In addition to the above, there are particularly preferred PAEC embodiments according to the invention, which are explained below.

It is not known with certainty why the particularly preferred PAEC embodiments according to the invention enable improved percutaneous absorption. However, the data obtained indicate that a synergistic effect occurs between components A and B, which can be moderated appropriately if desired by varying the proportion of diol as moderator.

It is believed that the materials such as the pyrrolidone type compounds and amides primarily act as solvents and materials such as the alkyl halides, fatty acid esters, higher aliphatic monoalcohols and aliphatic hydrocarbons act as auxiliaries which increase the solvating function of the solvent . It is also believed that the solvents carry the active agent while the tools open the stratum corneum. Without wishing to be bound by these theories, the terminology “solvents” and “auxiliary materials” is only used to draw a dividing line between these two classes of materials that must be used in combination.

The auxiliaries particularly preferred as component A of the preparation described are one or more members of the group consisting of alkyl halides, fatty acid esters, higher aliphatic monoalcohols, aliphatic hydrocarbons and mixtures of these substances.

Of the alkyl halides, those with 8-16 C atoms are particularly preferred, with chloride being the preferred halogen. Both alkyl bromides and iodides are potentially useful but tend to be unstable. Alkyl fluorides are also useful.

The alkyl part can be straight or branched chain, cycloaliphatic or unsaturated, e.g. alkanes and alkanes are useful.

Examples of the most preferred alkyl halides are given below.

Most preferred are aliphatic hydrocarbons with 10-18 carbon atoms, which can be straight or branched chain and cycloaliphatic or unsaturated, e.g. For example, alkanes and alkenes are useful.

The fatty acid esters are expediently represented by the formula RiCOOR.2, where Ri stands for the acid part and R2 for the alcohol part. A total number of carbon atoms in Ri and R2 of 10-17 is particularly preferred. Ri and R2 can be linear, branched, saturated or unsaturated.

Preferred higher monoalcohols are the aliphatic monoalcohols with 12-14 C atoms, which can be branched or straight-chain, saturated, unsaturated or cyclic.

The particularly preferred solvents as component B in the preparation described are the compounds of the pyrrolidone type and the amides.

The pyrrolidones are particularly preferably alkyl pyrrole-done of the formula

C = 0

(CH.) 2 n where R | Alkyl with up to 4 carbon atoms, and n is 3-5.

The amides are preferably represented by the formula

R.

20th

R-CON 2

'R,

wherein R2 can be hydrogen or alkyl with up to 3 C atoms, 25 and R3 and R4 can be an aliphatic group with up to 3 C atoms.

The basic composition according to the invention can be prepared by dissolving component A in component B and then mixing in the diol as a moderator. The order of mixing is not important. The proportion of component A is generally 0.1-80% by weight, preferably 0.5-50% by weight, based on the total weight of components A and B. Preferred proportions and properties of the diol as moderator 35 have already been mentioned. Of course, other pharmaceutically acceptable additives such as water and the like can be added to the preparation described.

The pharmaceutical preparations described for topical use can be prepared by mixing physiologically active agents with the composition described above. There are no particular restrictions on active funds, provided that they are systemically active and can be used percutaneously. Specific examples of active agents are

Benzodiazepine (e.g. diazepam, nitrazepam,

Flunitrazepam, lorazepam, fludiazepam, clonazepam), diuretic agents

(e.g. thiazides (such as bendroflumethiazide,

so polythiazide, methyclothiazide, trichloromethiazide, cyclopenthiazide, bentyl hydrochlorothiazide, hydrochlorothiazide, bumetanide)),

antihypertensive agents

(e.g. clonidine) antihistamines (e.g. aminoether 55 (such as diphenhydramine, carbinoxamine, diphenylpyraline); ethylenediamines (such as fenbenzamine);

Monoamines (such as chlorophenylamine),

non-steroidal anti-inflammatory agents (e.g. indomethacin, ibuprofen, ibufenac,

60 alclofenac, diclofenac, mefenamic acid, flurbiprofen, flufenamic acid, ketoprofen).

Antitumor agents (e.g. 5-fluorouracil, 1 - (2-tetrahydrofuryl) -5-fluorouracil, cytarabine,

Floxuridine).

65 steroids anti-inflammatory agents (e.g. cortisone, hydrocortisone, prednisolone, predonison, triamcinolone, dexamethasone, betamethasone)

anti-epileptic agents (e.g. ethosuximide),

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antiarrhythmic agents (e.g. ajmaline, purajmaline, pindolol, propranolol, quinidine),

psychotropic agents (e.g. clofluperol, trifluperidol, haloperidol, moperon);

Scopolamines (e.g. methylscopolamine, butylscopolamine); Metoclopramide, chlorpromazine, atropine (e.g. methyl atropine bromide, methyl anisotropin bromide); Vasodilators (e.g. isosorbide dinitrate, nitroglycerin, pentaerythritol tetranitrate, propanyl nitrate,

Dipyridamole);

Antibiotics (e.g. tetracycline (such as tetracycline, oxytetracycline, metacyclin, doxycycline, minocycline); chloramphenicols, erythromycins, etc.

The method according to the invention can also be used to administer peptides such as LH-RH, insulin and the like percutaneously. Of course, the pharmaceutically acceptable salts such as hydrochloride, sodium, potassium, hydrobromide salts can be used.

Since the present invention is particularly suitable for the use of benzodiazepine materials, these are explained in more detail below. Particularly preferred benzodiazepine materials are those with the benzodiazepine skeleton shown schematically below:

n

\

\ N

where X is Cl, Br or NO 2 and Y is a group of the structural formula

or n '

n:

, R * r

(R is H, CH3 or CH2

<J.

or CH2-CH2-N (C2H5) 2 or R, is C (R) = N * (R is H or CH3) and is bound to R2 via «*» (a single bond as follows:

io c) 1,2 and 4, 5 are saturated: R i is H; - R2 is = O; R3 is H and positions 4 and 5 form a second ring system as follows

15

20th

where R and R1 are H and CH3, respectively.

Specific examples of benzodiazepines administered percutaneously using the active agent / penetration / adjuvant preparation of the invention. can include:

a) Chlordiazepoxide:

30th

b) Diazepam:

c) oxazepam: 35 d) temazepam:

e) Lorazepam:

40 f) Prazepam:

stands, with varying degrees of unsaturation and substitution in positions 1,2, 3,4 and 5 as follows:

a) 1, 2 and 4, 5 are unsaturated: Ri and R3 are H; R2 is n;

(R is H or CH3) and N-Z is N-> 0.

b) 1,2 are saturated and 4,5 are unsaturated: R3 is H or OH; —R2 is —H or = 0 or = N *; R! is

/ g) Fludiazepam:

45

h) Flurazepam:

i) Medazepam:

50

j) Bromazepam:

k) Nitrazepam:

551) Nimetazepam:

m) Clonazepam:

n) Flunitrazepam:

60

65

o) Estazolam: p) Triazolam:

q) Alprazolam:

7-chloro-2-methylamino-5-phenyl-3H-1,4-benzodiazepine-4-oxide 7-chloro-1,3-dihydro-l-methyl-5-phenyl-2H-1,4-benzodiazepine-2 -on 7-chloro-l, 3-dihydro-3-hydroxy-5-phenyl-2H-l, 4-benzodiazepin-2-one 7-chloro-1,3-dihydro-3-hydroxy-1-methyl-5 -2H-1,4-benzodiazepin-2-one 7-chloro-5- (o-chlorophenyl) -1,3-dihydro-3-hydroxy-2H-1,4-benzodiazepin-2-one

7-chloro-1-cyclopropylmethyl-1,3-

dihydro-5-phenyl-2H-l, 4-benzodi-

azepin-2-one

7-chloro-1,3-dihydro-5- (2-fluorophenyl) -1-methyl-2H-1,4-benzodi-azepin-2-one

7-chloro-l- (2-dimethylamino) ethyl-5- (o-fluorophenyl) -l, 3-dihydro-2H-l, 4-benzodiazepin-2-one 7-chloro-2,3-dihydro-1 - methyl-5-phenyl-1H-5,4-benzodiazepine

7-bromo-5- (2-pyridyl) -3H-1,4-benzodiazepin-2 (1H) -one

1,3-dihydro-7-nitro-5-phenyl-2H-

1,4-benzodiazepin-2-one l-methyl-7-nitro-5-phenyl-l, 3-dihydro-2H-1,4-benzodiazepin-2-one 5- (o-chlorophenyl) -7-nitro-1 H -1,4-benzodiazepin-2 (3H) -one 5- (o-fluorophenyl) -l, 3-dihydro-l-methyl-7-nitro-2H-1,4-benzodiaze-pin-2-one

8-chloro-1,6-phenyl-4H-s-triazolo- (4,3-a) - (1,4) -benzodiazepine 8-chloro-6- (o-chlorophenyl) -1-methyl-4H-s -triazolo (4,3-a) - (1,4) benzodiazepine

8-chloro-1-methyl-6-phenyl-4H-s-tri-azolo- (4,3-a) - (1,4) -benzodiazepine

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r) oxazolam: 10-chloro-2,3,5,6,7, llb-hexahydro-

2-methyl-11 b-phenylbenzo (6,7) -1,4-diazepino (5,4-b-oxazol-6-one) cloxazolam: 10-chloro-llb- (o-chlorophenyl) -

2,3,5,6,7,11 b-hexahydrobenzo (6,7) -l, 4-diazepino- (5,4-b) oxazol-6-one t) haloxazolam: 10-bromo-llb- (o -fluorophenyl) -

2,3,7,1 lb-tetrahydro-oxazolo (3,2-d) - (1,4) benzodiazepin-6 (5H) -one

Benzodiazepines b), e), i), k), 1) n) and o) are particularly preferred.

The proportion of active agent (s) added is sufficient if it is effective to achieve the desired pharmaceutical effect, which varies depending on the active agent (s) body weight of the patient, symptoms, etc. The proportion of quantity to be used can therefore be selected appropriately depending on these factors. In general, the proportion of active agent is preferably 0.01-50% by weight, in particular 0.05-10% by weight, based on the total weight of components A and B.

The dosage of the active agent administered can be controlled by enlarging or reducing the area of the skin to which the pharmaceutical preparation is applied. As a result, the proportion of active funds is not necessarily limited to the above information.

It is obvious to the person skilled in the art that with increasing concentration of the active agent, increasing amounts of active agent are absorbed by the treated patient. The explanations below are related to blood concentrations of the therapeutic agent (ng / ml plasma), which depends on the total area of the treated Skin, since there is a practically linear relationship with regard to the area of the treated skin and the amount of active agent absorbed.

With a constant application area and constant absolute amount of auxiliaries, the blood concentration of active agent at all times is a function of the concentration of the active agent in the preparation, i.e. increased concentration of active agent in the preparation results in faster penetration of the active agent and higher blood concentration.

Another factor to be considered is that the amount of active agent absorbed depends on the application site, for example scalp, ventral, forearm, behind the ear, chest, etc. Typically an application area richly covered with blood vessels is chosen.

For most applications, the concentration of the active agent in the PAEC is generally in the range from 0.01-50% by weight, based on the total weight of components A and B, and the amount of PAEC applied is in the range from 0.1-100 mg / cm2 and the total application area in the range of 0.5-100 cm2, wherein therapeutic blood concentrations of the respective active agent are generally achieved.

However, these areas should not be considered as limitations.

In general, the rate of absorption of transepidermal active agent approaches that of oral absorption depending on the factors listed above (type and amount of PAEC, concentration of active agent in the preparation, and surface area of application to the skin). Peak blood concentrations of active agent can thus be reached more slowly or at approximately the same rate and reach approximately the same value when administered orally. Alternatively, the blood concentration of active agent achieved by oral administration in a single dose can be maintained for an extended period of time by subsequent percutaneous administration of the active agent. In the latter case, the initial oral dose may be lower than the normal therapeutic oral dose, so that side effects associated with a therapeutic blood concentration higher than the minimum can be avoided and a therapeutic blood concentration can be achieved and maintained at a corresponding rate by means of reduced oral dose and subsequent transepidermal administration.

Therapeutic oral doses of diazepam in humans result in a blood concentration of approximately 100 ng / ml plasma (S.A. Kaplan, M.L. Jack, K. Alexander and R.E. Weinfield, "J. Pharm. Sei.", 62, 1789-1796 (1973)). Such a blood concentration is easily attainable by percutaneous administration using the preparation described and gives pharmacological behavioral signs of therapeutic effectiveness in appropriate experimental animals for humans, e.g. B. Rhesus monkeys.

The preparation described can be used both for humans and for mammals, in particular pets, such as cows, sheep, horses, dogs, cats and the like.

The pharmaceutical preparation described can, in the form of a simple mixture or a medical preparation with the addition of pharmaceutically acceptable third-party components, in the form of solutions, ointments (ointment-containing creams and gels), lotions, self-adhesive tapes, plasters, etc., get onto the outer skin for administration. Solutions can, for example, simply contain the active agent dissolved in the PAEC, optionally with other components, such as glycerol, and be incorporated in absorbents, such as gauze, porous membranes, etc.

Ointments, gels or creams can contain conventional components, such as polyethylene glycol, hydroxypropyl cellulose, etc., for their formation and can be spread on cover materials, such as plastic films.

Similarly, plasters or self-adhesive tapes can contain the active agent and PAEC in an adhesive primer such as acrylic copolymers or other synthetic rubbers.

The components listed above should of course be inert in the system and should not increase or decrease the effect of the PAEC.

The PAEC can be added to such a preparation as desired in varying proportions, generally from 10 to 99% by weight.

In the development of the present invention, both diffusion cells and experimental animals were used. The methods with diffusion cells gave a qualitative assessment of the effect on percutaneous absorption of active agent / PAEC. The test with rhesus monkeys as experimental animals also showed an acceptable pharmacokinetic model for humans, as in «J. Soc. Cosmet. Chem. », 30, 297 - 307, Sept./Oct. 1979 and «Toxicol. Appi. Pharmacol. », 32, 394-398, 1975.

In vitro studies of skin penetration using the diffusion cell method

Rat skins of full thickness were used according to the diffusion cell method described by Michaels in “AIChE Journal”, 21, (5), 985-996, 1975. The rat skin was placed vertically in the diffusion cell between the upper and lower sections and the exposed area of the skin was approximately 4.15 cm 2.

The skin was taken from the shaved abdominal side of male albino rats weighing 250-300 g and

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After carefully removing the subcutaneous fat, use scissors to wash it with normal brine. An active agent / PAEC solution of known concentration was poured into the overhead compartment of the cell facing the epithelial side of the skin and the normal brine solution was poured into the compartment below.

The penetration rate was observed in a thermostated bath at 30 ° C. At appropriate intervals, samples were drawn downwards from the compartment with outflow and then analyzed according to standard analysis methods for the concentration of active agent.

Alternatively, according to the one described by Franz in «Curr. Probi. Dermatol. », Vol. 7, pp. 58-68 (Karger, Basel, 1978). The rat skin is inserted horizontally into a diffusion cell apparatus with an exposed area of the skin of about 0.7 cm 2.

The active agent / PAEC solution of known concentration is poured into the upper compartment, which faces the epithelial side of the skin, and a normal brine solution into the lower compartment.

In vivo rhesus monkey test

If desired, the in vivo Rhesus monkey test described below can be used to determine the effectiveness of the combination of PAEC and diol as a moderator according to the invention.

Male Rhesus monkeys weighing 10-40 kg can be used as experimental animals. A suitable area of the monkey's chest is shaved 24 hours before the preparation is applied.

Embodiments of the preparation described and to be tested are then applied to the shaved skin surface of the test monkey, the monkey being tied in a chair to prevent the breast from touching it.

Blood samples are taken at appropriate intervals after the test preparation has been applied. The heparinized blood is centrifuged and the plasma removed and stored at -20 ° C until analysis.

Diazepam in plasma can be described by Aingales in «J. Chromatog. », 75, 55 - 78,1973 described GLC method de be analyzed.

The invention is explained below with reference to examples.

Examples of certain combinations of components A and B according to the invention were filed prior to the priority date under reference number A-4271 by S. Satoh et al. "Method for percutaneously administe-ring physiologically active agents", where no diol was used as moderator, and under reference number A-4556, by K. Saito et al. "Method for percutaneously ad-ministering physiologically active agents using an alcohol adjuvant and a solvent".

Preparations were prepared by previously dissolving component A with component B, then admixing the active agent into the mixture and finally mixing in the diol. The order of mixing is not important. If component B is solid at ambient temperature or cannot be mixed homogeneously with component A, 20% by weight of ethylene glycol monobutyl ether, based on the total weight of components A and B, were used as solubilizers, s in the examples below the following abbreviations are used:

Ci2OH = dodecanol

C12CI = dodecyl chloride

DMAc = dimethyl acetamide

MP = 1-methyl-2-pyrrolidone

Unless otherwise stated, the active agent in the examples below was diazepam or metoclo-pramide hydrochloride. The flow of the active agent is 15 in | ig / cm2 / 8 h. 25% by volume of component A, based on the total volume of components A and B, with or without addition of diol, together with 2.5% by weight of active ingredient, were used in the preparation. For comparison purposes, the results of preparations not according to the invention, on the one hand without addition of diol and on the other hand without addition of component B, are given and are shown in the diagram of the drawing as curves A and D.

example 1

The diagram of the drawing is a representation of the flow of diazepam per unit of time in h against time in h to explain the modifying effect of diols.

Curves AD were determined using the following embodiments of preparations:

A = 25% C12CI in DMAc (comparison test) B = 25% C12CI in 1: 1 mixture of DMAc / 2,3-butane

diol (according to the invention) C = 25% C12CI in a 1: 2 mixture of DMAc / 2,3-butane

diol (according to the invention) D = 25% C12CI in 2,3-butanediol (comparative experiment).

Example 2

40 In this example the moderating effect of diols for the embodiments of the preparation of 25% Ci2OH in MP as a comparison test and of 25% C12OH in a 1: 1 vol. Mixture of MP / l, 2-propanediol is explained.

45 The following table shows the flow over 8 h.

table

50 flow, | ig / cm2 / 8h

25% C12OH in MP 4382

25% C12OH in 1: 1 vol. Mixture

MP / 1,2 propanediol 1369

55

While the invention has been described in detail above with reference to specific embodiments, it will be apparent to those skilled in the art that numerous changes and modifications are possible within the scope of the invention.

65

s

1 sheet of drawings

Claims (2)

658 993 2nd 1. A preparation for the percutaneous administration of physiologically active agents to humans and mammals, characterized in that it contains at least one physiologically active agent, a component A, a component B and a diol as a moderator in a mixture with one another, component A an optionally mono- or polysubstituted halogen, straight-chain or branched-chain or cyclic aliphatic hydrocarbon with 5-24 C atoms, an alcohol ester of an aliphatic carboxylic acid with a total of 7-18 C atoms, a mono- or diether with 10-18 C atoms -Atoms, a ketone with 11-15 C atoms, an aliphatic monoalcohol with 10-26 C atoms or a mixture of such substances, and component B a thioglycerol, a lactic acid or a lactic acid ester, a lactone with 4-6 C- Atoms, a cyclic urea, a compound of the formula R, N - C - N \ wherein R] to R4 each represent hydrogen, lower alkyl having 1 to 4 carbon atoms, or acyl having 1 to 2 carbon atoms, a compound of the formula R V j (CH_) 2. n is selected from the group of compounds of pyrrolidone type of the formula R, N C = 0 10th (CH ") _ 2 n 15 wherein n is 3-5, and R i is alkyl with 1, or amides of the formula -4 carbon atoms 20th R_ - CON ./ \ R, 25 in which R2 is hydrogen or alkyl with up to 3 C atoms, and R3 and R4 alkyl with up to 3 C atoms with the proviso that the total number of C atoms in R2 to R4 is at least 3. 3. Preparation according to claim 1 or 2, characterized in that the diol has 3 to 8 carbon atoms as moderator. 4. Preparation according to one of claims 1-3, characterized in that the diol as moderator is an aliphatic diol with 3-6 C atoms. 35 wherein R5 is hydrogen or lower alkyl having 1-4 C atoms, and n is an integer of 3-5, a compound of the formula R. - CON o \ wherein R6 is hydrogen or alkyl with 1-3 carbon atoms, and R7 and Rg each alkyl with 1-3 carbon atoms with the proviso that R6, R7 and R8 have a total of at least 3 carbon atoms, and are the components A and B are present in effective proportions to increase the percutaneous absorption of the physiologically active agent and the diol is present in an effective proportion to modify the rate of percutaneous absorption, each in the range of therapeutically effective rates. 2. Preparation according to claim 1, characterized in that component A is selected from the group of halogen-substituted alkyl halides with 8-18. Carbon atoms, aliphatic hydrocarbons with 10-18 carbon atoms, fatty acid esters of the formula RiCOOR2, in which the total number of carbon atoms in Rj and R2 is 10-17, aliphatic monoalcohols with 12-24 carbon atoms, and mixtures of these substances, and that component B