CS276300B6 - Transdermal penetration accelerator - Google Patents

Abstract

it concerns the accelerator . transderal penetration intended for thermoplastic medicinal products to facilitate the penetration of medicinal products fly skin human or animal, characterized by! tle, 2c build ncjoen z One compound from the group of substances type H 2 N- (CH 2) j -COO-R wherein K is C 1 -C 4 alkyl or C 1 -C 6 cycloalkyl. active ingredient and / or the substances are in the range 0.1 to 30 ha. dispersed in physiologically Inert * vehicle along with safe and effective release agents or active substances compatible with vehlkule ·. The accelerator is designed to increasing the efficiency of deep layer treatment skin or transcalalar systea therapy.

Description

The present invention relates to a transdermal penetration enhancer intended to increase the skin penetration of drugs applied externally to human or animal skin.

Currently, are substances for which the name transdermal penetration accelerator can be used intensively studied with targets? to find those that would facilitate the entry of topically applied drugs into certain layers of the skin, possibly increasing the transdermal permeability of therapeutically active substances in order to ensure their systemic action. Search for suitable transdermal penetration accelerators, referred to as sorption promoters, penetration enhancers (Ri tschell, η'.Λ., Angew. Chee., Int. Ed. 0, 1969, 699) or penetration accelerators (Allenby, AC et al., Grit J. Dermatol., 31, 31) in both mentioned cases the use is important for topical application of such substances, whose own potential for skin penetration is small and is limited by natural barrier properties of the skin, located mainly in the stratum corneum epidermis. Such drugs alone cannot reach the sites where they are to have their therapeutic effect, whether it is localized in the deeper levels of the skin or a systemic effect, after their transdermal transition to the bloodstream or lymphatic system. For many of the advantages of transdermal delivery of substances to the systemic circulation (substances with a short biological half-life, small therapeutic width, first past effect limitation, compliance, etc.), the concept of using transdermal penetration enhancers is very promising in this context (Chlen, YW , Drug Oev. Ind. Pharn., 13, 1987, 539-651). The summary of properties that transdermal penetration enhancers should exhibit is quite extensive (Barry, 3.N., Dermatological Formulations. Percutaneous Absorption, he York, Marcel Dekker, 1983, 160-172), expressed in abbreviated form, should be pharmacologically inert. be toxic, not irritating or allergenic, their effect should be rapid, predictable and, after removal of the accelerators, the normal barrier properties of the skin must be restored rapidly. physically compatible with the Wide Range of Medicinal and Pharmaceutical Excipients, to be cosmetically acceptable, inexpensive.

The substances tested so far or used as transdermal penetration accelerators are quite numerous and are very diverse in terms of chemical structure. Rieger, Ν.ΛΧ., Cosmetics and Toiletries, 94, 1979, 32-37 and ibid., 95, 1930, 26-38 and 3arry, 0. U. vc in the above-cited monograph extensively, with a rich list of references to original works , summarize the knowledge about dialkylsulfoxide (dimethylsulfoxide, hexylmethylsulfoxide, decylmethylsulfoxide (oxide), dialkylamides (N, N-dimethylformamide, Ν, Η-dimethylacetamide), alkylphosphino-;

xidcch (trimethylphosphine oxide, dodecylecthylphosphine oxide), scipolar alcohols (ethanol, propylene glycol, tetrahydrofurfural alcohol) and a large group of surfactants. ^:

The substances or groups of lutyl are mentioned; According to the reviews cited above, they do not always meet any of the essential requirements for transdermal penetration accelerators. For example, the very often tested dimethyl sulfoxide is not physiologically inert, its own effects are clinically manifested in many disease states, in addition it is locally irritating and allergenic. Uncommon disadvantages have been reported for dialkylamides, the efficacy of scipolar alcohols and many surfactants is questionable.

In this context, X, the N-diethyl-α-toluamide (Wind-houser, March 3, and Phar. Sci., 71, 1932, 1211-13) such as mandelic acid and acrolactic acid (de; loij, TA 3. N., Res. Clin. Forums, 6, 1931, 7-13), as appropriate (Kasscm, A., Schulte, K. E-, 3. Cr. 4,299,826), alkylamides of carbocyclic acids (Pat. U.S. Pat. No. 2,99C, 331), butanedicyl (Pat. U.S. Pat. ₍ fatty acids and their esters (Pat. USA 3,535,122), urea (X.arion-Landais, U., Xrum,; t. 3., Churr. (her. Res., Clin. £ xp., 23. 197? 55-55, Wcnlrab V., Dermatol. Honatschc., 174, 1935, 94-53), lower aliphatic

: s 27 «300 35 tick ·· acids such as prupionic and caprylic acids (Kadir, R. et al., J. Phare. Sei., 74,

1757. 774 to 7)

More successful uses include pyrrolidone derivatives, in particular 2-pyrrolidone (U.S. Pat. No. 3,932,653) or lower alkyl derivatives such as dimethylpyrrolidone (U.S. Pat. No. 3,937,516), optionally also in mixtures (U.S. Pat. No. 4,039,661). N- (2-hydroxyethyl) pyrcolidone (Pat. Eur. 129.2U5), which has also been used commercially in a mixture with methyl lauric acid or oleic acid ester. So far, however, substances of this type have been shown to facilitate skin penetration but are not very effective (Southwell, U. et al., 8th. Pharm. Cent. Com., 1930, 93).

The most important and most recently accelerated accelerator to date is l-dodeccylazacycloheptan-2-one (Inurokaprum), which was patented in 1976 by Rajadhyaksha, V. 3., Vico, K. (U.S. Pat. No. 3,939, 115 with U.S. Pat. No. 3,939,016 ) and whose properties were discussed more extensively first by Stounnton, X. 3., Arch. Sera., 113, 1932 ^ 7 * to 7, Drug Oev. Indian. Pharm., 9, 1933, 725-11). This substance has recently become an unofficial standard in the field of accelerators, and the number of drugs for which its penetration-accelerating effect has been proven is already in the hundreds. It is non-toxic and non-irritating, derivatives with other alkyls have also been derived from it, but the lauryl derivative still remains the most important.

Its disadvantages include that it must not be dispersed in the form of a solution in order to have the appropriate effect. Its effect is inhibited by the presence of a number of excipients commonly used in medicinal products. Paraffinic hydrocarbon excipients (liquid paraffin, petroleum jelly) present in small amounts in the vehicle can completely eliminate its penetration-accelerating effect (Stoughton, R. 0., Mc Clure, f. 0., Drug Dcv., Ind. Pharm. , 9, 1933, 725- * 4). In addition, laurocapram is an oily liquid at ordinary temperatures, the synthesis of which, especially in compliance with the usual purity requirements of the final product, is difficult and time-consuming.

These disadvantages are eliminated by a transdermal penetration enhancer for topical preparations to facilitate the penetration of drugs through human or animal skin in the treatment of the deeper layers of the skin or in transdermal systemic therapy, characterized in that it consists of at least one compound of formula (I).

NH ₂ -CCH ₂ ) ₅ -CO 3 R wherein: <is -C 1-6 alkyl or cycloalkyl. The substance and / or substances are dispersed in an amount of from 1 to 33% by weight in a physiologically inert vehicle together with a safe and effective amount of the active substance or active substances compatible with the vehicle.

The accelerator according to the invention is further characterized in that it is present in the hydrophobic environment of the toxic preparation in an amount of 0.1 to 3 4 wt.%, Preferably 0.5 to 10 4 wt. up to 20 4 wt. preferably 0.2 to hmot 5 wt.

The accelerator according to the invention is prepared by dispersing at least one of the compounds of the formula (I), preferably obtained synthetically, in an amount of 0.1 to 30% by weight, using a stirrer or an ultrasonic bath, in solution, emulsion or suspension in a or a hydrophobic, physiologically inert liquid vehicle, while respecting the generally accepted pharmacopoeial cautery of the preparation of dispersions of this type. It is possible to incorporate the compatible drug substance at the same time as the accelerator dispersion or subsequently.

The following derivatives of ε-aminocuproic acid have proved to be suitable as preferred substances for the accelerator according to the invention; hexyl ester, octyl ester, dccyloster, dodecyl ester, hexaducyl ester, cyclopentyl ester. Their dispersion is possible using conventional hydrophilic liquid vehicles such as water and / or ethanol and / or propylene glycol and / or glycerol by weight, or hydrophobic liquid vehicles of the glyceride nature such as sunflower oil and olive oil. / ncbo the nature of the waxes, such as isoprapsilite and / or isopropyl myristate and / or isopropyl stearate.

CS 275 300 06

The accelerator according to the invention has several advantages over the hitherto known. The above-mentioned esters of alalkapeic acid are crystalline substances at ordinary temperatures, which can be easily obtained synthetically in high purity. Handling them as powdered substances does not complicate. They are less expensive to manufacture than laurocapram and also show their effect in low concentrations. Another advantage of the accelerator according to the invention is that the transderial penetration is accelerated not only in the form of an emulsion or suspension, but also, unlike, for example, laurocapram, 1 in the form of a solution. Dispersion of the accelerator is feasible at ordinary temperatures or with gentle heating (25 ° C to * 0 ° C), using conventional mixing and homogenizing equipment, including a scraper. Another significant advantage of the accelerator according to the invention is that 2c acts in relatively low concentrations from Wide Polar Scale vehicles, which is a significant advantage over accelerators used hitherto.

Also the data found on the toxicity and dermal irritability of the accelerator according to the invention are favorable. The toxicity of the substance which showed the highest acceleration efficiency from the respective group of ε-aminocaproic acid esters was determined by a test according to the 4th edition of the Czechoslovak Pharmacopoeia (1987). Medium sartná dose intraperitoneally in mice after administration of defective dispersion of the accelerator was 750 mg / kg at _q LOi variation determination without comparison to a standard.

The skin irritation test, performed according to the provisions of the 4th edition of the Czechoslovak Pharmacopoeia (1907), yielded the following results for the most effective accelerators of the respective group of β-aminocaproic acid esters. In tests in which the local reaction of intact and scarred rabbit skin to dispersions with a graded concentration of the accelerator according to the invention in white Vaseline was read, the test samples were shown to have zero irritation up to a concentration of 1% by weight. Samples with a concentration of 5 * t hoot. The most effective substances from the defined group of accelerators according to the invention induced a local hyperemic reaction on the shaved scarred skin of male and female rabbits after 8 hours of application of samples followed by crustal separation of the stratum corncum. These samples caused skin irritation expressible by grade no. 4 in the sense of the Czechoslovak Pharmacopoeia. After stopping a 5-day application of samples containing 5 X masses, the given accelerator and subsequent repeated application of a verified sample of white Vaseline, the skin regenerated within 3 days. From these results, it can be preliminarily concluded that the respective dispersions to the I X content by weight absorbed on the accelerators according to the invention can be considered suitable for dermal irritation in terms of dermal irritation, while achieving a significant accelerating effect on transderial drug penetration.

To demonstrate the effects of the accelerator according to the invention, a table is given in which selected results of 24-hour in vitro experiments are used, in which excised human skin with a thickness of about 500 micrometers was used as a concentration barrier. The arrangement of the experiments was performed so as to be as close as possible to the conditions already verified in the works dealing with an analogous topic. The choice of composition and temperature * of the sink acceptor phase (isotonized phosphate buffer pH 7.4 at 37 ° C) took into account the work of Kadira, R. et al., 0. Pharm. Sel., 76, 1937, 774-9, choice of in vitro finite dose technique followed by the work of Southwell, O. and Barry, 8. M., Int. J. Pharm., 22, 1984, 291 a2 <1. The presented results are combined with the use of theophylline as a model substance for transderal penetration. Theophylline is a substance of medium high polarity and is often used in the given context, because as such it has a low permeability through the skin and therefore it can serve well to clarify the penetration enhancing effects. In addition, the results obtained in penetration studies with theophylline in vitro correlate well with the results of in vivo experiments (Wearlcy, L. et al., Drug Oev. Xnd. Pharm., 14, 1933, 13-29). Determination of theophylline in the action motor phase was performed by HPLC under the following analytical conditions: Glass column 3.3 m in diameter, length 15 ca, packed with Scpharon SGX C 10 sorbent with a particle size of 7 micrometers, methanol-water mobile phase (1: 1), UV detection at 272 nm.

C5 27Λ J.fÍ .U.

Samples to be tested when applied to excised skin with an exposure cage of 2 c ^Z were prepared from discrocation theophylline, or accelerators, in a liquid medium of selected vehicles of a wide spectrum of polarity with the help of a friction with a scraper and magnetic stirrers. All donor samples, applied in an amount of 0.7 ml, each contained 1.5% by weight. (i.e. 75.5 mmol / l) of theophylline. In addition to blank samples, boz esters - aminocaproic acid (SAK), a series of samples with different contents of different ΕΛΧ esters were tested.

The results are expressed in columns Q 24 of the table · / values of the average concentration (mg / 100 ml) of theophylline which penetrated through the skin into the acceptor medium in 24 hours, including the corresponding standard deviations in columns s (n * 1). Columns 5 show the steady state flux rates of theophylline (.mu.g / cm @ 2) from the time range I sl 3 h of the experiment, the correlation coefficient of the respective linsarizations corresponding to a level of 95.

These results demonstrate that the accelerator of the invention significantly increases the transdermal penetration of theophylline as a model substance. For example, at a content of 5% by weight of t-aminocaproic acid n-ester in a vehicle with 1.5% by weight of theophylline, the final concentration of theophylline in the acceptance medium after 24 hours of experiment, Q 24, is higher for the donor sample with isotonized phosphate buffer pH 7. 20 times, for its mixture with propylglycol about 25 times, for alcohol 95 wt.%, For 230 times, for propylene glycol about 300 times, for Isopropyl palmitate about 30 times and for sunflower oil about 35 times. A similar relation is also provided by the comparison of the respective values f of the steady flow of theophylline.

The invention is further elucidated on the basis of exemplary embodiments, which, however, do not limit or exhaust its scope.

Example l

The prescribed amount of sieved indomethacin is triturated with the prescribed amount of ε-aminckaproic acid octyl ester, about 5 l) of sunflower oil is added to the resulting powder mixture and a concentrated dispersion is prepared by stirring at about 35 ° C, which is stirred with gentle heating ( 25 ° C to 40 ° C), adjusted in portions with added sunflower oil to a final amount of indomethacin (VII) 1.0 by weight octyl EAST1.0 sunflower oil90.0

Example 2

By a procedure similar to Example 1, a dispersion with a weight composition of ibuprofen (VII) 1.0 dodecyl ester EAX1.0 olive oil93.0 is prepared.

Example 3

Following a procedure similar to Example 1, a dispersion is prepared from the composition of fluorouracil (VII) 1.5 cyclopentyl ester EAK2.0 glycerol 35% by weight.25.0 water71 5

Example 4

By a procedure similar to Example 1, a dispersion with a weight composition of hydrocortisene acetate (micron) of 1.0: with 27 $ 30U 86 was prepared.

dccylcster ΕΛΧ 1.0 propylene glycol 30.0 water «0.0

Example 5

In a manner similar to Example 1, a dispersion of weight composition was prepared

nystatin (VII) 0.5 octyl ester EAK 1.0 hexadcyl ester EC 0.5 sunflower oil 99.0

Example i

In a manner similar to Example 1, a dispersion of a composition by weight is prepared

lldokaln (VII) 0.5 octyl ester E * K ' 0.5 isopropyl palmeth 9.0 olive oil 90.0

PATENT M 4 K 0 K r

Claims (3)

PATENT M 4 K 0 K r 1. A transdermal penetration enhancer for topical preparations to facilitate the penetration of drugs through human or animal skin in the treatment of the deeper layers of the skin or in transderal systemic therapy, characterized in that it consists of at least one compound of formula (I). M ₂ K - (cm ₂ ) _s -COO - R (I), where «is - C _1-3 alkyl or C 3-8 cycloalkyl. 2. An accelerator according to claim 1, characterized in that it is present in an amount of 0.1 to 30% by weight in the hydrophobic environment of the topical preparation. preferably in an amount of 0.5 to 10 wt. 3. An accelerator according to claim 1, characterized in that it is present in the hydrophilic medium of the topical preparation in an amount of 0.1 to 20% by weight, preferably in an amount of 0.2 to 5% by weight.