EP1638521A1

EP1638521A1 - Transmucosal form of administration with reduced mucosal irritation

Info

Publication number: EP1638521A1
Application number: EP04740100A
Authority: EP
Inventors: Tina Rademacher; Christian Von Falkenhausen
Original assignee: LTS Lohmann Therapie Systeme AG
Current assignee: LTS Lohmann Therapie Systeme AG
Priority date: 2003-06-27
Filing date: 2004-06-19
Publication date: 2006-03-29
Also published as: AU2004251018B2; ZA200508801B; MXPA05013270A; AU2004251018A1; DE10328942A1; CN1812765B; JP2007506670A; WO2005000263A1; CA2524937A1; BRPI0411832A; US20060182786A1; CN1812765A; KR20060037279A

Abstract

The invention relates to film-type forms of administration for the transmucosal administration of active ingredients to the human or animal body. Said forms of administration are characterised by an adaptation or approach of the pH value of the base mass used to produce the form of administration and comprising a solvent or a solvent mixture, at least one matrix-forming polymer and at least one active ingredient, to the physiological pH value of the mucosa for the application. The invention also relates to a method for producing such preparations and to the use of the same as forms of administration, especially for pharmaceutical active ingredients, in such a way that mucosal irritation is reduced or even prevented by the application of the resulting forms of administration.

Description

Transmucosal dosage form with reduced irritation of the mucous membrane

The present invention relates to film-like preparations for the transmucosal administration of active substances to the human or animal body, the use of which reduces or even prevents irritation of the mucous membrane. The invention further relates to processes for the production of such preparations and their use as a dosage form, in particular for active pharmaceutical ingredients.

An advantage of transmucosal administration of active substances is that the gastrointestinal route is ^avoided , as a result of which the “first pass ^λλ effect after oral administration, ie the metabolism of a significant proportion of the active substance during the first liver passage after active substance ^absorption in the gastrointestinal tract, is avoided.

Transmucosal dosage forms can be in the form of pellets, capsules or tablets. A particularly advantageous dosage form for the transmucosal administration of active substances is film-like preparations, which are preferably applied in the form of thin leaflets or wafer-shaped structures ("wafers").

The film-like dosage forms also increase compliance, among other things, since a special discipline is not required for their application. The application of fil-like dosage forms is generally not perceived as disruptive by the persons to be treated due to their small layer thickness. The transmucosal administration of active substances can take place by means of films containing the active substance, which are glued onto the mucous membrane as a mucoadhesive dosage form. In the contact area of the application area, the active ingredient can be released directly from the dosage form to the mucous membrane. During the application period, the active ingredient contained in the dosage form, for example when applied in the oral cavity, can also be released into the surrounding saliva and subsequently absorbed by the oral mucosa.

The application of the mucoadhesive dosage forms in the form of thin leaflets or wafer-shaped structures is preferably carried out on the oral mucosa, in particular sublingually or buccally, where the dosage form remains adherent due to its mucoadhesive properties. In addition, other mucosal surfaces can also be considered as the application site, e.g. B. the nasal mucosa.

During application, the film-like dosage form can also absorb saliva and the active ingredient can then escape to the outside by diffusion. It is advantageous here that the active ingredient is released into the saliva after a very short delay, so that the saliva active ingredient mixture can immediately reach all areas of the oral mucosa and be resorbed there. The amount of saliva in which the released active ingredient is dissolved or dispersed per unit of time is relatively small and there is no excessive flow of saliva, so that ingestion of the active ingredient (with the disadvantages of gastrointestinal absorption mentioned) is largely ruled out. Active substance-containing dosage forms for transmucosal administration of active substances can be designed such that they disintegrate into liquids. When this dosage form is applied, the active ingredient is then present in a very high local concentration on the mucous membrane. As a result of the high thermodynamic pressure built up, the active ingredient quickly becomes systemically or locally available. Because of their low layer thickness and their ability to disintegrate or dissolve, these film-like, flat dosage forms are particularly suitable for the very rapid release of medicaments and other active substances, particularly in the oral cavity.

However, when applying film-like dosage forms for transmucosal administration of active substances, in particular when administering mucoadhesive and disintegrable dosage forms, clear mucosal irritations were observed, which manifested themselves as a strong reddening of the application site and in some cases persisted for more than 24 hours, in some cases even only disappeared after about 48 hours. After multiple application of film-like dosage forms, cell damage to the epidermal tissue was even detected by histological examinations.

From a safety point of view, however, mucous membrane irritation and cell damage after application of film-like dosage forms are not acceptable, and such transmucosal dosage forms would not meet the regulatory requirements.

The object of the present invention was therefore to provide a formulation for film-like dosage forms To provide transmucosal administration of active ingredients which avoids or at least reduces irritation of the mucous membrane.

The problem is solved, based on the following preliminary considerations, in that the pH in the polymer mass used for the production of fil-like preparations is specifically adjusted, ie. H. is approximated or adapted to the physiological pH of the mucous membrane intended for the application, so that the pH of the polymer mass does not differ or does not differ significantly from the physiological pH of the mucous membrane to which the dosage form is to be applied.

For the production of film-like preparations, a base mass comprising a solvent or solvent mixture, at least one matrix-forming polymer and at least one active ingredient and, if appropriate, further auxiliaries which assume different functions in the mass or in the dried film are usually prepared, which are to be moistened with suitable tools Films is extracted or extruded. The moist films are then dried and separated.

Water is preferably used as the solvent or as one of the solvents of the solvent mixture.

A pharmaceutical active ingredient is usually added as a solid phase, often using a salt of this pharmaceutical active ingredient and more rarely its free base. Hydrochlorides are preferably used as active ingredient salts, but other salts such as citrates or salicylates can also be used. About that In addition, the active ingredient salts can be present as anhydrates or in hydrated forms.

The cation of active ingredient salts is often present as a protonated base, which dissociates more or less strongly in solution, depending on the pKa value. The dissociation then leads to an increase in the concentration of hydronium ions and thus to a lowering of the pH. This shift in the pH value into the acidic range frequently occurs in the manufacture of compositions for film-like dosage forms.

The conditions in the moist film are fixed after the coated film has dried. If this dried film comes into contact with moisture, the conditions that prevailed during the mass production are restored. As a result, the pH value can also be changed at the application site if the pH value of the film deviates significantly from the physiological pH value of the mucous membrane, and lead to the observed mucosal irritations, especially if the local pH value is significantly below the physiological one pH of the mucous membrane drops. This is the case if the mass has a pH value during its production which is significantly lower than the physiological pH value of the mucous membrane with which the film is brought into contact.

The task of providing film-like dosage forms for transmucosal administration of active substances, the application of which reduces or even prevents irritation of the mucous membrane, is essentially achieved in that the pH value of the base composition for the film-like preparation is targeted to the physiological pH value of the mucosa in question for the application is approximated or adapted. For example, the pH of the oral mucosa is in herbivores, such as. B. horses or cows in about 8 to 9 and in humans between 5.5 and 6.5. The pH of the human nasal mucosa is around 8 and the human vaginal mucosa has a pH of around 4.

By adding e.g. Potassium hydroxide, sodium hydroxide or ammonia can raise the pH of the base mass for the film-like preparation or lower it by adding, for example, hydrochloric acid or phosphoric acid. By titrating in alkaline or acidic substances, the pH of the base mass can be adjusted so that after application of the dry film to a mucous membrane, there is little or no change in the local physiological pH, so that none or only one subsequently marginal skin irritation can be detected.

In a particular embodiment, the pH of the polymer mass can also be determined using a physiological buffer system, such as. B. phosphate buffer can be adjusted to the desired pH.

When adjusting the pH value, care must be taken to ensure that the active ingredient, which is usually in salt form, does not precipitate. When adjusting the pH, the active substance base could be formed, which does not dissolve or is very difficult to dissolve in an aqueous medium, so that at least part of the active substance is bound as a base and is no longer available as an effective component in the film-like dosage form.

In a preferred embodiment, the dosage form according to the invention is mucoadhesive, whereby it can have a polymer matrix which serves as an active substance reservoir and has mucoadhesive properties. In the simplest case, the dosage form can consist of a single layer or comprise several layers. In the case of a multilayer structure, at least one of the layers contains active ingredients and at least one layer or at least one surface of the dosage form has mucoadhesive properties.

The polymer matrix of a mucoadhesive dosage form preferably contains one or more polymers which are water-soluble and / or swellable in aqueous media. The choice of such polymers can influence the mucoadhesive properties and the release behavior.

In a further preferred embodiment, the dosage form according to the invention, including the mucoadhesive embodiment, is designed to be decayable. These medicinal preparations are distinguished by the fact that they have a matrix which is decomposable in aqueous media, which is formed from at least one matrix-forming polymer and in which at least one active ingredient is dissolved or dispersed. An essential feature of this embodiment is that it quickly disintegrates after being introduced into an aqueous medium or into body fluids, ie the disintegration process is essentially complete within 15 minutes if the dosage form is removed from an aqueous medium, e.g. B. a body fluid was surrounded. According to preferred embodiments of the invention, the pharmaceutical forms are designed such that they disintegrate within 3 min and particularly preferably within 60 s after introduction into an aqueous medium. After application to a mucous membrane surface and the drug form adhering to it, the drug form begins under the influence of moisture or the surrounding aqueous medium, e.g. B. body fluids to disintegrate, for example by forming a gel or a solution. At the same time, the active ingredient contained in the pharmaceutical form is released and can now directly over the mucous membrane in question, for. B. the oral mucosa, are absorbed.

The mucoadhesive properties and / or the disintegration properties are essentially determined by the type of the matrix-forming polymer (s) and the relative proportions of these polymers in the preparation.

The following water-soluble or at least partially water-soluble polymers are preferably suitable as matrix-forming polymers, which can be constituents of a formulation according to the invention, without excluding other suitable raw materials:

Polyvinyl alcohol (for example, Mowiol ^®.); Cellulose derivatives such as hydroxypropylmethyl cellulose, hydroxypropyl cellulose, sodium carboxymethyl cellulose (e.g. Waloσel), methyl cellulose, hydroxyethyl cellulose and hydroxypropylethyl cellulose; Starch and starch derivatives; Gelatin (various types); polyvinylpyrrolidones; Gum arabic; pullulan; Acrylates.

Polymers from the following group are also particularly suitable as water-soluble or swellable polymers: dextran; Cellulose derivatives such as carboxymethyl cellulose and ethyl or propyl cellulose; Polyacrylic acid, polyacrylates, polyethylene oxide polymers, polyacrylamides, polyethylene glycol, collagen, alginates, pectins, tragacanth, Chitosan, alginic acid, arabinogalactan, galactomannan, agar-agar, agarose, carrageenan, and natural gums.

The polymer content of a dosage form according to the invention is preferably 5 to 95% by weight, particularly preferably 15 to 75% by weight, based on the dry matter of the dosage form.

The film-like preparations are advantageously suitable as

Dosage forms for the administration of pharmaceutical

Agents. That is why it is preferred

Embodiment provided that such a preparation contains an active pharmaceutical ingredient or a combination of two or more active pharmaceutical ingredients.

The active ingredient (s) can be in dissolved, dispersed, suspended or emulsified form.

Optionally, further releasable substances can be included, e.g. B. flavorings or sweeteners.

Compounds which are therapeutically active in humans or animals are suitable as active substances without restriction. These can come from the following groups: agents for infection treatment, antivirals, anaesthetics such as fentanyl, sufentanil, buprenorphine, anesthetics, anorectics, active substances for the treatment of arthritis and asthma such as terbutalins, anticonvulsants, antidepressants, antidiabetic agents, antihistamines, antidiarrheal drugs, anti-diarrheal agents, anti-migraine agents , Nausea and nausea, travel or seasickness, such as scopolamine and ondansetron, antineoplastic agents, anti-Parkinson agents, antipsychotic agents, antipyretics, antispasmodics, anticholinergics, anti-ulcer agents such as ranitidine, sympathomimetics, calcium channel blockers such as nifediputin, beta-aminokin and betabi blockers Ritodrine, antiarrhythmic drugs, antihypertensive drugs such as atenolol, ACE inhibitors such as rnalapril, benzodiazepine agonists such as flumazenil, coronary, peripheral and cerebral vasodilators, stimulation for the central nervous system, hormones, hypnotics, immunosuppressants, muscle relaxants, pro-muscle relaxants, antioxidants, pro-muscle relaxants, pro-muscle relaxants, pro-muscle relaxants, antioxidants, pro-muscle relaxants, antioxidants, pro-muscle relaxants, antioxidants, muscle relaxants , Tranquilizer.

Suitable active substances can also be found in the active substance groups of the parasympatholytics (e.g. scopolamine, atropine, berlactyzine), the parasympathomimetics, the cholinergics (e.g. physostigmine, nicotine), the neuroleptics (e.g. chlorpromazine, haloperidol), the Monoamine oxidase inhibitors (e.g. tranylcypromine, selegiline), the sympathomimetics (e.g. ephedrine, D-norpseudoephedrine, salbutamol, fenfluramine), the sympatholytics and antisy pathotonics (e.g. propranolol, timolol, bupranolol, clerginidine, clergidine) Naphazoline), anxiolytics (e.g. diazepam, triazola), local anesthetics (e.g. lidocaine), central anaesthetics (e.g. fentanyl, sufentanil), anti-rheumatic drugs (e.g. indomethacin, piroxica, lornoxicam ), the coronary therapeutic agents (e.g. glyσerol trinitrate, isosorbide dinitrate), the estrogens, progestogens and androgens, the antihistamines (e.g. diphenhydramine, clemastine, terfenadine), the prostaglandin derivatives, the vitamins (e.g. vitamin E, Cholecalciferol), d he cytostatics and cardiac glycosides such as digitoxin and digoxin.

The active substance content is preferably 0.1 to 50% by weight, particularly preferably 0.5 to 20% by weight, based on the dry mass of the dosage form. A single dosage form preferably contains 0.5 to 20 mg, particularly preferably 1 to 10 mg of active ingredient. The dosage forms according to the invention can optionally contain one or more additives from the following groups: fillers, colorants, flavors, flavorings, fragrances, emulsifiers, plasticizers, sweeteners, preservatives, permeation-promoting substances and antioxidants. Substances suitable for this are basically known to the person skilled in the art.

The addition of flavors, smells and aromas, individually or in combination, is particularly advantageous because this increases the acceptance of the medicinal preparation in the case of direct oral administration. For example, the taste impression can be improved by adding a refreshing flavoring agent (e.g. menthol, eucalyptol). An unpleasant smell or taste caused by the active pharmaceutical ingredient can be superimposed by adding a suitable taste or aroma substance. At the same time, this enables the drug to be taken inconspicuously, since it smells like an ordinary refreshment candy. This also helps to improve compliance.

Particularly suitable are, for example, flavorings and aromas from the group that include menthol, eucalyptol, limonene, phenylethanol, camphene, pinene, spice flavors such as n-butylphthalide or cineol, as well as eucalyptus and thyme oil, methyl salicylate, turpentine oil, chamomile oil, ethylvanillin, 6-methylcoumarin, Citronellol and n-butyl acetate.

In the veterinary field in particular, the known preferences of the animals to be treated can be taken into account when selecting aroma substances. For example, it is known that cheese, cream and valerian aromas are used particularly advantageously in medicinal preparations that are intended for administration to cats. In addition, meat, sausage and fish flavors can also be used advantageously to increase an animal's willingness to take a medicinal preparation orally. In contrast, fruit or herbal aromas, such as banana, strawberry, mint, cocoa, nut or coffee aromas, are particularly suitable for certain groups of animals; Mixtures of different flavors can also be used.

The film-like preparations according to the invention can also be used, however, only. H. without the need for a pharmaceutical active ingredient in the preparation, one or more flavoring agents, such as. B. menthol or lemon aroma to release in the oral cavity.

The content of flavoring agent (s) is preferably 0.1 to 20% by weight, particularly preferably 1 to 10% by weight, in each case based on the dry mass of the film-like dosage form.

Substances from the following groups can advantageously be used as further auxiliaries: fillers such as SiO 2 dyes such as quinoline yellow or TiO 2; Disintegrants or wicking agents that draw water into the matrix and blow up the matrix from the inside, such as. B. Aerosil; Emulsifiers such as Tween (polyethoxylated sorbitan fatty acid esters), Brij (polyethoxylated fatty alcohols); Sweeteners such as aspartame, sodium cyclamate and / or saccharin; Plasticizers such as PEG (polyethylene glycol) or glycerin; Preservatives such as sorbic acid or its salts. The proportion of these auxiliaries can be up to 30% by weight, preferably 1 to 20% by weight, in each case based on the dry mass of the dosage form.

According to a preferred embodiment, the preparations according to the invention contain at least one flavoring agent and / or at least one sweetener and / or at least one plasticizer.

The total thickness of the preparations according to the invention, in particular the wafers, is preferably 5 μm to 10 mm, preferably 50 μm to 2 mm and particularly preferably 0.1 mm to 1 mm. To avoid a foreign body sensation, the layer thickness of the mucoadhesive embodiments should be as small as possible, preferably less than 0.2 mm.

The wafers can advantageously have round, oval, elliptical, triangular, quadrangular or polygonal shapes, but they can also have an arbitrarily rounded shape.

The wafers mentioned are comparatively dense structures and preferably have a density between 0.3 g / cm ³ and 1.7 g / cm ³ , particularly preferably between 0.5 g / cm ³ and 1.5 g / cm ³ , and most preferably between 0.7 g / cm ³ and 1.3 g / cm ³ .

In order to achieve special effects, the dosage forms according to the invention can be constructed in two or more layers. The individual layers can differ with regard to one or more of the following parameters: polymer composition, active substance content, active substance concentration, content of additives. The surface of the preparations according to the invention is usually smooth; however, it may be advantageous to provide the surface with elevations and depressions, e.g. B. in the form of knobs or grooves.

The invention also includes preparations of the type mentioned, which are in the form of thin, solid foams. Wafers in the form of thin foams are advantageous because they adhere quickly due to their large specific surface area, but they also disintegrate quickly. The density of these solidified foams is preferably between 0.01 g / cm ³ and 0.8 g / cm ³ , particularly preferably between 0.08 g / cm ³ and 0.4 g / cm ³ , and most preferably between 0, 1 g / cm ³ and 0.3 g / cm ³ . When calculating the density, the volume filled or enveloped by the entire body of the foam is used.

In connection with the present invention, “aqueous media” is understood to mean in particular water, aqueous solutions, suspensions, dispersions, aqueous solvent mixtures and physiological liquids or body fluids (eg body secretions, saliva, mucus).

Example:

As part of a veterinary project, an adhesive preparation for the transbuccal delivery of an active ingredient was tested. The composition of the mucoadhesive preparation, which is given in Table 1, was selected so that the preparation within a few minutes disintegrates in an aqueous medium and forms an adhesive gel.

Table 1

The original pH of the base mass for this preparation was 5.3. After application of this preparation on the oral mucosa of horses, there was a considerable delay in skin irritation.

The application of a preparation with the same composition, in which the pH of the base mass had been raised to 6.1, led to no or only very slight irritation of the mucous membrane in the treated horses.

By increasing the pH of the base mass, irritation of the mucous membrane could be reduced or prevented. The degree of skin irritation correlated with the pH of the polymer mass used to prepare the preparation or the difference between the pH of the Polymer mass and the physiological pH of the oral mucosa.

Claims

claims

1. Film-like dosage form for transmucosal administration of active ingredients, characterized in that the pH of the base composition for the preparation of the dosage form, comprising a solvent or solvent mixture, at least one matrix-forming polymer and at least one active ingredient, during its manufacture to the physiological pH of the mucosa intended for the application has been approximated or adapted.

2. Dosage form according to claim 1, characterized in that water is used as the solvent or at least as one of the solvents of the solvent mixture.

3. Dosage form according to claim 1 or 2, characterized in that the matrix-forming polymer is selected from the group consisting of polyvinyl alcohol, cellulose derivatives such as hydroxypropylmethyl cellulose, hydroxypropyl cellulose, sodium carboxymethyl cellulose, methyl cellulose, hydroxyethyl cellulose and hydroxypropyl ethyl cellulose, carboxymethyl cellulose and ethyl and propyl cellulose, starch and starch derivatives, gelatin, polyvinylpyrrolidones, gum arabic, pullulan, acrylates, dextran; Polyacrylic acid, polyacrylates, polyethylene oxide polymers, polyacrylamides,

Polyethylene glycol, collagen, alginates, pectins, tragacanth, chitosan, alginic acid, arabinogalactan, galactomannan, agar-agar, agarose, carrageenan, and natural gums.

4. Dosage form according to one of the preceding claims, characterized in that the polymer portion 5 to 95 wt. -5s, preferably 15 to 75 wt. 5s, based on the dry matter of the dosage form.

5. Dosage form according to one of the preceding claims, characterized in that the active ingredient is a pharmaceutically active ingredient and / or flavoring.

6. Darreiσhungsform according to claim 5, characterized in that the content of pharmaceutical active ingredient 0.1 to 50 wt. -5s, preferably 0.5 to 20 wt. 5s, based on the dry matter of the dosage form.

7. Dosage form according to claim 5, characterized in that the aroma content is 0.1 to 20% by weight, preferably 1 to 10% by weight, based on the dry mass of the dosage form

8. Dosage form according to one of the preceding claims, characterized in that the pH of the base mass is set to a value in the range between 5 and 9, preferably in the range between 6 and 8.5 and particularly preferably in the range between 6.5 and 8 has been.

9. Dosage form according to one of the preceding claims, characterized in that the pH has been adjusted with sodium hydroxide, potassium hydroxide, ammonia, hydrochloric acid, phosphoric acid or a buffer system such as, for example, phosphate buffer.

10. Dosage form according to one of the preceding claims, characterized in that it is mucoadhesive.

11. Dosage form according to one of the preceding claims, characterized in that it is disintegrable.

12. Dosage form according to claim 11, characterized in that it has disintegrated within 15 min, preferably within 3 min and particularly preferably within 60 s after introduction into an aqueous medium.

13. Dosage form according to one of the preceding claims, characterized in that it is multi-layered.

14. Dosage form according to one of the preceding claims, characterized in that it contains one or more auxiliaries from the group comprising fillers, dyes, foams, flavors, fragrances, emulsifiers, plasticizers, sweeteners, preservatives, permeation-promoting substances and antioxidants.

15. Dosage form according to claim 14, characterized in that the proportion of auxiliaries is up to 30 wt. -5s, preferably 1 to 20 wt. -5s, based on the dry matter of the dosage form.

16. Use of the dosage form according to one of the preceding claims for oral, gingival, vaginal or rectal application.

17. A process for the production of a film-like, dosage form for transmucosal administration of active substances, comprising - the production of a base mass comprising a solvent or solvent mixture, at least one matrix-forming polymer and at least one active substance, - the approximation or adjustment of the pH value of the base mass to the physiological pH of the mucous membrane intended for application of the dosage form, - extruding the mass, - drying the moist film, and - separating the dosage form.

18. The method according to claim 17, characterized in that water is used as the solvent or at least as one of the solvents of the solvent mixture.

19. The method according to claim 17 or 18, characterized in that the pH of the base mass is adjusted to a value in the range between 5 and 9, preferably in the range between 6 and 8.5 and particularly preferably in the range between 6.5 and 8 becomes.

20. The method according to any one of claims 17 to 19, characterized in that the pH is adjusted by means of sodium hydroxide, potassium hydroxide, ammonia, hydrochloric acid, phosphoric acid or a buffer system such as phosphate buffer.