WO1989010745A1

WO1989010745A1 - Compositions and in situ methods for forming films on body tissue

Info

Publication number: WO1989010745A1
Application number: PCT/US1988/002515
Authority: WO
Inventors: Pharmaceuticals Zila
Original assignee: Pomerantz, Edwin
Priority date: 1988-05-02
Filing date: 1988-07-25
Publication date: 1989-11-16
Also published as: KR940011240B1; NO901346D0; AU4053689A; KR900701251A; CN1048979A; JP3000104B2; ES2020655A6; EP0380647A4; NO180618B; NO901346L; MX21686A; EP0380647A1; WO1990001046A1; NZ232625A; IE902096A1; CA1337396C; JPH03503052A; FI901443A0; NO180618C; BR9002342A

Abstract

Methods and compositions for in situ formation of protective films on body tissues. The compositions include hydroxypropyl cellulose and a weak carboxylic acid in a non-toxic volatile polar solvent, e.g., ethyl alcohol. The preferred carboxylic acids are salicylic acid, tannic acid, and mixtures thereof. A cross-linking agent, e.g., boric acid, incorporated in these compositions improves the physical properties of the film. Methods for in situ deposition of such films include the steps of drying the body tissue, applying the compositions and air drying the compositions to form the film in situ. The films also function as sustained-release matrices for topical medicines. The films themselves act as effective barriers to air, saliva and foods, and provide effective pain relief in the treatment of recurrent aphthous stomatitis.

Description

COMPOSITIONS AND IN SITU METHODS FOR FORMING FILMS ON BODY TISSUE

This invention relates to compositions and methods for forming films in situ on body tissues.

According to another aspect, the invention relates to compositions and methods of forming a protective film on mucosal tissue.

In another respect, the invention relates to compo¬ sitions and methods for forming film in situ on body tissues which are effective carriers for medicinal components, to maintain such compositions at and on a treatment site on body tissue.

In still another respect, the invention relates to methods for treating aphthous ulcers, including recurrent aphthous stomatitis (RAS).

In still another more particular respect, the inventio relates to methods for symptomatic relief of pain associated with mucosal ulcers.

In the topical treatment of body tissue ulcers,incisio burns, weeping wounds, etc., problems are encountered in main¬ taining treatment compositions in contact with the treatment sit The problem arises because normal movement of the treatment site and surrounding tissue as well as abrasion of the treatment site causes topical compositions to be displaced.

In the case of mucosal tissue, it is considered practically impossible to maintain a treatment composition at the treatment site for more than a few minutes. The mucosal tissues are glaborous and initially wet which interferes with attempts to adhesively secure a treatment composition to the tis For example, it is estimated that upwards of 20-50% of the population periodically suffers from recurrent aphthous stomatitis (RAS) which occurs on non- eratinized (movable) oral mucosa. Aphthous ulcers found inside the mouth which are frequently called "canker sores". The lesions start out as an area of irritation, which develop vesicles within a few hours, These vesicles generally break, causing secondary infection and spreading to surrounding skin or mucous membranes. Pain is a prominent symptom, varying in severity from one patient to another, but usually of moderate intensity. While a single traumatic ulcer usually heals completely in three to four days, aphthous ulcers take two or more times longer.

The use of topical anesthetics for reducing pain is known. For example, commercially-available preparations containing benzocaine are widely used. However, these do not form coherent films in the mouth and are easily displaced from the ulcer site by saliva and physical movement of the surrounding tissues. An adhesive intra-oral ointment base for use in the oral cavity has been proposed which consists essentially of polymethylmethacrylate. However, such adhesive ointments have not achieved wide use and are not considered sufficiently persistent to solve the basic problem of maintaining a topical analgesic agent in contact with an ulcer for up to several hours.

Topical adhesive dosages for mucosal ulcers have also been proposed in the form of a two-phase tablet having an adhesive peripheral layer of hydroxypropyl cellulose with the medication carried in an oleaginous core of cocoa butter. This device adheres to the mucosa of dogs for thirty minutes to six hours.

Mixtures of hydroxypropyl cellulose and polyvinyl- acetate have been proposed as film-forming carriers for medications, but no use of such systems for intra-oral application of topical medicines has resulted.

Precast films of hydroxypropyl cellulose containing analgesics and antibiotics has been reported anecdotally for the treatment of pain of leukplakia.

I have now discovered that, under specific conditions, a film derived from a cellulosic compound, preferrably hydroxypropyl cellulose ( "HPC" ) , can be formed in situ on body tissues. The film is tough, resilient and adheres even to mucos tissues for a very substantial length of time.

Further, I have discovered that the barrier effect of such a film provides practically instantaneous and long-lasting substantial reduction of the pain associated with aphthous and other ulcers, apparently by excluding air, saliva and other foreign materials from the ulcerated site. Furthermore, for substantial periods of time this barrier prevents pain resulting from repeated insults of the ulcer by foods and drinks which would normally initiate pain episodes. This pain relief and prevention activity by the barrier action of the film is very surprising in view of the previous belief that it was necessary to provide an analgesic, e.g., benzocaine, at the ulcer site.

I have further discovered that the compositions for forming the HPC-derived films in situ on body tissues can also function as stable carriers for a wide variety of medicinal components. When such compositions are applied as a treatment on body tissue, the medicinal components are incorporated in the resulting in situ formed films, from which they are released to provide a sustained supply of the medicine at the treatment site.

Briefly, in accordance with the invention, I provide a composition for in situ formation of a protective film on body tissue. The composition consists essentially of a solution of a cellulosic compound, preferably HPC, in a non- oxic volatile polar solvent, and a weak carboxylic acid. A weak carboxylic acid is selected to react with the HPC to form a reaction product which is insoluble in aqueous body fluids at and above normal body temperature.

In accordance with another embodiment of the invention a method is provided for forming a protective film on body tissue which consists essentially of the steps of applying this composition to body tissue and air drying this composition to form the film in situ on the tissue.

In a more specific embodiment of the invention, I provide a method comprising the steps of forming a film derived from HPC on mucosal tissue by evaporation of a solution of HPC and a weak carboxylic acid in a non-toxic volatile solvent carrier and maintaining the film on the ulcer to exclude air and body fluids therefrom.

According to my present understanding, the carboxylic acid component of the compositions of the invention esterifies at least a portion of the HPC. This esterification reaction takes place primarily upon drying of the solvent carrier. The HPC and acid components of my composition, as well as any ester derivative which may form in solution prior to application of the composition to the body tissue are soluble in the solvent carrier at room temperature under normal pre-application and storage conditions. However, upon application of the compositio and air-drying of the solvent, with further esterification, a film is formed in situ which is insoluble in aqueous body fluids at and above normal body temperature of about 37°C.

In the presently preferred embodiment of the invention, I also incorporate a non-toxic weak cross-linking agent in the compositions of the invention. The resultant in situ formed film is somewhat tougher and more resilient and has better adhesion to body tissue than such films which are formed from compositions without such cross-linking agent. The cross-linking agent is selected from among known cross- linking agents for cellulosic compounds, the specific agent being chosen so as to avoid premature formation of an insoluble mass prior to application of the composition. According to present knowledge, boric acid is an appropriately selected effective cross-linking agent for use in practicing the present invention. While I do not wish to be bound by this mechanism, it appears that the cross-linking agent effectively binds un-esterified HPC into the film formed on drying of the composition after application to the body tissue. This belief is based on the observation that without a cross-linking agent in the composition, two film layers may actually form upon drying of the solvent, one of which is believed to be a film of the esterified HPC and the other of which is a less tenacious film of un-esterified HPC. Presence of the cross-linking agent apparently bonds these two film layers resulting in a more tenacious, tough and durable film formed in situ on the body tissue.

The HPC-derived films are soluble in ethyl alcohol and similar non-toxic volatile solvents, e.g., isopropyl alcohol and the like, but are insoluble in water and water-containing body fluids, e.g., saliva at normal human body temperature. Films formed by evaporation of the solutions are tough, resilien and adhesive to body tissues and form a protective barrier against air, other body fluids and foreign substances.

The cellulosic compound, which is reacted with weak carboxylic acids to form the film according to my invention, is selected for its ability to react with the carboxylic acid component to form a film which is insoluble in water and aqueous body fluids at a temperature equal to or greater than body temperature. According to present knowledge, hydroxypropyl cellulose (HPC) is suitable. Such cellulosic compound is - a- available commercially, for example, the product sold under the name "Klucel", a registered trademark of Aqualon Company. The type "MF" Klucel product is particularly suitable.

The solvent for forming the solutions of the HPC is selected for its ability to dissolve the HPC and HPC esters

and its non-toxic characteristics when the composition is applied in the amount necessary to form a protective film. For example, ethyl alcohol is preferred when the film is to be deposited in the oral cavity whereas isopropyl alcohol is suitable for use in depositing films on the skin. Other suitable solvents will be readily identified by those skilled in the art having a regard for the disclosures herein, e.g. , polar solvents which are medically compatible with body tissue.

The specific weak carboxylic acid components of the compositions of the invention is chosen for its ability to re- act with the HPC to form, upon air-drying of the composition, a tough resilient film which adheres to body tissue. Strong carboxylic acids, e.g., acetic acid, citric acid and the like do not provide this result. However, weak carboxylic acids, especially salicylic acid, tannic acid, and the like and mixtures thereof function effectively. The film formation in situ capability appears to be related to the solubility of the HPC derivative in water and aqueous body fluids at body temperature. Hence, any such weak carboxylic acid which is non-toxic and has the capability to form such in- soluble films can be effectively employed, the selection of such weak acids being within the capability of persons skilled in this art, having regard for this disclosure. Salicylic acid and tannic acid have been identified as particularly effective in the practice of my invention. In fact, it now appears that a mixture of these two acids in the film forming compositions of the invention produce a superior film in terms of adhesion and mechanical integrity although either of these acids alone provides an effective in situ deposited film.

The film of HPC which is formed by evaporation of the compositions of the invention is apparently a "physical film", i.e. , the cellulosic compounds do not polymerize. Evidence of the physical characteristics of these films is provided by the fact that such a film, once formed, simply re-dissolves upon further application of the compositions to the same site. - - The film forming composition of the invention can be applied to the body tissue by any convenient technique, e.g., spraying, dipping or simple direct application by a swab.

According to the presently preferred embodiments of the invention, the HPC component is present in the solution in an amount from about 0.1 - 20% by weight of the final composition. The proportion of the HPC in the composition affects the time required for the composition to air dry and form the tough adhesive film. At lower contents of the HPC compound, the composition dries more slowly, but the resultant film is more coherent and abrasion-resistent. At higher content the film forms more quickly by air drying, but the resultant film is less coherent and adhesive owing to the fact that the portion of the film at the surface of the applied composition and at the body tissue surface dries at different rates.

At present, I prefer to employ some 0.1 - 10% by weight of HPC in the final composition, which provides an easily-applied gel, as distinct from a runny liquid. Best results are obtained with about 2.5% by weight of HPC in the gel composition. The carboxylic acid component of the com¬ position of the invention can be a single acid alone or in combination with other weak carboxylic acids. Whether present alone or in combination, however, the proportion of the carboxylic acid can vary from about 1 to about 10% by weight of the composition of the invention with the optimum concentrati being closer to the upper portion of this range. Indeed, there are indications that higher proportions of the carboxylic acids do not appreciably interfere with the film formation. In the lower range, the film forms more slowly and is less coherent.

The compositions of the invention provide a method for forming a protective film on body tissues which consists of applying the composition, typically in localized areas, to the body tissue and air drying the composition to form the film in situ, adhesively secured to the tissue. For best results, when applied to wet or moist tissue, steps should be taken to remove as much of the water moisture or other body fluids from the surface of the body tissue before applying the com- position. For example, when applied inside the mouth, normal dental procedures for substantially drying the mucous membrane before application are employed and air is drawn or blown over the surface of the applied composition to promote more rapid evaporation of the solvent and formation of the film.

The compositions and methods of the invention have been found especially useful in the treatment of aphthous ulcers of the mucosa (including recurrent aphthous stomatitis). This treatment provides essentially immediate and long-lasting relief of the exquisite pain associated with such ulcers in the formative and pre-localizing steps. The particular composition which has been found most effective in alleviating such pain includes HPC, ethyl alcohol solvent, a mixture of tannic and salicylic acids as the weak carboxylic acid com- ponent and boric acid as the cross-linking agent. The composition is applied directly to the surface of the ulcer and surrounding mucosa with a swab and is air dried by simply ensuring that the patient breathes normally through the mouth. The film is adhesively retained on the ulcer site and surrounding mucosal tissue for extended periods of time, upwards of several hours. Furthermore, the initial pain relief, obtained by the exclusion of air and saliva from the ulcer, continues during this extended retension period and even prevents recurrence of the pain despite repeated attempts to cause pain onset by deliberately insulting the ulcer with irritating foods such as orange juice.

The following examples are presented to illustrate the preferred practice of the invention and not by way of limitation of the scope thereof. EXAMPLE 1 :

A composition is prepared by mixing the following components in the indicated proportions:

Components % (wt. )

ethyl alcohol 87 hydroxypropyl cellulose 2.5 tannic acid 7.0 salicylic acid 2.5 boric acid 1.0

L EXAMPLE 2 :

The composition of Example 1 is tested for pain reduction capability in comparison with the commercially available medication sold under the name "Orabase".

Twenty otherwise healthy human subjects who suffer from recurrent aphthous stomatitis are separated into test and control groups of ten members each.

Comparable test sites consisting of an aphthous ulcer and surrounding healthy mucosal tissue is selected in the mouths of each of the subjects. These sites are prepared by irrigating with distilled water and then carefully drying with cotton gauze pads.

The composition of the invention prepared according to this example is applied as a thin coating to the prepared aphthous ulcer sites in the mouths of the test group and a similar thin coating of the Orabase control medication is applied to aphthous ulcer sites in the mouths of the control '. group.

The patients of both the test group and the control group are required to breathe normally through the mouth for a period of two minutes, after which point it is noted that the composition of Example 1 has dried in the mouths of the test group patients to form a film over the aphthous ulcer site.

Observation of the test and control patients demonstrates that the films of the test composition are still present in place in 80% of the test subjects' mouths two hours after application, whereas the control medication completely disappears from the ulcer sites in all subjects in the control group. -11 - EXAMPLE 3 :

The procedure of Example 2 is repeated except that, just prior to the preparation of the ulcer sites, the aphthous ulcers in the mouths of both the test and control patients are insulted by application of orange juice. The incidence of pain is clinically observed for a period of one hour, at which time the treated ulcer sites are once again insulted with orange juice. Pain observation is continued for an additional three hours.

In both the test and control groups, all patients experience a large increase in pain after the first insult, followed by a mild to significant decrease in pain after the immediate application of both the test and control compositions.

At the second insult, the patients in the test group which are treated with the composition of the present invention experience no increase in pain and continue to experience mild to substantial pain reduction for the succeeding three hours. However, the patients in the control group experience a large increase in pain at the second insult which decreases only slightly during the ensuing three hours.

EXAMPLE 4 :

The procedures of Examples 1 - 2 are repeated except that the compositions contain, respectively, 10% tannic acid, 10% salicylic acid and 7% boric acid. Both of these compositions yield comparable results to those set forth in Examples 2 and 3.

-13- EXAMPLE 5 :

The boric acid cross-linking agent is omitted from the compositions of the preceeding Examples. The in situ deposited films formed from these compositions actually comprise two layers which can be mechanically separated. Although these two-layer films are effective in pain treatment, they are less persistent.

EXAMPLE 6 :

Therapeutically effective quantities of various topical medicines are incorporated into the compositions of Example 1. Upon in situ formation of the films the medicines are retained at treatment sites on human tissue for sustained release.

- - Having described my invention in such terms as to enable those skilled in the art to understand and practice it, and having described the presently preferred embodiments thereof, I Claim:

Claims

: 1. A composition for in situ formation of a protective film on body tissue, consisting essentially of:

(a) a solution of a hydroxypropyl cellulose in a non-toxic volatile polar solvent; and

(b) a weak carboxylic acid.

- -

2. The method of forming a protective film on body tissue, consisting essentially of the steps of:

(a) applying the composition of Claim 1 to body tissue; and

(b) air drying said composition to form said film in situ on said tissue.

3. The method of Claim 2 including the steps of:

(a) forming thereon a film on said tissue by evaporation of a solution of hydroxypropyl cellulose and a weak carboxylic acid in a non-toxic volatile polar solvent; and

(b) maintaining said film on said tissue.