KR20050021003A - Film-shaped mucoadhesive administration form for administering cannabis active ingredients - Google Patents

Abstract

The present invention relates to film-like mucoadhesive dosage formulations containing one or more active ingredients from the group of hemp active ingredients.

Description

FILM-SHAPED MUCOADHESIVE ADMINISTRATION FORM FOR ADMINISTERING CANNABIS ACTIVE INGREDIENTS

The present invention relates to a mucoadhesive dosage form in the form of a film having a content of hemp agents and suitable for administration of hemp agents for therapeutic purposes. The present invention also relates to the use of said dosage form for treating a disease state of a human or animal.

The components of the plant of Indian hemp (Cannabis sativa L.) are most widely known for their various pharmacological and psychotropic effects. In addition to this, the hemp component also has antivomiting, anticonvulsive, muscle relaxation, analgesic, sedative and appetite enhancing effects.

Because of the psychotropic or euphoric effects and the potential for dependence in this regard, the therapeutic application of hemp components is subject to strict limitations.

Hemp ingredients can be used with good effects in treating rheumatism of insomnia, neuralgia, pain in addition to gastric and intestinal disorders. The desired therapeutic effect of the hemp component is also observed for the following applications:

Conditions of pain in the case of carcinoma and as a result of chemotherapy; Conditions of pain and "wasting" syndrome in connection with AIDS; Nausea and vomiting as a side effect of chemotherapy as well as associated with AIDS or hepatitis; Neuropathic pain; Anorexia or cachexia, especially in relation to AIDS or carcinoma, with significant progression of the disease.

Paralysis symptoms associated with multiple sclerosis or traumatic transverse lesions; Dystonic motor disturbance; Bronchial asthma; Epileptic seizures or systemic epilepsy; Withdrawal symptoms associated with alcohol dependence, benzodiazepine dependence and opiate dependence; Parkinson's disease; Dementia, in particular Morbus Alzheimer's disease; nausea; arthritis; glaucoma; migraine; Dysmenorrhea.

Currently, only synthetically produced hemp agonist R- (6a, 10a) -Δ-9-tetrahydrocannabinol (Dronabinol) is marketable. The isomer of tetrahydrocannabinol (THC) is marketed under the trade name of Marinol; The medicament is administered orally in the form of a capsule. Marinol is used to treat severe weight loss in AIDS patients and cancer patients suffering from severe vomiting as a result of chemotherapy.

In addition to the THC isomers, hemp extract and hemp oil for therapeutic treatment purposes are also suitable. Application is usually achieved via the oral route, for example in the form of capsules.

Hemp extract is a pharmacologically active ingredient as tetrahydrocannabinol (mainly Δ-9-tetrahydrocannabinol, in small proportions: Δ-8-tetrahydrocannabinol), cannabidiol, cannabinol And cannabichromen. These active agents are also called cannabinoids (see the list "The Merck Index", 12th ed., 1996, page 285, No. 1794 and page 1573, No. 9349).

Oral of hemp agents, in particular R- (6a, 10a) -Δ-9-tetrahydrocannabinol, in the form of capsules, tablets, pills or other solid oral dosage forms, or in the form of liquid formulations administered orally. Administration is disadvantageous for a variety of reasons:

In the use of such dosage forms, the onset of action is delayed because the absorption of the active agent occurs in the gastrointestinal tract. This is particularly disadvantageous for such applications, which generally require rapid onset of action (eg pain treatment).

Hemp agonists are inactivated at least partially lowered during gastric and intestinal passage under the influence of acids and enzymes, so that only a portion of the dose is absorbed and available systemically.

In this regard, unwanted plasma peak values, which are often the cause of side effects, may occur.

In addition, after oral administration, a significant amount of the active substance is already metabolized upon the first passage of the liver (“first passage effect”).

This disadvantage is of particular importance for the permitting of these agents to meet in the applications indicated above. In the oral dosage form, there is also a disadvantage that the patient considers the prolonged retention of, for example, a tablet or capsule (filled with an oily solution) in the mouth, in certain certain circumstances, to be particularly unpleasant.

It is therefore an object of the present invention to provide a dosage form for the administration of hemp agents which is free from the above disadvantages and which has good pharmacokinetic properties, in particular its rapid onset of action as well as its improved tolerance and compliance.

This object is achieved by a film-shaped mucoadhesive dosage form with the inclusion of at least one active agent in the group of hemp agents according to claim 1; Further preferred embodiments are described in the subclaims.

This object is also achieved by the use of a film-shaped mucoadhesive dosage form according to the invention in the treatment of diseases and conditions.

Dosage formulations according to the invention are applied to oral mucosa to which they adhere due to their mucoadhesive properties in the form of thin, small flat pieces or wafer shapes ("wafers"). Application to the oral mucosa is preferably sublingual or buccal. In addition, other mucosal surfaces may also be considered as sites of application, for example nasal mucosa.

During the period of application, the hemp agent (s) contained in the dosage form is released into the surrounding saliva and then absorbed by the oral mucosa (ie transmucosally). In the contact area of the application surface, the active agent may also be released directly from the dosage form to the oral mucosa. In application, the dosage form absorbs saliva so that the active substance contained therein reaches outwards by diffusion.

In this regard, there is an advantage that the active agent is released into saliva only after a short delay and immediately reaches all areas of the oral mucosa where the saliva-active agent mixture can be absorbed. The amount of saliva per unit of time during which the released active agent is dissolved or dispersed is relatively small, and no hyperalibration occurs, so swallowing of the active agent (regarding the above disadvantage of gastrointestinal absorption) is largely ignored.

Because active agent absorption occurs by bypassing the gastrointestinal route, the above disadvantages of other oral dosage forms (eg tablets) (delayed onset of action, “first pass effect”) are avoided.

In the dosage form of the present invention, compliance is also increased because its application does not require special discipline. Because of their small layer thickness, the application of film-like dosage forms is generally not felt uncomfortable by the person being treated.

According to a preferred embodiment, the dosage form of the invention acts as an active agent reservoir and comprises a polymer matrix having mucoadhesive properties. One or more layers or one or more surfaces of the dosage form possess mucoadhesive properties. Dosage formulations may consist of one monolayer or may comprise multiple layers. In the case of a multilayer structure, at least one layer contains the active agent (s).

In the simplest case, the dosage form is made of a mucoadhesive, preferably monolayer polymer matrix containing one or more hemp agents. The active agent (s) may be present in dissolved, dispersed or emulsified form in the dosage form.

The polymer matrix preferably contains at least one polymer that is water soluble and / or swellable in an aqueous medium. By choosing such polymers, mucoadhesive properties and release behavior can be influenced.

Polymers of the following groups are particularly suitable as water-soluble or swellable polymers: starch and starch derivatives, dextran; Cellulose derivatives such as carboxymethyl cellulose, hydroxypropyl cellulose, hydroxyethyl cellulose, hydroxypropylmethyl cellulose, hydroxypropylethyl cellulose, sodium carboxymethyl cellulose, ethyl cellulose or propyl cellulose; Polyacrylic acid, polyacrylate, polyvinylpyrrolidone, polyethylene oxide polymer, polyacrylamide, polyethylene glycol, gelatin, collagen, alginate, pectin, pullulan, tragacanth, chitosan, alginic acid, arabinogalactan ), Galactomannan, agar, agarose, carrageenan, and natural gums.

The polymer portion is preferably 5 to 95% by weight, particularly preferably 15 to 75% by weight, relative to the dry matter of the dosage form.

According to a preferred embodiment, the dosage form according to the invention preferably contains hemp extract or hemp oil in an amount of 0.5 to 50% by weight, particularly preferably in an amount of 1 to 30% by weight. Methods of making pharmacologically acceptable hemp extracts or hemp oils are known to those skilled in the art.

The present invention includes dosage forms of this type containing one or more cannabinoid active agents from the group consisting of tetrahydrocannabinol, cannabinol, cannabidiol, and cannabichromen. Tetrahydrocannabinol, in particular R- (6a, 10a) -Δ-9-tetrahydrocannabinol, is particularly preferred as an active agent. Cannabinoid active agents may be natural, partially synthetic or synthetically derived.

The active substance content is preferably from 0.1 to 20% by weight, particularly preferably from 0.5 to 10% by weight, relative to the dry matter of the dosage form.

The individual dosage forms preferably contain 0.5 to 20 mg, particularly preferably 1 to 10 mg of active agent, for example tetrahydrocannabinol.

Optionally, the dosage form according to the invention may contain one or more additives from the following groups: fillers, colorants, flavors, aromatic compounds, odorous substances, emulsifiers, plasticizers, sweeteners, preservatives, penetration enhancers, pH adjusting agents and antioxidants My. Suitable materials for this purpose are basically known to those skilled in the art.

A particular advantage is the addition of flavors, odorous substances and aromatic compounds, alone or in combination. For example, the taste of taste can be improved by adding a refreshing flavor (for example, menthol and eucalyptol). Since it smells like ordinary refreshments, at the same time, it makes it possible to ingest the medicine without distinct consciousness. This additionally contributes to improving compliance.

For example, menthol, eucalyptol, limonene, phenylethanol, camphene, pinene, seasoning aromatic compounds such as n-butyl, in addition to eucalyptus oil and thyme oil Butyl phthalide or cineol, methyl salicylate, turpentine oil, chamomile oil, ethyl vanillin, 6-methyl coumarin, citronellol, and acetic acid Among the group consisting of n-butyl esters, flavors and aromatic compounds are particularly suitable.

Dosage formulations of the present invention containing hemp agents are, for example, in the form of thin small flat pieces or small wafers, ie thin and flat film shapes. These film forms may be of various geometric shapes, for example round, oval or thin.

Their thickness is preferably 0.01 to 2 mm, particularly preferably 0.05 to 0.5 mm. To avoid foreign body feeling, the layer thickness should be as small as possible (preferably less than 0.2 mm).

In order to achieve a particular effect, the dosage form according to the invention may have a bilayer or monolayer structure. The individual layers may differ in terms of one or more of the following parameters: polymer composition, active substance content, active substance concentration, content of additives.

Due to the properties already mentioned, hemp agonist containing dosage forms according to the invention can be adapted for use in the treatment of a disease or condition, in particular in the following cases:

Conditions of pain in the case of carcinoma and as a result of chemotherapy; Conditions of pain and "wasting" syndrome in connection with AIDS; Nausea and vomiting, especially as well as AIDS or hepatitis, as well as side effects of chemotherapy; Neuropathic pain; Anorexia or cachexia, especially in relation to AIDS or carcinoma, with the disease progressing significantly; Paralysis symptoms associated with multiple sclerosis or traumatic lateral injury; Dystonic movement disorder; Bronchial asthma; Epileptic seizures or systemic epilepsy; Withdrawal symptoms associated with alcohol dependence, benzodiazepine dependence and opiate dependence; Parkinson's disease; Dementia, especially Alzheimer's disease; nausea; arthritis; glaucoma; migraine; Dysmenorrhea.

Claims (14)

A film-shaped mucoadhesive dosage form containing at least one active agent in the group of hemp active agents. The dosage form of claim 1 having a polymeric matrix that acts as an active substance reservoir and has mucoadhesive properties. 3. The polymer matrix of claim 2, wherein the polymer matrix contains at least one polymer that is water soluble and / or swellable in an aqueous medium, wherein the polymer preferably comprises starch and starch derivatives, dextran, carboxymethylcellulose, hydroxypropylcellulose, hydride. Hydroxyethyl cellulose, hydroxypropylmethyl cellulose, hydroxypropylethyl cellulose, carboxymethyl cellulose sodium, ethyl cellulose or propyl cellulose, polyacrylic acid, polyacrylate, polyvinylpyrrolidone, polyethylene oxide polymer, polyacrylamide, polyethylene glycol , Gelatin, collagen, alginate, pectin, pullulan, tragacanth, chitosan, alginic acid, arabinogalactan, galactomannan, agar, agarose, carrageenan, And it is selected from the group consisting of natural gums, Body portion is preferably dosage form, characterized in that 5 to 95% by weight, particularly preferably 15 to 75% by weight. 4. The hemp extract according to any one of the preceding claims, characterized in that it contains hemp extract or hemp oil in an amount of 0.5 to 50% by weight, particularly preferably in an amount of 1 to 30% by weight. Dosage Forms. 5. The at least one cannabi of claim 1, wherein the group consists of tetrahydrocannabinol, cannabinol, cannabidiol, and cannabichromen. 6. A dosage form comprising a cannabinoid active agent. 6. The dosage form according to claim 5, wherein the substance (s) is contained in a proportion of 0.1 to 20% by weight, preferably in a proportion of 0.5 to 10% by weight. The compound according to any one of claims 1 to 6, containing tetrahydrocannabinol, preferably R- (6a, 10a) -Δ-9-tetrahydrocannabinol, wherein the active substance content is preferred. Preferably from 0.1 to 20% by weight, particularly preferably from 0.5 to 10% by weight. Dosage form according to any one of the preceding claims, characterized in that it contains 0.5 to 20 mg, preferably 1 to 10 mg of active agent (s), preferably tetrahydrocannabinol. . The process according to any one of claims 1 to 8, wherein among the groups of flavors, odorants and aromatic compounds, in particular, menthol, eucalyptol, limonene, phenylethanol, camphene, pinene ( seasoning aromatic compounds such as pinene, n-butyl phthalide or cineol, eucalyptus oil, thyme oil, methyl salicylate, turpentine oil, chamomile oil, ethyl vanillin And 6-methyl coumarin, citronellol, and acetic acid n-butyl ester, wherein the dosage form contains at least one substance. 10. The dosage form according to claim 1, wherein the layer thickness is from 0.01 to 2 mm, preferably from 0.05 to 0.5 mm. The method according to any one of claims 1 to 10, characterized in that it contains at least one inert component from the group consisting of fillers, colorants, emulsifiers, plasticizers, sweeteners, preservatives, pH regulators, penetration enhancers, and antioxidants. Dosage Forms. 12. The dosage form according to any one of the preceding claims, having a multi-layered structure with at least one layer containing an active agent. Conditions of pain in the case of carcinoma and as a result of chemotherapy; Conditions of pain and "wasting" syndrome in connection with AIDS; Nausea and vomiting, especially as well as AIDS or hepatitis, as well as side effects of chemotherapy; Neuropathic pain; Anorexia or cachexia, especially in relation to AIDS or carcinoma, with the disease progressing significantly; Paralysis symptoms associated with multiple sclerosis or traumatic transverse lesions; Dystonic motor disturbance; Bronchial asthma; Epileptic seizures or systemic epilepsy; Withdrawal symptoms associated with alcohol dependence, benzodiazepine dependence and opiate dependence; Parkinson's disease; Dementia, especially Alzheimer's disease; arthritis; glaucoma; migraine; Dysmenorrhea Use of a dosage form according to any one of claims 1 to 12 for therapeutic treatment, in particular treatment. Use according to claim 13, characterized in that it is applied to the oral mucosa, in particular sublingually or buccally.