WO2004052347A1 - Transmucosal and transdermal medicaments with an improved active ingredient absorption - Google Patents

Abstract

The invention relates to medicaments for transmucosal or transdermal administration, characterised in that they contain at least one substance from the group containing monoterpenes and at least one substance from the group containing polyalcohols, in order to improve the absorption of active ingredients.

Description

 Transmucosal and transdermal drugs with improved drug absorption.

The present invention relates to medicaments for transmucosal or transdermal administration of active substances, these medicaments containing a combination of auxiliaries which improve or accelerate the transmucosal or transdermal absorption of active substances (“enhancers”). The invention further comprises the use of such medicaments for the administration of active substances, and also preparations for the production of transmucosal or transdermal dosage forms, these preparations having a content of absorption-improving additives.

The transmucosal administration of active substances, in particular the administration via the oral mucosa (e.g. by means of buccal dosage forms), is extremely advantageous from a galenical point of view, because it results in a quick onset of action and a higher bioavailability. So far, sprays or sublingual tablets have mainly been used for this type of administration.

Film-like systems (“wafers”) which can be administered orally have become known as a novel dosage form for oral transmucosal or transbuccal administration. These film-shaped systems can be equipped with mucoadhesive properties, so that they remain on the mucous membrane, e.g. B. on the buccal (or gingival) mucosa, can adhere. Furthermore, the film-shaped systems can - by suitable selection of the formulation constituents - be designed as films which are decomposable, partially decomposable or non-decomposable in aqueous media.

After application of a film-shaped system in the oral cavity, the active ingredient contained in the system is released to the environment released and partially transmucosal resorbed, but partially swallowed with saliva. The swallowed portion of the amount of active substance released is therefore not available for transmucosal absorption, which reduces the bioavailability of the active substance. To avoid this disadvantage, it is necessary for the active ingredient to be absorbed as quickly as possible via the mucous membrane in the oral cavity.

The problem of improving drug absorption also arises in the case of transdermal therapeutic systems which are intended to enable the controlled administration of pharmaceutical drugs over a longer period of time, usually over several hours or days. Since the skin is a barrier for many active substances, it is crucial with transdermal drugs to improve the absorption of active substances through the skin.

The object of the present invention was therefore to show substances or mixtures of substances which improve the transmucosal and transdermal absorption of active substances (so-called "enhancers"), and also medicaments which are distinguished by improved transdermal or transmucosal absorption of active substances.

According to the main claim, this problem is solved by medicaments for transmucosal or transdermal administration, which contain at least one substance from the group of monterpenes and at the same time at least one substance from the group of polyalcohols. The addition of such a combination of substances improves the absorption of the active substance through the oral mucosa.

In addition, it was found that in the case of medicaments for transdermal administration, the addition of the combination of enhancers mentioned brings about an improvement in the transdermal absorption of the active substance. The combination according to the invention of at least one substance from the group of Monoterpenes and at least one substance from the group of the polyalcohols thus acts as an enhancer with regard to the transmucosal as well as the transdermal absorption of the active substance.

Without being bound by any particular theory, it is assumed that the enhancer effect could be due to the fact that the monoterpenes act as vasodilators for accelerated removal of the active substance, whereas the polyalcohols which are also present serve as plasticizers.

From the group of monoterpenes, the following are particularly suitable:

- Aliphatic monoterpenes, such as. B. Myrcen, Oci en; - Cyclic monoterpenes, such as. B. alpha-pinene, camphene, i-monene, phellandrene, pinene, sabine, terpinene;

- aromatic monoterpenes, such as. B. Cymol;

- alcoholic monoterpenes such as B. Borneol, Carveol, Dihydrocarveol, Geraniol, Linalool, Perilla alcohol, Sabine hydrate, Terpineol;

- Monoterpenes with a carbonyl group, such as. B. Campher, Carvon, Citral, Cuminaldehyde, Dihydrocarvon, Fenchon, Safranal, Thujon;

- phenolic monoterpenes, such as. B. anethole, carvacrol, eugenol, eucalyptol, methylcavicol, thymol, trans-anethole;

- more complicated phenolic monoterpenes, such as. B. Picrococin;

- Compounds derived from monoterpenes, such as. B. 5-methoxyl- (2-methyl-butyryloxy) -1-propenylbenzene, allyl-tetramethoxibenzene, anisaldehyde, anisketone, apiol, eleminine, hydroxyanethomethylbutyric acid ester, zingeron;

- Phenylpropane, such as. B. 5-methoxyl- (2-methyl-butyryloxy) -1-propenylbenzene, Allyltetramethoxibenzol, Anethol, Cuminaldehyde, Elemicin, Estragol, Eugenol, Eucalyptol, Foeniculin, Hydroxyanetholmethylbuttersäureester, Methyl-Chavicol, Myristicin, Safolole, Safrol zingerone. Polyhydric alcohols such as glycol, propanediol, butanediol etc. can preferably be used as polyalcohols, furthermore trihydric or polyhydric alcohols, in particular glycerol. Among the higher alcohols, polyvinyl alcohols are particularly suitable. These can also act as matrix formers, ie as a component that is involved in the formation of the solid matrix of the drug.

According to preferred embodiments of the invention, it is further provided that the enhancer mixture contained in the medicament contains a combination of two or more substances from the group of monoterpenes or / and a combination of two or more substances from the group of polyalcohols. In any case, the enhancer mixture contains at least one substance from the group of the monoterpenes and at least one substance from the group of the polyalcohols.

Menthol or a mixture of other monoterpenes containing menthol is preferably used as an enhancer mixture in combination with at least one polyalcohol selected from the group comprising propanediol, butanediol and glycerol.

Furthermore, it has been shown that particularly good results are obtained in the absorption of active substances if the transmucosal or transdermal medicaments additionally contain dex-panthenol and / or one or more salts of pantothenic acid.

The enhancer substances are preferably present in the pharmaceutical formulation in the proportions mentioned below (based on the dry matter): monoterpenes: 0.5 to 40% by weight, preferably 3 to 30% by weight, particularly preferably 5 to 20 wt .-%; Polyalcohols: 0.5 to 80% by weight, preferably 3 to 30% by weight, particularly preferably 5 to 20% by weight;

Dexpanthenol or pantothenic acid salt (s): 0.5 to 40% by weight, preferably 3 to 30% by weight, particularly preferably 5 to 20% by weight.

The pharmaceuticals according to the invention preferably have an essentially solid matrix; this may contain one or more matrix-forming substances, at least one active substance and the substances mentioned which improve the absorption of the active substance.

The medicaments for transmucosal active ingredient delivery, which contain the enhancer mixtures according to the invention, are preferably formulated as film-like pharmaceutical forms. By selecting suitable matrix formers and auxiliaries, these can be endowed with mucoadhesive properties; however, the invention also encompasses non-mucoadhesive film-shaped drugs.

The invention further extends to mucoadhesive or non-mucoadhesive film-shaped medicaments which are soluble or / and disintegrable in aqueous media or physiological liquids. Suitable matrix formers and auxiliary substances are known to the person skilled in the art.

In this way, the release of the active ingredient by the solubility or by the disintegration in aqueous media, for. B. saliva can be controlled. For example, the films can be formulated as either fast or slow release systems.

Alternatively, the transmucosal drugs can also be formulated as dosage forms which are insoluble or non-disintegrating in aqueous media. In addition to water, “aqueous media” means in particular physiological liquids, in particular saliva.

The transmucosal, in particular film-shaped drugs according to the invention are preferably formulated as oral dosage forms; in addition, the invention also includes medicaments which are intended for vaginal or rectal administration.

The manufacture of medicaments for transmucosal active ingredient delivery, in particular of film-like dosage forms, and the matrix-forming substances, auxiliaries and solvents suitable for this purpose are known to the person skilled in the art. Substances, in particular polymers, are referred to as matrix-forming substances which are suitable for forming the solid or semi-solid matrix (basic structure) of a medicament. This matrix generally represents the reservoir for the active substance (s) to be administered. The proportion by weight of the matrix-forming constituents is preferably in the range from 10 to 95% by weight, particularly preferably in the range from 15 to 70% by weight. %, in each case based on the entire drug (dry matter).

Particularly suitable matrix-forming polymers are: polyvinyl alcohol (PVA), polyethylene oxides, copolymers of methyl vinyl ether and maleic acid, cellulose derivatives such as hydroxypropylmethyl cellulose (HPMC), hydroxypropyl cellulose (HPC), sodium carboxymethyl cellulose (NaCMC), methyl cellulose (MC) , Hydroxyethyl cellulose (HEC), hydroxypropyl ethyl cellulose (HPEC), polysaccharides, starch and their derivatives, gelatins, polyvinylpyrrolidones (PVP), gum arabic, pullulan or acrylates. Mixtures of two or more of the polymers mentioned can also be used. Substances from the following groups can advantageously be used as auxiliary substances which are known in principle to the person skilled in the art: fillers such as SiC>2; Dyes like

Quinoline yellow or Ti <_> 2; Disintegrants or wicking agents, the

Draw water into the matrix and blow up the matrix from the inside, e.g. B. Aerosil; Emulsifiers such as Tween (polyethoxylated sorbitan fatty acid esters), Brij (polyethoxylated fatty alcohols); Sweeteners such as aspartame, sodium cyclate and saccharin; Plasticizers such as PEG (polyethylene glycol) or glycerin; Preservatives such as sorbic acid or its salts; Antioxidants. The proportion of these auxiliaries can preferably be up to 30% by weight, in particular 1 to 20% by weight, in each case based on the entire medicament (dry matter).

The active substance content is generally 0.5 to 50% by weight, preferably 1 to 40% by weight, particularly preferably 5 to 30% by weight, in each case based on the entire medicament (dry matter).

The total thickness of a transmucosal, in particular a film-like drug can be 5 µm to 5 mm, preferably 30 µm to 2 mm and particularly preferably 50 µm to 1 mm. The surface shape can advantageously be round, oval, triangular or quadrangular, polygonal or have any shape that is rounded. Such dosage forms are often referred to as "afer".

The medicinal products according to the invention for transmucosal administration are generally produced in such a way that a coating composition is first prepared using water, alcohol or other solvents and contains the active substance (s), matrix-forming constituents and optionally auxiliary substances. This coating composition is coated onto an inert base by doctor blade, roller application, spraying or extrusion processes and dries, forming a film layer. This is then divided into surface sections of a suitable size.

The present invention further relates to medicaments for the transdermal administration of active substances, in particular transdermal therapeutic systems (TTS) such as, for. B. transdermal patches. The structure of such systems, the matrix-forming substances and auxiliaries suitable for this, and also production processes suitable for this are known in principle to the person skilled in the art. The transdermal medicaments according to the invention are preferably designed as pressure-sensitive adhesive systems on the skin.

The typical structure of a TTS comprises a backing layer which is impermeable to active substances and auxiliary substances (for example plastic film, such as PETP, PE), an associated active substance-containing reservoir and a removable protective layer (for example PE or PETP film, siliconized) or fluorosiliconized), which covers the skin contact side of the active substance reservoir during storage or before application.

Polymers from the following groups are particularly suitable as polymers for producing the active substance reservoir: polyacrylates, poly (meth) acrylates, polyacrylic acid, cellulose derivatives, in particular methyl and ethyl celluloses, isobutylene,

Ethylene vinyl acetate, natural and synthetic rubbers such as styrene-diene copolymers, styrene-butadiene block copolymers, isoprene block copolymers, acrylonitrile-butadiene rubber, butyl rubber or neoprene rubber, silicone pressure sensitive adhesive and hot-melt adhesive. Suitable mixtures of the polymers mentioned can also advantageously be used. The polymer matrix of the active substance reservoir can be constructed in one or more layers. The proportion of these polymers can preferably be 10 to 90% by weight, preferably 20 to 70% by weight, in each case based on the total weight of a TTS in the dried state. The active substance reservoir of the TTS according to the invention can also contain various auxiliaries or additives, for example from the group of solubilizers, solvents, plasticizers, tackifiers, pH regulators, antioxidants and preservatives; Suitable substances are known to the person skilled in the art. The active substance content in the reservoir is preferably in the range from 0.1 to 50% by weight, particularly preferably in the range from 5 to 30% by weight, in each case based on the total weight of a TTS in the dried state.

In the preparation of the TTS according to the invention, the procedure can be such that active ingredient (s), matrix-forming polymers and, if appropriate, auxiliary (s) are dissolved or suspended in a suitable solvent or solvent mixture and the resulting coating composition is placed on a suitable base, for example one with a Plastic film provided with silicone layer, is coated. After the solvent components have been dried and evaporated, the active substance-containing matrix layer is covered with a further film, which represents the later back layer of the TTS. By punching flat structures in the desired geometric shape and size

(e.g. 2 to 50 cm ^) individual TTS are made from such a laminate.

As active substances which can be administered transdermally or transmucosally by means of the medicaments according to the invention, in principle all compounds or mixtures of substances which are therapeutically or prophylactically active in humans or animals are suitable. These can come in particular from the following groups: agents for infection treatment, antivirals; Analgesics such as feritanyl, buprenorphine, anesthetics; Anorectika; Drugs for the treatment of arthritis and asthma, such as terbutaline; anticonvulsants; Antidepressants; antidiabetics; antihistamines; antidiarrheals; Anti-migraine drugs; Anti-nausea and nausea drugs, Travel or seasickness, such as B. scopolamine and ondansetron; antineoplastic agents; Anti-Parkinson agents; Antipsychotics; Antpyretika; antispasmodics; anticholinergics; Anti-ulcer agents such as ranitidine; sympathomimetic; Calcium channel blockers such as nifedipine; Beta-blockers; Beta-agonists; Antiarrhythmics; Antihypertensives such as atenolol; ACE inhibitors such as enalapril; Benzodiazepine agonists such as flumazenil; coronary, peripheral and cerebral vasodilators; substances acting on the central nervous system; hormones; hypnotics; Immunosuppressants; muscle relaxants; prostaglandins; Proteins, peptides; Psychostimulants; Sedatives, tranquilizers.

Suitable active substances can also be found in the active substance groups of the parasympatholytics (e.g. scopolamine, atropine), the parasympathomimetics, the cholinergics (e.g. physostigmine, nicotine), the neuroleptics (e.g. chlorpromazine, haloperidol), the Monoamine oxidase inhibitors, the sympathomimetics (e.g. ephedrine, D-norpseudoephedrine, salbutamol, fenfluramine), the sympatholytics and antisympathotonics (e.g. propranolol, timolol, bupranolol, clonidine, dihydroergotamine) (the anx. B. diazepam, triazolam), local anesthetics (e.g. lidocaine), central anaesthetics (e.g. fentanyl, sufentanil), antirheumatic drugs (e.g. indomethacin, piroxicam, lornoxicam), coronary drugs (e.g. Eg glycerol trinitrate, isosorbide dinitrate), the estrogens, progestogens and androgens, the antihistamines (eg diphenhydramine, clemastine, terfenadine), the prostaglandin derivatives, the vitamins (eg vitamin E, cholecalciferol), the Cytostatics and cardiac glycosides like for example digitoxin and digoxin.

The invention further extends to preparations which can be used for the production of transmucosal or transdermal dosage forms, the preparations containing at least one matrix former and at least one pharmaceutical active ingredient. According to the invention these preparations additionally contain at least one substance from the group of the monoterpenes and at least one substance from the group of the polyalcohols, as indicated above.

The medicaments according to the invention can advantageously be used for the transdermal or transmucosal, in particular oral, vaginal or rectal administration of active substance (s) for the treatment or prophylaxis of diseases in humans or animals.

The invention is illustrated by the following formulation example:

(a) Natrium-Carboxymethylcellulose; als Matrixbildner, (b) Detomidin.

(a) sodium carboxymethyl cellulose; as matrix former, (b) detomidine.

1 shows the in vivo application of the enhancer system according to the invention (upper curve or upper bar) in comparison with a reference system (lower curve or lower bar). Of particular importance is the significantly earlier flooding of the active ingredient concentration in the plasma, as a result of which an earlier onset of action is achieved.

Claims

Expectations 1. Medicament for transmucosal or transdermal administration of active substances, characterized in that they contain at least one substance from the group of monoterpenes and at least one substance from the group of polyalcohols to improve the absorption of the active substance. 2. Medicament according to claim 1, characterized in that it additionally contains dexpanthenol. 3. Medicament according to claim 1 or 2, characterized in that the group of monoterpenes comprises the following classes: aliphatic monoterpenes, cyclic monoterpenes, aromatic monoterpenes, alcoholic monoterpenes, monoterpenes with carbonyl group, phenolic monoterpenes, more complicated phenolic monoterpenes, compounds derived from monoterpenes , Phenylpropane. 4. Medicament according to one of claims 1 to 3, characterized in that the group of polyalcohols comprises the following classes of substances and substances: dihydric alcohols, in particular glycol, propanediol, butanediol; trihydric alcohols, especially glycerin; higher quality alcohols, especially polyvinyl alcohol. 5. Medicament according to one of claims 1 to 4, characterized in that it contains menthol or a mixture of other monoterpenes containing menthol, and at least one polyalcohol from the group propanediol, butanediol, glycerol. 6. Medicament according to one of claims 1 to 5, characterized in that it is present as a transmucosal dosage form, preferably as a film-shaped transmucosal dosage form. 7. Medicament according to claim 6, characterized in that it is mucoadhesive. 8. Medicament according to claim 6, characterized in that it is not mucoadhesive. 9. Medicament according to claim 7 or 8, characterized in that the film-like dosage form is soluble and / or disintegrable in aqueous media or physiological liquids. 10. Medicament according to claim 7 or 8, characterized in that the film-like dosage form is not decayable in aqueous media or physiological liquids. 11. Medicament according to one of claims 6 to 10, characterized in that it is formulated as an oral, vaginal or rectal dosage form. 12. Medicament according to one of claims 1 to 5, characterized in that it is present as a transdermal dosage form, preferably as a transdermal therapeutic system. 13. Medicament according to one of claims 6 to 12, characterized in that it has a solid matrix which contains one or more matrix-forming substances, at least one active substance and the substances which improve the absorption of active substances. 14. Medicament according to claim 12 or 13, characterized in that the said matrix is mucoadhesive or pressure-sensitive adhesive on the skin. 15. Use of a medicament according to one of the preceding claims for transdermal or transmucosal, in particular oral, vaginal or rectal administration of active ingredient (s). 16. Preparation for the production of a transmucosal or transdermal dosage form, wherein the preparation contains at least one matrix former and at least one pharmaceutical active ingredient and is characterized in that it additionally contains at least one substance from the group of the monoterpenes and at least one substance from the group of the polyalcohols. 17. Preparation according to claim 16, characterized in that it additionally contains dexpanthenol. 18. Preparation according to claim 16 or 17, characterized in that the group of monoterpenes comprises the following classes: aliphatic monoterpenes, cyclic monoterpenes, aromatic monoterpenes, alcoholic monoterpenes, monoterpenes with carbonyl group, phenolic monoterpenes, more complicated phenolic monoterpenes, compounds derived from monoterpenes , Phenylpropane. 19. Preparation according to one of claims 16 to 18, characterized in that the group of polyalcohols comprises the following classes of substances and substances: dihydric alcohols, in particular glycol, propanediol, butanediol; trihydric alcohols, especially glycerin; higher quality alcohols, especially polyvinyl alcohol.