CA2020962A1 - Enhanced delivery systems for pharmaceutical or therapeutic actives - Google Patents
Enhanced delivery systems for pharmaceutical or therapeutic activesInfo
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- CA2020962A1 CA2020962A1 CA 2020962 CA2020962A CA2020962A1 CA 2020962 A1 CA2020962 A1 CA 2020962A1 CA 2020962 CA2020962 CA 2020962 CA 2020962 A CA2020962 A CA 2020962A CA 2020962 A1 CA2020962 A1 CA 2020962A1
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Abstract
ENHANCED DELIVERY SYSTEMS FOR PHARMACEUTICAL
OR THERAPEUTIC ACTIVES
ABSTRACT OF THE DISCLOSURE
A biocompatible, substantive, gase permeable film-forming system for the delivery of pharmaceutical or therapeutic actives to a desired topical site of a subject, said system comprising at least one pharmaceutical or therapeutic active, at least one aminopolysaccharide selected from the group consisting of chitosonium polymers and covalent chitosan derivatives, and at least one delivery enhancer for delivering the active through the topical site.
OR THERAPEUTIC ACTIVES
ABSTRACT OF THE DISCLOSURE
A biocompatible, substantive, gase permeable film-forming system for the delivery of pharmaceutical or therapeutic actives to a desired topical site of a subject, said system comprising at least one pharmaceutical or therapeutic active, at least one aminopolysaccharide selected from the group consisting of chitosonium polymers and covalent chitosan derivatives, and at least one delivery enhancer for delivering the active through the topical site.
Description
- 2020~62 ENEiANCED DELIVERY SYSTEMS FOR PHARMACEUTICAL
OR THERAPEUTIC ACTIVES
FELD OF THE INVENTION
This invention relates, in general, to novel delivery systems useful for the topical delivery of pharmaceutical or therapeutic actives. In one aspect, this invention relates to delivery systems con-taining certain aminopolysaccharides and derivatives thereof which are effective systems for the delivery of a variety of pharmaceutical and therapeutic actives. In a further aspect, this invention is directed to the preparation and use of such systems.
BACKGROUND OF THE INVENllON
Traditionally, pharmaceutical and therapeutic actives can be administered to the body by a number of routes, including ingestion, injection, inhalation, and topical application. Absorption of an active by ingestion, injection, or inhalation generally gives systemic distribu-tion o~ the active throughout the body. Systemic distribution of the active may be unsatisfactory for three reasons. First, these modes of administration produce non-specific distribution. The active is dis-tributed through the entire body and not localized. Second, there may be undesirable effects such as toxic or irritating reactions on non-target organs or regions. Finally, to achieve the desired effect at the target organ or region, a higher dosage than might otherwise be desired must be administered to compensate for systemic dilution of the ac~ive.
In contrast to systemic delivery, topical delivery is application of an active in a manner so that it acts primarily at the site of .
.
.:
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~ , , .
OR THERAPEUTIC ACTIVES
FELD OF THE INVENTION
This invention relates, in general, to novel delivery systems useful for the topical delivery of pharmaceutical or therapeutic actives. In one aspect, this invention relates to delivery systems con-taining certain aminopolysaccharides and derivatives thereof which are effective systems for the delivery of a variety of pharmaceutical and therapeutic actives. In a further aspect, this invention is directed to the preparation and use of such systems.
BACKGROUND OF THE INVENllON
Traditionally, pharmaceutical and therapeutic actives can be administered to the body by a number of routes, including ingestion, injection, inhalation, and topical application. Absorption of an active by ingestion, injection, or inhalation generally gives systemic distribu-tion o~ the active throughout the body. Systemic distribution of the active may be unsatisfactory for three reasons. First, these modes of administration produce non-specific distribution. The active is dis-tributed through the entire body and not localized. Second, there may be undesirable effects such as toxic or irritating reactions on non-target organs or regions. Finally, to achieve the desired effect at the target organ or region, a higher dosage than might otherwise be desired must be administered to compensate for systemic dilution of the ac~ive.
In contrast to systemic delivery, topical delivery is application of an active in a manner so that it acts primarily at the site of .
.
.:
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~ , , .
2 ~ 6 2 .
application. This type of application is used typically for dermatolog-ical disorders. The above-described deficiencies of systemic delivery are not encountered when an active is applied topically. Rather, top-ical application affords the opportunity to minimize the dosage and confine the active to the region of the body to which it is applied.
Thus, systemic distribution of the active throughout the body is obvi-ated. For example, ingestion of acetone could cause fetal problems which dermal delivery should avoid. Typical sites of topical delivery include application to the dermal, opththalmic, and mucous mem-branes and tissues, such as the hair, skin, eyes, ears, mouth, nose, throat, rectum, vagina, and urethra.
However, despite these advantages of topical delivery, most current topical delivery formulations are inefficient and therefore have limited utility. There are four reasons for this inefficiency of current topical delivery technology. First, skin and mucous mem-branes possess good barrier properties and the permeability of most actives through these barriers generally is poor. Second, actives applied topically are subject to migration and loss due to perspiration, natural tissue lavation, and mechanical action. Third, because most pharmaceutical or therapeutic actives are relatively simple, low molecular weight compounds or mixtures, these actives are not applied alone, but in combination with a variety of additives to deliver the active to the application site and control the dosage.
Fourth, the choice of a proper delivery system can minimi~e undesir-able crystallization of the active, and hence optimize its availability in its active form. Most known topical delivery systems are petrolatum-based cremes and ointments. These unctuous formulations are unsatisfactory because they are at best uncomfortable and messy when applied.
A topical delivery system cannot be considered fully satisfac-tory if it is deficient with regard to any of the above-described crite-ria. For example, a delivery system which does not ensure that the active efficiently penetrates the application site is not satisfactory 202~62 because it requires that an excess of active be incorporated into the delivery system to ensure delivery of an effective quantity. The remaining active, i.e., that which does not penetrate the application site, is wasted. Similarly, active which is allowed to migrate from the application site, or to crystallize before it penetrates the site, is wasted. Further, a delivery system which satisfies each criterion will be adjudged a failure by a consumer who is dissatisfied because the delivery system leaves an unpleasant residue. For example, an unctu-ous residue, which is unpleasant to the touch and messy, may cause a consumer not to utilize the treatment. Thus, such delivery systems are unsatisfactory.
SUMMARY OF THE INVENTION
The present invention is directed to novel delivery systems comprised of certain aminopolysaccharides, including chitosan deriva-tives, pharmaceutical or therapeutic actives, and a delivery enhancer.
The invention also relates a method for preparing the delivery sys-tems, and to a method for their application to a subject.
The delivery system of the present invention is a biocompatible, substantive, film-forming system for the delivery of pharmaceutical or therapeutic actives to a desired topical site of a sub~ect or host. The system comprises at least one pharmaceutical or therapeutic active, at least one aminopolysaccharide selected from the group consisting of chitosonium polymers and covalent chitosan derivatives, and at least one delivery enhancer.
The system efficiently delivers the actives to the user at the application site and provides at the site a non-irritating, essentially imperceptible, substantive, gas permeable film over the application site.
DETAILED DESCRlPTlON OF THE INVENTION
This invention is based on the discovery that a delivery system for pharmaceutical or therapeutic actives comprising at least one pharmaceutical or therapeutive active, at least one aminopolysaccharide selected f rom the group consisting of .~
,.. ~ ., ~ .
.
.
application. This type of application is used typically for dermatolog-ical disorders. The above-described deficiencies of systemic delivery are not encountered when an active is applied topically. Rather, top-ical application affords the opportunity to minimize the dosage and confine the active to the region of the body to which it is applied.
Thus, systemic distribution of the active throughout the body is obvi-ated. For example, ingestion of acetone could cause fetal problems which dermal delivery should avoid. Typical sites of topical delivery include application to the dermal, opththalmic, and mucous mem-branes and tissues, such as the hair, skin, eyes, ears, mouth, nose, throat, rectum, vagina, and urethra.
However, despite these advantages of topical delivery, most current topical delivery formulations are inefficient and therefore have limited utility. There are four reasons for this inefficiency of current topical delivery technology. First, skin and mucous mem-branes possess good barrier properties and the permeability of most actives through these barriers generally is poor. Second, actives applied topically are subject to migration and loss due to perspiration, natural tissue lavation, and mechanical action. Third, because most pharmaceutical or therapeutic actives are relatively simple, low molecular weight compounds or mixtures, these actives are not applied alone, but in combination with a variety of additives to deliver the active to the application site and control the dosage.
Fourth, the choice of a proper delivery system can minimi~e undesir-able crystallization of the active, and hence optimize its availability in its active form. Most known topical delivery systems are petrolatum-based cremes and ointments. These unctuous formulations are unsatisfactory because they are at best uncomfortable and messy when applied.
A topical delivery system cannot be considered fully satisfac-tory if it is deficient with regard to any of the above-described crite-ria. For example, a delivery system which does not ensure that the active efficiently penetrates the application site is not satisfactory 202~62 because it requires that an excess of active be incorporated into the delivery system to ensure delivery of an effective quantity. The remaining active, i.e., that which does not penetrate the application site, is wasted. Similarly, active which is allowed to migrate from the application site, or to crystallize before it penetrates the site, is wasted. Further, a delivery system which satisfies each criterion will be adjudged a failure by a consumer who is dissatisfied because the delivery system leaves an unpleasant residue. For example, an unctu-ous residue, which is unpleasant to the touch and messy, may cause a consumer not to utilize the treatment. Thus, such delivery systems are unsatisfactory.
SUMMARY OF THE INVENTION
The present invention is directed to novel delivery systems comprised of certain aminopolysaccharides, including chitosan deriva-tives, pharmaceutical or therapeutic actives, and a delivery enhancer.
The invention also relates a method for preparing the delivery sys-tems, and to a method for their application to a subject.
The delivery system of the present invention is a biocompatible, substantive, film-forming system for the delivery of pharmaceutical or therapeutic actives to a desired topical site of a sub~ect or host. The system comprises at least one pharmaceutical or therapeutic active, at least one aminopolysaccharide selected from the group consisting of chitosonium polymers and covalent chitosan derivatives, and at least one delivery enhancer.
The system efficiently delivers the actives to the user at the application site and provides at the site a non-irritating, essentially imperceptible, substantive, gas permeable film over the application site.
DETAILED DESCRlPTlON OF THE INVENTION
This invention is based on the discovery that a delivery system for pharmaceutical or therapeutic actives comprising at least one pharmaceutical or therapeutive active, at least one aminopolysaccharide selected f rom the group consisting of .~
,.. ~ ., ~ .
.
.
chitosonium polymers and covalent chitosan derivatives, and at least one delivery enhancer, provides unexpectedly efficient delivery of the active. The delivery enhancer is selected to enhance the efficiency of the delivery of the active through the topical application site, e.g., through the stratum corneum or mucosa or into hair at the applica-tion site.
The delivery system of this invention encompasses divers aminopolysaccharides, particularly chitosan derivatives, and delivery enhancers, in addition to the actives.
Typically, delivery systems of the invention are fluids, i.e., dispersions, emulsions, and aqueous solutions and lotions, comprising an aqueous fraction. Other components of the delivery system may be non-aqueous vehicles which may be soluble or insoluble in the aqueous fraction. If the non-aqueous fraction is soluble in the aqueous fraction, a single-phæe delivery system is formed. If the non-aqueous fraction is not soluble in the aqueous fraction, an emulsion or disper-sion is formed; a suitable emulsifier may be used. The delivery enhancer then may act æ an emulsirier between the phases, and the active can be in either phase. The delivery systems of the invention possess a vafiety of useful characteristics which make these materials supefior for the delivery of pharmaceutical and therapeutic actives.
As used throughout the specification and claims, the phræe llpharmaceutical active" is considered to be a drug, i.e., a substance which, when applied to or introduced into the body, alters body fun tions in some way. The phræe ~therapeutic active~ is broader in scope and includes any substance which is capable of altering either body function or cosmetic appearance, but which is not traditionally or technically ~onsidered a drug. For example, mineral oil does alter the skin in at least a cosmetic manner or in some cases may be thera-peutic. Therefore, mineral oil is considered to be a 'Itherapeutic active" for purposes of the present invention.
There are several features which make the delivery systems of the present invention supefior delivery vehicles. In the first instance, . .
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-202~962 the de~very systems of this invention are substantive with hair, skin,and mucous membrane. Throughout the specification and claims, the term "substantive" means that there exists a cohesive interaction between the aminopolysaccharide and a proteinaceous substrate, i.e., the hair, skin, or mucosa, to which the delivery system is applied. In the delivery systems of the present invention, substantivity typically is obtained by ensuring that the aminopolysaccharide is cationically charged. The cationic charge is imparted by protonation or quaternization of the aminopolysaccharide. Incorporation of appro-priate hydrophobic groups or combinations thereof may be used.
Thus, the delivery systems of the present invention exhibit a cohesive interaction with the proteins of hair, skin, and mucosa.
Aminopolysaccharides, particularly chitosan derivatives, are good film-formers, i.e., a polymeric film is readily formed when an aqueous solution of a water-soluble aminopolysaccharide is applied topically. Upon topical application of the delivery system of this invention, a polymeric film forms and serves as a reservoir from which the active is continuously delivered. The film also serves to protect the application site from insult or injury.
Cationically-charged chitosan derivatives exhibit substantive properties to keratin and other pro~ein constituents of hair, skin, and mucosa. Thus, upon application of a cationic chitosan derivative to these tissues, the resulting film is bound to the substrate. This close relationship minimizes loss or migration of the film and the active.
Any form of the delivery system, such as a lotion (non-aqueous frac-tion is dispersed in aqueous fraction), creme or ointment (both emul-sions), spray (aerosol, for example) conveniently may be utilized to form the sub~ect delivery system. The system may also be applied to the skin or mucosa in the form of a pre-formed film, sponge, powder or other composite, as described below.
Application of an active- and aminopolysaccharide-containing delivery system which forms a film provides uniform distribution of the active on the tissue and prevents migration or loss of the active 202~962 .
from the site of application. The reservoir o~ active in the film helps to control the dosage at a constant level, thus controlling the rate of release. Also, chitosan derivatives which are free of naturally-associ-ated proteins, heavy metals, and the like, are biocompatible and non-irritating to living tissue. These derivatives also do not elicit an inflammatory, allergic, or pyrogenic response in humans. In addition, the films these chitosan derivatives form on skin and mucosa are essentially imperceptible to the patient and cosmetically comfortable to wear. Further, the films are gas permeable.
The chitosan derivatives are also good humectants.
Moisturization of the skin and mucous membranes enhances the absorption and permeation of many pharmaceutical and therapeutic actives into those tissues. When these chitosan derivatives are applied to skin or mucous membranes, their humectant properties therefore enhance the absorption of the actives into these tissues.
AS indicated above, there are two types of aminopolysaccharide derivatives which can be employed in the com-positions of this invention. First are the chitosonium polymers.
These chitosonium polymers are soluble in water and in mixtures oI
water and alcohol, readily form humectant films, and are substantive to skin and mucosa. Chitosonium polymer prepared by any method may be utilized in the subject invention. For example, these chitosonium polymers may be prepared by a number of known meth-ods, including direct dissolution, spray drying, lyophilization, and the acid decrystallization process described in International Application Number PCT/US87/01246, published December 17, 1987 as Wo 87/07618.
Examples of chitosonium derivatives include those wherein one or more of the amino groups have been neutralized by acids, which may include: pyrrolidone carboxylic, acetic, lactic, glycolic, glyceric, mandelic, salicglic, benzoic, itaconic, malic, nicotinic, glutamic, aspartic, and the acid form of other amino acids such as N-acetyl ;` .
` D-16246 :
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20~962 methionine, N-acetyl tyrosine, N-acetyl glycine, N-benzoyl serine, and the lLce.
The second type of chitosan derivative included in this inven-tion is covalent derivatives. These derivatives are prepared by the reaction of chitosan with one or more electrophilic reagents such as ethylene oxide, propylene oxide, glycidol, alkyl halides (from Cl to C24), glycidyl trialkylammonium salts (alkyl groups from C1 to C24), 3-chloro-2-hydroxypropyl ammonium salts, 1 ,3-propanesultone, haloacetates, succinic anhydride, maleic anhydride, carboxylic acyl halides, the N-carboxy-alpha-amino acid anhydrides, and the like.
These chitosan derivatives are readily soluble in water, alcohol, water/alcohol mixtures, or, depending upon the structure of the derivative, may be soluble in ether, acetone, or ethyl acetate. These derivatives are good film formers, good humectants, and are substan-tive if cationic and/or hydrophobic groups are included in the polymer backbone.
Aminopolysaccharides suitable for use in the subject invention can be conveniently prepared by a method which comprises the steps of:
(a) forming a mixture of a pulverulent, partially deacetylated aminopolysaccharide and (1) a diluent medium in which the aminopolysaccharide is swellable but essentially insoluble; the medium comprised of:
(i) an inert, water soluble, polar organic diluent in which the aminopolysaccharide is insoluble and the aminopolysaccharide derivative is insoluble; and (ii) at least one organic acid which is at least partially soluble in water, is sufficiently acidic tO form the ammonium salt of the aminopolysaccharide and yet not sufficiently acidic to cause degradation of the aminopolysaccharide or derivative, and which is present in an amount sufficient tO protonate the reactive sites of the deacetylated aminopolysaccharide: and ~
-.
.
- . .
(2) water in an amount up to about 65 weight percent of said medium;
(b) agitating the mixture at a temperature and for a period of time to effect at least partial decrystallization of the aminopolysaccharide to form an aminopolysaccaride derivative; and (c) recovering the aminopolysaccharide derivative from the mixture.
As described above, a variety of derivatives of decrystallized aminopolysaccharides, such as chitosan, can be prepared. These derivatives can be ionic compositions (salts) or covalent compositions.
To prepare covalent chitosan derivatives such as esters, amides, and ethers, the swollen, decrystallized slurry of the chitosan salt prepared by the aforementioned method, is causticized with a stoichiometric excess of a base such as sodium hydroxide and then reacted with an electrophile, such as ethylene oxide, propylene oxide, glycidol, 1,2-epoxy dodecane, chloroacetic acid, succinic anhydride, and the like.
To prepare ionic derivatives in the form of salts of chitosan, the acid used in the decrystallization step is chosen to provide the desired functional group and both decrystalliza~ion and derivatization, i.e. salt formation, is accomplished simultaneously. Alternatively, the organic acid utilized in the decrystallization step can be selected so that the chitosan is not only decrystallized but the salt is obtained containing the desired organic function present in the acid employed.
The decrystallization method described herein differs îrom other known methods in several respects. ~irst, the acid decrystallization process does not involve dissolution of aminopolysaccharide, such as chitosan, in an aqueous medium. Since chitosan is a very rigid molecule, only a small quantity of chitosan having a moderately high molecular weight (between about 20,000 and greater than 1 million) can be rendered water soluhle before the solu-tion becomes too viscous to be easily handled. If the solu~ion is fu~
ther diluted to reduce the viscosity, the concentration of chitosan is `:~
, 1 ..
':~
.
, , ' ' ' ..
. . ~ , - . ~ -2~20~2 reduced even further. The dilute nature of such a solution makes chemical reaction to derivatize the molecule inefficient and economi-cally unattractive.
For example, literature currently available from a company engaged in the commercial sale of chitosan in the United States indi-cates that chitosan is soluble in solutions of most acids, particularly organic acids such as formic acid, malic, tartaric, citric, adipic, and the like. It is further indicated that in order to make a one percent solution of chitosan in water, chitosan is mixed with water and then an equal volume of acid solution is added. For concentrated solutions of chitosan, which are indicated in the literature reference to be from about 2 to 4 percent by weight, an equal weight of acid to that of the chitosan is employed. With inorganic acids such as hydrochloric or nitric acids chitosan is soluble within the range of 0.15 to 1.1 percent acid by weight. Chitosan is not soluble in sulfuric acid and has only marginal solubility in phosphoric acid at concentrations below 0.5 percent.
Thus, the decrystallization method described herein provides the only method known to the inventors whereby aminopolysaccharides are economically decrystallized and derivatized, and recovered, by a simple and efficient process.
A variety of acids can be used in the decrystallization process.
It is, of course, necessary that the acid be at least partially soluble in water or hydrophilic media, be sufficiently acidic to form the ammo-nium salt of the aminopolysaccharide and yet not sufficiently acidic to cause hydrolysis of the aminopolysaccharide or derivative, and be present in an amount sufficient to protonate the reactive sites of the deacetylated aminopolysaccharides.
Such acids can be represented by the formula:
R-(COOH)n wherein n has a value of 1 or 2 and R represents a monovalent or divalent organic radical composed of carbon, hydrogen, and optionally at least one moiety selected from the group consisting of oxygen, :' .
-.
202~62 nitrogen, and sulfur. Combinations of such acids also may be utilized.
Preferred acids are the mon~ and di-carboxylic acids composed of carbon, hydrogen, oxygen, and nitrogen, which are at least partia~y water soluble and biologically and/or pharmaceutically acceptable for use in the delivery systems of the present invention.
Accordingly, a wide variety of acids can be employed to simul-taneously decrystallize chitosan and provide derivatives suitably uti-lized in the present invention. Such acids, in addition to those previ-ously identified, include formic, acetic, t~-acetylglycine, acetylsali-cylic, fumaric, gallic, glycolic, iminodiacetic, itaconic, DL-lactic, maleic, DL-malic, methacrylic, 2-pyrrolidone-5-carboxylic, salicylic, succinamic, succinic, ascorbic, aspartic, adipic, glutamic, glutaric, malonic, nicotinic, pyruvic, sulf onyldiacetic, thiodiacetic, and thioglycolic acids.
The medium employed in the decrystallization of the chitosan is a diluent system combining water and an organic compound.
Organic compounds which are useful in this diluent system are those which are water soluble, in which the aminopolysaccharide is insolu-ble, and in which the aminopolysaccharide derivative is insoluble.
Organic compounds suitably empldyed include acetone, methanol, ethanol, n-propanol, isopropanol, tertiary butyl alcohol, acetonitrile, tetrahydrofuran, dioxane, 2-ethoxyethanol, dimethoxyethane, and the like.
The second component of the diluent medium is water, which is present in an amount up to about 65 weight percent of the total medium, i.e., the total of the water plus the organic compound. In practice, optimum results are obtained when the diluent medium con-tains rrom about 30 to about 45 weight percent water and more pref-erably about 40 weight percent.
In contrast to other methods, the decrystallization described herein avoids l?ormation of a chitosan solution. Rather chitosan is caused to swell and it is unnecessary to form viscous solutions which contain only a few percent chitosan.
,................. . . .
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The sequence of mixing the diluent medium and the deacetylated chitosan is not critical. However, it has been observed that excellent results are obtained if the diluent medium is prepared from the urater and organic compound together with the acid and then the chitosan added.
Chitosan, which is a deacetylated form of chitin, has a very rigid strueture, as iLlustrated in the following formula:
t~ t~o ffO~ ~O~ ao~~
wherein x is between 0 and 0.5; y is between 0.5 and 1, and x + y = 1.
The degree of deacetylation and the molecular weight which occurs in natural chitin depends upon the species, e.g., shellfish from which the chitin is obtained and the method by which it is purified. In chitosan, typical ranges are y is between about 0.5 and 0.9 and x is between about 0.1 and 0.5. Dissolution of chitosan having a low degree of deacetylation in acid solution yields a very viscous product, with a significant insoluble fragment.
For chitosan salts or derivatives be soluble in water, they should be prepared from starting materials which have a relatively large number of free primary amine groups, i.e., y should be larger than about 0.5. Preferably, the degree of deacetylation of chitosan used herein is in excess of 60 percent, and more preferably in excess of 70 percent. The molecular weight range of chitosan employed in the presene inYentlon can range from about 5000 to over a million and more preferably from about 10,000 to about 500,000. Particularly preferred is chitosan having a molecular weight of from about 20,000 to about 250,000.
The above-described mono- and di-carboxylic acids or other combinations can be employed in the preparation of derivatives of ' .
2020~2 . .
chitosan usefuI in this invention. Thus, derivatives of chitosan suit-able for use in the present invention include chitosan salts of carboxylic acids (R~COOH) having the formula:
ON o~
(~ (~0 NO~O~) Lo o.o-o.s 0~5 1.t~ ~, For example, pyrrolidone carboxylic acid (PCA) is an effective mois-turizing agent which has a low order of irritation. Chitosonium pyrrolidone carboxylate has a large number of useful applications such as topical medical formulations. The pyrrolidone carboxylic acid salt of chitosan is useful in delivery systems of the present invention.
Such a polymer is prepared by reacting a finely ground slurry of chitosan with PCA in a polar solvent such as aqueous isopropanol or other suitable solvent that will dissolve PCA and swell the chitosan pyrrolidone carboxylic acid salt, but not dissolve it.
Other chitosan derivatives, e.g., salts of other organic acids that are soluble in polar organic solvents such as isopropanol, may be made by this decrystallization process. For example, glycolic acid or lactic acid in aqueous isopropanol can be reacted with chitosan to give the glycolate salt or lactate salt, which also are useful as deliv-ery systems.
When rree of its naturally associated proteins, chitin or chitosan is not antigenic to human tissue, and may be used on or inserted under the skin, or placed in cantact with body fluids without harm. Chitin in the body is slowly attacked by lysozyme and is absorbed. In addition, chitin and chitosan may be safe~y ingested by humans, for example, common foods such as bread, beer, wine, shrimp, crabs, and mushrooms all contain some chitin.
In addition to the chiosonium polymers and covalent chitosan derivatives prepared as described above, the delivery systems of the ~-16246 :
2~2~962 .
present invention can be comprised of chitosan derivatives prepared by known methods.
Chitosonium polymers suitable for use in the present invention include salts of chitosan prepared with the following acids:
Acetic N-Acetyl-L-cysteine N-Acetyl glycine Acetylsalicylic Adipic L-Aspartic Citric Fumaric 2-Furoic Gallic L-Glutamic Glutaric Glycolic Hydrochloric 4-Hydroxybenzoic Iminodiacetic Itaconic 3-Ketoglutaric DL-Lactic Maleic DL-Malic Malonic Nlcotinic (Nlacin) 2,3-Pyridinedicarboxylic 2-Pyrrolidone-5-carboxylic Pyruvic Salicyclic Succinamic Succinic Sulfanilic Sulfonyldiacetic L-Tartaric Thioacetic Thiolactic Vanillic Combinations of these acids also are suitable.
These salts are readily soluble in water at room temperature, except for the malate, maleate, itaconate, salicylate, fumarate, and succinate salts, which require heating tO about ~5C to effect dissolu-tion, after which they remain soluble. The products from the reaction :
:
; ~ :
, 20209~2 acrylic, citric, gallic, 4-hydroxybenzoic, and vanillic acids, when used alone, are only slightly soluble in water, because the reaction by which the derivative is formed has limited efficiency.
Chitosan derivatives which can be prepared by the above pro-cess include, but are not limited to, chitosonium pyrrolidone carboxylate, chitosonium itaconate, chitosonium niacinate, chitosonium salicylate, chitosonium lactate, chitosonium formate, chitosonium aceeate, chitosonium gallate, chitosonium glutamate, chitosonium maleate, chitosonium succinamate, chitosonium aspartate, chitosonium glycolate, and combinations thereof. Each is suitable for use in the subject invention.
In general, the amount of chitosan derivative employed in the compositions of this invention will vary depending upon the particular pharmaceutical or therapeutic active being delivered, whether diluent is present, the type of additives, and the like. In practice, however, it has been found that a concentration of the chitosan derivative in the composition can range up to about 20, preferably between about 0.05 and 10, weight percent, based on the total weight of the composition.
The delivery systems of the present invention contain pharma-ceutical and therapeutic actives that can be applied topically either singularly or in combination. Examples of these actives include, but are not limited to compounds such as the following:
Anti-inflammatory analgesics such as salicylic acid, salicylate esters and salts, acetylsalicylic acid, diflunisal, acetaminophen, phenylbutazone, oxyphenbutazone, sulf inpyrazone, indomethacin, sulindac, fenoprofen, flurbiprofen, ibuprofen, ketoprofen, naproxen, mefenamic acid, floctafenine, tolmetin, zomepirac, diclofenac, piroxicam, and the like.
Loca~ anaesthetics such as cocaine, benzocaine, tetracaine, lidocaine, bupivacaine, their hydrochloride salts, and the like.
Antibiotic agents such as penicillins, cephalosporins, vancomycin, bacitracin, cycloserine, polymyxins, colistin, nystatin, amphoterlcin B, mupirocim, tetracyclines, chloramphenicol, 2~2~62 erythromycin, neomycin, streptomycin, kanamycin, gentamicin, tobramycin, amikacin, netilmicin, spectinomycin, clindamycin, rifampin, nalidixic acid, flucytosine, griseofulvin, and the like.
Sulf anilamide antibacterial agents such as sulf anilamide, sulfacetamide, sulfadiazine, sulfisoxazole, sulfamethoxazole, trimethoprim, pyrimethamine, and the like.
Antiviral agents such as vidarabine, acyclovir, ribavirin, amantadine hydrochloride, rimantadine, idoxyuridine, interferons, and the like.
Antiseptic agents such as acridine dyes, alcohols, bronopol, chlorhexidine, phenols, hexachlorophene, organic mercurials, organic peroxides, i.e., benzoyl peroxide, quaternary ammonium compounds, and the like.
Vitamin and vitamin defivatives such as Vitamin A, retinol, retinoic acid ~both cis and trans), alpha-tocopherol (Vitamin E), 7-dehydrocholesterol (Vitamin D), Vitamin K, thiamine, riboflavin, niacin, wridoxine, biotin, pantothenic acid, ascorbic acid, choline, inositol, and the like.
Anti-inflammatory corticosteroids such as progesterone, hydroco~tisone, prednisone, fluorocortisone, triamcinolone, dexamethasone, betamethasone, fluocinolone, and the like.
Anti-fungal agents such as miconazole, tolnaftate, naftifine hydrochloride, loceryl, undecylic acid and iB salB, and other hetero-cyclic compounds including morpholine, imidazoles and derivatives thereof.
Vasodilators such as niacin, nicotinate esters and salts, nitro-glycerine, amyl nitrite, prazosln, minoxidil and diazoxide and calcium channel blockers such as nifedipine, diltiazem, indomethacin, and the like.
Gonadal hormones such as gonadotropin-releasing hormone, human chorionic gonadotropin, gonadotropins, 17-beta-estriol, ethinyl estradiol, diethyl stibestrol, norethindrone, norethynodrel, medroxyprogesterone acetate, d-norgestrel, testosterone, .. , . ~
-:
.
202~962 fluoxymesterone, androstenedione, norethandrolone, nandrolone phenpropionate, methylandros~enediol, and the like.
Anti-histamines such as diphenhydramine, chlorpheniramine, chlorcyclizine, promethazine, cimetidine, ranitidine, and the like.
Autacoids such as prostaglandins, prostacyclin, thromboxanes, leukotrienes, angiotensins (captopril), as well as other pharmaceuti-cally active peptides such as serotonin, endorphins, vasopressin, oxytocin, and the like.
Kerolytic agents such as benzoyl peroxide, salicylic acid, trichloroacetic acid, and piroctone, and wart treatment compounds such as salicyclic acid, trichloroacetic acid and lactic acid, singularly or in combination with anti-viral agents.
Anti-diarrhea agents such as bismuth salts (especially the subsalicylate), opium and its derivatives, diphenoxylate, difenoxin, loperamide, nufenoxole, lidamine and the like.
Anti-alopecia agents such as niacin, nicotinate esters and salts, and minoxidil.
Moisturizing agents such as lactic acid, pyrrolidone carboxylic acid, glycolic acid, glycerine, propylene glycol, sorbitol, other alpha-hydroxy carooxylic acids, and various salts of these esters and salts, and the like.
As indicated above, this list of pharmaceutical and therapeutic actives is not inclusive, but is presented merely to demonstrate the scope of the invention. A wide variety of other actives can be employed either alone or in combination.
Glycosaminoglycans (GAGS) comprise a class of polysaccharides that occur in the connective tissue of mammals, and include byaluronic acid, chondroitin su~tate, and heparin, and which can be included in delivery systems of the invention. Some of these polysaccharides, hyaluronic acid in particular, have been used suc-cessfully for wound healing and tissue regeneration in both humans and laboratory animals. The exact mechanism of tissue regeneration is not known, but oligomeric metabolites of N-acetylglucosamines and ~' `~
~' , , -- , - -- ~.
2020~62 glucosamine functionality present in glycosaminoglycans such as hyaluronic acid is present in chitin and chitosan, and similar wound healing and tissue regeneration properties have been reported for chitin and chitosan.
Preferably, hyaluronic acid is added only to delivery systems containing covalent derivatives of chitosan. Hyaluronic acid inter-acts with chitosonium salts and may cause precipitation thereof.
The amount of active employed will be that amount necessary to deliver a pharmaceutically or therapeutically effective amount to achieve the desired result at the site of application. In particular, an effective amount depends, lnter alia, upon the particular active, the severity of the condition, and other factors. In general, the concen-tration of the actives in the delivery systems can vary from as little as 0.001 up to 50 percent or higher, by weight of the delivery system.
More typically, the active concentration is between about 0.01 and 10 wt percent of the delivery system. Skilled practitioners will be able to adjust the quantity of active in the delivery system.
If desired, the delivery systems of this invention can contain one or more pharmaceutically acceptable diluents or vehicles in addi-tion to the chitosan derivative, the active component, and the deliv-ery enhancer. In many instances, the chitosan derivative itself can be about 0.5 to about 20 weight percent of the system with the remain-der being diluent and optionally, other additives. Suitable diluents include among others, water, ethanol, aqueous ethanol, isopropanol, glycerine, din.ethylether, polyethylene glycol, ethoxylated or propoxylated glucose, sorbitol derivatives, and the like.
Additives for the enhanced percutaneous absorption of various pharmaceutical or therapeutic actlves also may be utilized. Such percutaneous enhancers include propylene glycol, glycerol, urea, diethyl sebecate, sorbitan ethoxylates, nicotinate esters (such as hexyl nicotinate), oleic acid, pyrrolidone ~arboxylate esters, (such as dodecyl pyrrolidone carboxylate), N-methyl pyrrolidone, N,N-diethyl-m-toluamide, dimethyl sulfoxide, decyl methyl sulfoxide, ;
- , - , .
2020~2 ah~cyl methyl sulfoxides, N,N-dimethyl formamide, cis-ll-octadecenoic acid, l~odecylazacycloheptan-2-one, and 1,3-dioxacyclopentane or 1,2-dioxacyclohexane containing at least one aliphatic group of four to eighteen carbon atoms.
It has been discovered that incorporation of delivery enhancers into delivery systems of the present invention unexpectedly improves absorption of the active at the application site. Delivery enhancers are useful whenever the active is to be delivered through the stratum corneum. The improved efficiency of delivery can be utilized in a number of ways. For example, it affords the opportunity to deliver, in a topical system, an unexpectedly high concentration of active. A
high concentration of active could be utilized to reduce the number of times the treatment must be applied during a given period. Skilled practitioners recognize other manners of utilizing the unexpected results obtained herein.
Delivery enhancers of the invention preferably are not com-pletely hydrophobic or oleophobic. Rather, they are both hydrophilic and oleophllic to varying degrees. Thus, delivery enhancers of the invention may be at least slightly soluble in aqueous solutions and in a non-aqueous component.
Some delivery enhancers also can act as an emulsifier between the oil phase and the aqueous phase. Addition of such an emulsifying delivery enhancer before the emulsion is formed typically causes the drop size of the oil phase to be smaller. Smaller drop size may con-tribute to increasing delivery efficiency.
The delivery enhancers of the invention are distinct from the above-described percutaneous enhancers. The percutaneous enhanc-ers typically act as humectants, lubricants, softening agents, moistur-izers, debris removers, and impart cleansing and other effects. These enhancers therefore prepare the application site to receive active by ensuring that the site is sof tened, free of debris, and amenable to pen-etration. In contrast, the delivery enhancers of the subject invention do not serve such functions. Rather, the delivery enhancers of the E~-16246 ' ' ' .
. '.
-.
.
-` 2020~62 invention serve to provide a path or bridge through the skin, reduce the hydrophobicity of the skin, or otherwise delivering the active more efficiently.
Benzyl alcohol is a preferred delivery enhancer. Other deliv-ery enhancers include dimethyl sulfoxide and AZONE. In particular, benzyl alcohol is a preferred delivery enhancer for steroids.
Certain compositions serve to further enhance the effect of the delivery enchancers. For example, propylene glycol, described above as a percutaneous enhancer, further improves the delivery of steroids when benzyl alcohol is utilized as a delivery enhancer.
Propylene glycol thus is a preferred percutaneous enhancer in con-junction with benzyl alcohol as a delivery enhancer. Hexylene glycoland cis-octadecen-11-oic acid also are ~ompositions which enhawe delivery.
An example of the unexpected results obtained by using deliv-ery enhancers include delivery of steroid products. It has been dis-covered that benzyl alcohol is an especially suitable delivery enhancer for steroids. In particular, benzyl alcohol may be a delivery enhancer for steroids such as Amcinonide Betamethasone Dipropionate Betamethasone Valerate Clobestasol Propionate Desonide Desoximetasone Diflorasone Diacetate Fluocinolone Fluocinolone Acetonide Fluocinonide Halcinonide Hydrocortisone Hydrocortisone Valerate Mometasone Furoate Triamcinolone Triamcinolone Acetonide Triamcinolone Acetonide USP
Tridesilon Desonide :, ~' ~............................... .
: . .- : . . ~ , .
- . . ~ . ~
. 202~62 The delivery systems of the ,oresent invention are particularly efficient for delivery of steroids. The chitosan salt forms a film over the application site, ensuring that the steroid and delivery enhancer do not migrate and are not removed from the site, e.g., by perspira-tion or contact with clothing. Further, the delivery enhancer, espe-cially benzyl alcohol, promotes efficient introduction of the steroid into the treatmen~ site. This increased efficiency, together with the excellent site protection afforded by the chitosan film which forms over the site, afford the opportunity to deliver to a site an increased quantity of steroid per application. Therefore, instead of requiring three or more applications of steroid daily, as typically is required by known delivery systems, the delivery system of the present invention may be applied only once daily. This decreased application frequency provides several benefits, including increased consumer acceptance and improved treatment derived, inter alia, from an easily understood and executed treatment schedule.
Known methods for topically delivering actives such as steroids typically re~uire repeated applications during a 24-hour period to ensure that a sufficient quantity of active is delivered to the site.
Repeated application is at best inconvenient, and at worst leads to uneven treatment, such as lack of treatment because the scheduled application time fell during a period of sleep, or at a time when appli-cation was impossible.
Repeated application of known topical treatments is necessary because the treatments cannot deliver a sufficient quantity of active in one application, e.g., without feeling greasy or delivering the active at an uneven rate. However, the delivery system of the inven-tion affords an even delivery rate over a long period.
Delivery systems of the invention typically comprise solutions, lotions, dispersions, or oil-in-water emu~sions. Oil-in-water emulsions feel relatively "non-greasy~ when applied, whereas water-in-oil emul-sions tend to have a greasy or oily feel. Therefore, oil-in-water emul-sions are preferred by consumers.
D-162~6 .
;-. ' -- 2020~2 Emulsion-type delivery systems of the invention are made by the lldirectl' method or by the ~inversion~ method. In the lldirectl' method, the oil phase is dispersed into the continuous aqueous phase to form the oil-in-water emulsion directly. An oil-in-water emulsion is made by the ~inversion~ method by emulsifying the aqueous phase into a continuous oil phase. At first, a wate~in-oil emulsion is formed, but, as the quantity of aqueous phase is increased, the emul-sion becomes l'invertedll and forms an oil-in-water emulsion. Either preparation method can be used to prepare emulsion-type delivery systems of the invention.
The delivery enhancer may be part of either fraction of the delivery system. The delivery enhancer may be added tO the system either as part of one of the fractions, or as a separate component after the remainder of the delivery system is formed. In the latter technique, the delivery enhancer is distributed by agitation.
The quantity of delivery enhancers should not exceed the mini-mum quantity which will produce delivery enhancement. Addition of an excess quantity is not economically or therapeutically efficient.
Therefore, the quality of delivery enhancer is up to about 20 wt pe~
cent of the delivery system, preferably between about 0.25 and 10 wt percent, and more preferably between about 0.5 and S wt percent.
In practice, the delivery systems of the invention are readily formulated by mixing a delivery enhancer with a solution or suspen-sion of the chitosan derivative. The active or actives are dissolved or suspended either in the aqueous solution or, if it is present, in a non-aqueous fraction, or in a component of a fraction. For example, a water~oluble active may be incorporated directly into the aqueous fraction or may first be dissolved in a water-soluble non-aqueous com-ponent in which it is soluble, such as propylene glycol or isopropanol.
The non-aqueous fraction then is mixed with a solution or suspension of the desired chitosan derivative. An emulsion is formeci if the non^aqueous fraction is not soluble in the aqueous phase: a suitable ~ emulsifier maybe used. Other adjuvant ingredients such as glycerine, ; ~ D-16246 ~ .
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.
- 2020~62 propylene glycol, sorbitol, preservatives, steari~ acid, cetyl alcohol, other high molecular weight alcohols, surfactants, menthol, eucalyp-tus oil, other essential oils, fragrances, penetration enhancers, and the like to give stable delivery systems, such as cremes, ointments, lotions, and aerosols, may also be included.
Alternatively, solutions or mixtures of the actives with the chitosan derivatives may be fabricated into films, rods, sheets, sponges, or fibers for use as suppositories, medicated sutures, medi-cated sheets, medicated bandages, patches, and the like.
The following examples are intended to further illustrate the invention, not to limit it in any way. The scope of the lnvention is limited only to the scope of the appended claims.
Example 1 is directed to the preparation of delivery systems of the present invention using derivatives prepared by the acid decrystallization method as well as known derivatives prepared by methods disclosed in the literature. Unless otherwise indicated the solution viscosity of the chitosan polymers is between about 5 and 5000 cP at 1% and 20C, as measured using a Brookfield viscometer model LVT, spindle #2.
EXAMPLES
Throughout the Examples, all parts are parts by weight, unless ~ otherwise identified.
,~ ~ ExamDle 1 This example illustrates various comparative compositions and delivery systems of the invention wherein the active is a steroid.
A solution of triamcinolone acetonide (TA) in propylene glycol was prepared by stirring 0.55 parts TA into 100 parts prowlene glycol for about lS minutes. This solution was utilized in the preparations of this Example. In each case, benzyl alcohol was the delivery enhancer.
A. Lotion-tvDe DeliverY SYstem of the lnvention A delivery system of the invention in the form of a lotion was prepared by blending 20.11 parts of the TA solution, ~ parts of chitosan lactate (viscosity of 1 percent solution is 5 cP), 52.39 parts ~`
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.
. ~ ~
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, 2~
bolled dlst~ed water ~ olutlon oS chito~an l~ctat~), 20 parto Isopropyl alcohol, and 0.5 parts benzyl alcohol.
B, Emulslon-tvpe Dellverv Svstem ot ehe rnve~tlon A dell~lery system Or the invention usln~ low molecular welght chltosan lactate was prepared in accordance wlth the method of tne invention.
The aqueous phase was prepared by blending 7.02 partS low molecular weight chltosan lactate (vlscos~ty of 1 percent solutlon is 5 cP) in 56.87 parts bo~led distllled water (as solutlon of chltosan lac-tate), together with 20.11 parts or the TA solution. This n~ixture was heated to about 50-55C. then 3.0 parts Myr~ 52 (polyoxyethylene (40) stearate, ICI Amerlcas, ~nc.) was added.
The oll pha~e was prepared by blending 7.5 part~ Prom~g~n D, (cetearyl alcohol, a blend of cetyl alcohol and stearyl alcohol, and c~teareth 20 from Amerchol) 4.0 parts white petrolatum, and 0.5 parts glycerol monostearate. The emulslon then was ~ormed by addin~
the oll phase to the water phase, both at 75C.
The temperature o~ the emulslon was ad~usted to S0C, at which tlme ~.0 part ben2yl aJcohol was added. Aglta~lon was di~con-tlnued after the temperature was decre~sed below 40C.
C. Emulsion-tv~e ~2eliverv S~tstem of the Inventlon A dellvery system ot the invention us~ng both low and high molecu~ar welght chltosan lactates w~s prepare~ by the dlrect method.
The aqueous pha~e was pr~pared ~y mlxlng 10 parts or a 10%
- aqueou~ solutlon ot low molecular welght chitosan lactato (vlscosityof 1 percent solution Is 5 cP) an~ 30 parts ot a 4 percent solutlon ot hlgher molecular weieht chitosan lactate ~viscos~ty Or 1 percent &olu-tlon ~s 230 cP) wlth 20.11 parts ot TA solutlon and 4 parts bollod d~s-tllled water. The temperature or the mixture ~s ad~usted to SSC, and 3 parts Myr~ 52 was added.
The remainder o~ the preparation was as described in Example lB.
;1 ;~
~ . :
, ' -24- 2020~2 D. DeliverY SYstem of the Invention The direct method was utilized to prepare a delivery system of the invention. The aqueous phase was prepared as in Example lC, except that 4 parts water was omitted.
The oil phase was prepared by mixing 7.5 parts Promulgen D, 4.0 parts white petrolatum, O.S parts glycerol monostearate, and S
parts benzyl alcohol.
The oil phase then was emulsified at a temperature of about 75C. Afitation was continued during cooling until the temperature was below about 40C.
* * ~ * J
Each of the delivery systems lA-lD was compared to two commercially-available triamcinolene acetonide products (Aristocort creme and ointment; Lederle Laboratories Div. of American Cyana-mide Co., Wayne, NJ). In two blind tests by an independent labora-tory, Examples lA, lC, and lD scored higher than the commercially-available product. Example lB scored higher in one test.
* ~ ~ ~
Although preferred embodiments of the invention have been discussed herein, those skilled in the art will appreciate that changes and modifications may be made without departing from the spirit of this invention, as defined in and limited only by the scope of the appended claims.
':~
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The delivery system of this invention encompasses divers aminopolysaccharides, particularly chitosan derivatives, and delivery enhancers, in addition to the actives.
Typically, delivery systems of the invention are fluids, i.e., dispersions, emulsions, and aqueous solutions and lotions, comprising an aqueous fraction. Other components of the delivery system may be non-aqueous vehicles which may be soluble or insoluble in the aqueous fraction. If the non-aqueous fraction is soluble in the aqueous fraction, a single-phæe delivery system is formed. If the non-aqueous fraction is not soluble in the aqueous fraction, an emulsion or disper-sion is formed; a suitable emulsifier may be used. The delivery enhancer then may act æ an emulsirier between the phases, and the active can be in either phase. The delivery systems of the invention possess a vafiety of useful characteristics which make these materials supefior for the delivery of pharmaceutical and therapeutic actives.
As used throughout the specification and claims, the phræe llpharmaceutical active" is considered to be a drug, i.e., a substance which, when applied to or introduced into the body, alters body fun tions in some way. The phræe ~therapeutic active~ is broader in scope and includes any substance which is capable of altering either body function or cosmetic appearance, but which is not traditionally or technically ~onsidered a drug. For example, mineral oil does alter the skin in at least a cosmetic manner or in some cases may be thera-peutic. Therefore, mineral oil is considered to be a 'Itherapeutic active" for purposes of the present invention.
There are several features which make the delivery systems of the present invention supefior delivery vehicles. In the first instance, . .
. ",~.. .. . .
~: `
-202~962 the de~very systems of this invention are substantive with hair, skin,and mucous membrane. Throughout the specification and claims, the term "substantive" means that there exists a cohesive interaction between the aminopolysaccharide and a proteinaceous substrate, i.e., the hair, skin, or mucosa, to which the delivery system is applied. In the delivery systems of the present invention, substantivity typically is obtained by ensuring that the aminopolysaccharide is cationically charged. The cationic charge is imparted by protonation or quaternization of the aminopolysaccharide. Incorporation of appro-priate hydrophobic groups or combinations thereof may be used.
Thus, the delivery systems of the present invention exhibit a cohesive interaction with the proteins of hair, skin, and mucosa.
Aminopolysaccharides, particularly chitosan derivatives, are good film-formers, i.e., a polymeric film is readily formed when an aqueous solution of a water-soluble aminopolysaccharide is applied topically. Upon topical application of the delivery system of this invention, a polymeric film forms and serves as a reservoir from which the active is continuously delivered. The film also serves to protect the application site from insult or injury.
Cationically-charged chitosan derivatives exhibit substantive properties to keratin and other pro~ein constituents of hair, skin, and mucosa. Thus, upon application of a cationic chitosan derivative to these tissues, the resulting film is bound to the substrate. This close relationship minimizes loss or migration of the film and the active.
Any form of the delivery system, such as a lotion (non-aqueous frac-tion is dispersed in aqueous fraction), creme or ointment (both emul-sions), spray (aerosol, for example) conveniently may be utilized to form the sub~ect delivery system. The system may also be applied to the skin or mucosa in the form of a pre-formed film, sponge, powder or other composite, as described below.
Application of an active- and aminopolysaccharide-containing delivery system which forms a film provides uniform distribution of the active on the tissue and prevents migration or loss of the active 202~962 .
from the site of application. The reservoir o~ active in the film helps to control the dosage at a constant level, thus controlling the rate of release. Also, chitosan derivatives which are free of naturally-associ-ated proteins, heavy metals, and the like, are biocompatible and non-irritating to living tissue. These derivatives also do not elicit an inflammatory, allergic, or pyrogenic response in humans. In addition, the films these chitosan derivatives form on skin and mucosa are essentially imperceptible to the patient and cosmetically comfortable to wear. Further, the films are gas permeable.
The chitosan derivatives are also good humectants.
Moisturization of the skin and mucous membranes enhances the absorption and permeation of many pharmaceutical and therapeutic actives into those tissues. When these chitosan derivatives are applied to skin or mucous membranes, their humectant properties therefore enhance the absorption of the actives into these tissues.
AS indicated above, there are two types of aminopolysaccharide derivatives which can be employed in the com-positions of this invention. First are the chitosonium polymers.
These chitosonium polymers are soluble in water and in mixtures oI
water and alcohol, readily form humectant films, and are substantive to skin and mucosa. Chitosonium polymer prepared by any method may be utilized in the subject invention. For example, these chitosonium polymers may be prepared by a number of known meth-ods, including direct dissolution, spray drying, lyophilization, and the acid decrystallization process described in International Application Number PCT/US87/01246, published December 17, 1987 as Wo 87/07618.
Examples of chitosonium derivatives include those wherein one or more of the amino groups have been neutralized by acids, which may include: pyrrolidone carboxylic, acetic, lactic, glycolic, glyceric, mandelic, salicglic, benzoic, itaconic, malic, nicotinic, glutamic, aspartic, and the acid form of other amino acids such as N-acetyl ;` .
` D-16246 :
, .. . .
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20~962 methionine, N-acetyl tyrosine, N-acetyl glycine, N-benzoyl serine, and the lLce.
The second type of chitosan derivative included in this inven-tion is covalent derivatives. These derivatives are prepared by the reaction of chitosan with one or more electrophilic reagents such as ethylene oxide, propylene oxide, glycidol, alkyl halides (from Cl to C24), glycidyl trialkylammonium salts (alkyl groups from C1 to C24), 3-chloro-2-hydroxypropyl ammonium salts, 1 ,3-propanesultone, haloacetates, succinic anhydride, maleic anhydride, carboxylic acyl halides, the N-carboxy-alpha-amino acid anhydrides, and the like.
These chitosan derivatives are readily soluble in water, alcohol, water/alcohol mixtures, or, depending upon the structure of the derivative, may be soluble in ether, acetone, or ethyl acetate. These derivatives are good film formers, good humectants, and are substan-tive if cationic and/or hydrophobic groups are included in the polymer backbone.
Aminopolysaccharides suitable for use in the subject invention can be conveniently prepared by a method which comprises the steps of:
(a) forming a mixture of a pulverulent, partially deacetylated aminopolysaccharide and (1) a diluent medium in which the aminopolysaccharide is swellable but essentially insoluble; the medium comprised of:
(i) an inert, water soluble, polar organic diluent in which the aminopolysaccharide is insoluble and the aminopolysaccharide derivative is insoluble; and (ii) at least one organic acid which is at least partially soluble in water, is sufficiently acidic tO form the ammonium salt of the aminopolysaccharide and yet not sufficiently acidic to cause degradation of the aminopolysaccharide or derivative, and which is present in an amount sufficient tO protonate the reactive sites of the deacetylated aminopolysaccharide: and ~
-.
.
- . .
(2) water in an amount up to about 65 weight percent of said medium;
(b) agitating the mixture at a temperature and for a period of time to effect at least partial decrystallization of the aminopolysaccharide to form an aminopolysaccaride derivative; and (c) recovering the aminopolysaccharide derivative from the mixture.
As described above, a variety of derivatives of decrystallized aminopolysaccharides, such as chitosan, can be prepared. These derivatives can be ionic compositions (salts) or covalent compositions.
To prepare covalent chitosan derivatives such as esters, amides, and ethers, the swollen, decrystallized slurry of the chitosan salt prepared by the aforementioned method, is causticized with a stoichiometric excess of a base such as sodium hydroxide and then reacted with an electrophile, such as ethylene oxide, propylene oxide, glycidol, 1,2-epoxy dodecane, chloroacetic acid, succinic anhydride, and the like.
To prepare ionic derivatives in the form of salts of chitosan, the acid used in the decrystallization step is chosen to provide the desired functional group and both decrystalliza~ion and derivatization, i.e. salt formation, is accomplished simultaneously. Alternatively, the organic acid utilized in the decrystallization step can be selected so that the chitosan is not only decrystallized but the salt is obtained containing the desired organic function present in the acid employed.
The decrystallization method described herein differs îrom other known methods in several respects. ~irst, the acid decrystallization process does not involve dissolution of aminopolysaccharide, such as chitosan, in an aqueous medium. Since chitosan is a very rigid molecule, only a small quantity of chitosan having a moderately high molecular weight (between about 20,000 and greater than 1 million) can be rendered water soluhle before the solu-tion becomes too viscous to be easily handled. If the solu~ion is fu~
ther diluted to reduce the viscosity, the concentration of chitosan is `:~
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. . ~ , - . ~ -2~20~2 reduced even further. The dilute nature of such a solution makes chemical reaction to derivatize the molecule inefficient and economi-cally unattractive.
For example, literature currently available from a company engaged in the commercial sale of chitosan in the United States indi-cates that chitosan is soluble in solutions of most acids, particularly organic acids such as formic acid, malic, tartaric, citric, adipic, and the like. It is further indicated that in order to make a one percent solution of chitosan in water, chitosan is mixed with water and then an equal volume of acid solution is added. For concentrated solutions of chitosan, which are indicated in the literature reference to be from about 2 to 4 percent by weight, an equal weight of acid to that of the chitosan is employed. With inorganic acids such as hydrochloric or nitric acids chitosan is soluble within the range of 0.15 to 1.1 percent acid by weight. Chitosan is not soluble in sulfuric acid and has only marginal solubility in phosphoric acid at concentrations below 0.5 percent.
Thus, the decrystallization method described herein provides the only method known to the inventors whereby aminopolysaccharides are economically decrystallized and derivatized, and recovered, by a simple and efficient process.
A variety of acids can be used in the decrystallization process.
It is, of course, necessary that the acid be at least partially soluble in water or hydrophilic media, be sufficiently acidic to form the ammo-nium salt of the aminopolysaccharide and yet not sufficiently acidic to cause hydrolysis of the aminopolysaccharide or derivative, and be present in an amount sufficient to protonate the reactive sites of the deacetylated aminopolysaccharides.
Such acids can be represented by the formula:
R-(COOH)n wherein n has a value of 1 or 2 and R represents a monovalent or divalent organic radical composed of carbon, hydrogen, and optionally at least one moiety selected from the group consisting of oxygen, :' .
-.
202~62 nitrogen, and sulfur. Combinations of such acids also may be utilized.
Preferred acids are the mon~ and di-carboxylic acids composed of carbon, hydrogen, oxygen, and nitrogen, which are at least partia~y water soluble and biologically and/or pharmaceutically acceptable for use in the delivery systems of the present invention.
Accordingly, a wide variety of acids can be employed to simul-taneously decrystallize chitosan and provide derivatives suitably uti-lized in the present invention. Such acids, in addition to those previ-ously identified, include formic, acetic, t~-acetylglycine, acetylsali-cylic, fumaric, gallic, glycolic, iminodiacetic, itaconic, DL-lactic, maleic, DL-malic, methacrylic, 2-pyrrolidone-5-carboxylic, salicylic, succinamic, succinic, ascorbic, aspartic, adipic, glutamic, glutaric, malonic, nicotinic, pyruvic, sulf onyldiacetic, thiodiacetic, and thioglycolic acids.
The medium employed in the decrystallization of the chitosan is a diluent system combining water and an organic compound.
Organic compounds which are useful in this diluent system are those which are water soluble, in which the aminopolysaccharide is insolu-ble, and in which the aminopolysaccharide derivative is insoluble.
Organic compounds suitably empldyed include acetone, methanol, ethanol, n-propanol, isopropanol, tertiary butyl alcohol, acetonitrile, tetrahydrofuran, dioxane, 2-ethoxyethanol, dimethoxyethane, and the like.
The second component of the diluent medium is water, which is present in an amount up to about 65 weight percent of the total medium, i.e., the total of the water plus the organic compound. In practice, optimum results are obtained when the diluent medium con-tains rrom about 30 to about 45 weight percent water and more pref-erably about 40 weight percent.
In contrast to other methods, the decrystallization described herein avoids l?ormation of a chitosan solution. Rather chitosan is caused to swell and it is unnecessary to form viscous solutions which contain only a few percent chitosan.
,................. . . .
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202~2 .
The sequence of mixing the diluent medium and the deacetylated chitosan is not critical. However, it has been observed that excellent results are obtained if the diluent medium is prepared from the urater and organic compound together with the acid and then the chitosan added.
Chitosan, which is a deacetylated form of chitin, has a very rigid strueture, as iLlustrated in the following formula:
t~ t~o ffO~ ~O~ ao~~
wherein x is between 0 and 0.5; y is between 0.5 and 1, and x + y = 1.
The degree of deacetylation and the molecular weight which occurs in natural chitin depends upon the species, e.g., shellfish from which the chitin is obtained and the method by which it is purified. In chitosan, typical ranges are y is between about 0.5 and 0.9 and x is between about 0.1 and 0.5. Dissolution of chitosan having a low degree of deacetylation in acid solution yields a very viscous product, with a significant insoluble fragment.
For chitosan salts or derivatives be soluble in water, they should be prepared from starting materials which have a relatively large number of free primary amine groups, i.e., y should be larger than about 0.5. Preferably, the degree of deacetylation of chitosan used herein is in excess of 60 percent, and more preferably in excess of 70 percent. The molecular weight range of chitosan employed in the presene inYentlon can range from about 5000 to over a million and more preferably from about 10,000 to about 500,000. Particularly preferred is chitosan having a molecular weight of from about 20,000 to about 250,000.
The above-described mono- and di-carboxylic acids or other combinations can be employed in the preparation of derivatives of ' .
2020~2 . .
chitosan usefuI in this invention. Thus, derivatives of chitosan suit-able for use in the present invention include chitosan salts of carboxylic acids (R~COOH) having the formula:
ON o~
(~ (~0 NO~O~) Lo o.o-o.s 0~5 1.t~ ~, For example, pyrrolidone carboxylic acid (PCA) is an effective mois-turizing agent which has a low order of irritation. Chitosonium pyrrolidone carboxylate has a large number of useful applications such as topical medical formulations. The pyrrolidone carboxylic acid salt of chitosan is useful in delivery systems of the present invention.
Such a polymer is prepared by reacting a finely ground slurry of chitosan with PCA in a polar solvent such as aqueous isopropanol or other suitable solvent that will dissolve PCA and swell the chitosan pyrrolidone carboxylic acid salt, but not dissolve it.
Other chitosan derivatives, e.g., salts of other organic acids that are soluble in polar organic solvents such as isopropanol, may be made by this decrystallization process. For example, glycolic acid or lactic acid in aqueous isopropanol can be reacted with chitosan to give the glycolate salt or lactate salt, which also are useful as deliv-ery systems.
When rree of its naturally associated proteins, chitin or chitosan is not antigenic to human tissue, and may be used on or inserted under the skin, or placed in cantact with body fluids without harm. Chitin in the body is slowly attacked by lysozyme and is absorbed. In addition, chitin and chitosan may be safe~y ingested by humans, for example, common foods such as bread, beer, wine, shrimp, crabs, and mushrooms all contain some chitin.
In addition to the chiosonium polymers and covalent chitosan derivatives prepared as described above, the delivery systems of the ~-16246 :
2~2~962 .
present invention can be comprised of chitosan derivatives prepared by known methods.
Chitosonium polymers suitable for use in the present invention include salts of chitosan prepared with the following acids:
Acetic N-Acetyl-L-cysteine N-Acetyl glycine Acetylsalicylic Adipic L-Aspartic Citric Fumaric 2-Furoic Gallic L-Glutamic Glutaric Glycolic Hydrochloric 4-Hydroxybenzoic Iminodiacetic Itaconic 3-Ketoglutaric DL-Lactic Maleic DL-Malic Malonic Nlcotinic (Nlacin) 2,3-Pyridinedicarboxylic 2-Pyrrolidone-5-carboxylic Pyruvic Salicyclic Succinamic Succinic Sulfanilic Sulfonyldiacetic L-Tartaric Thioacetic Thiolactic Vanillic Combinations of these acids also are suitable.
These salts are readily soluble in water at room temperature, except for the malate, maleate, itaconate, salicylate, fumarate, and succinate salts, which require heating tO about ~5C to effect dissolu-tion, after which they remain soluble. The products from the reaction :
:
; ~ :
, 20209~2 acrylic, citric, gallic, 4-hydroxybenzoic, and vanillic acids, when used alone, are only slightly soluble in water, because the reaction by which the derivative is formed has limited efficiency.
Chitosan derivatives which can be prepared by the above pro-cess include, but are not limited to, chitosonium pyrrolidone carboxylate, chitosonium itaconate, chitosonium niacinate, chitosonium salicylate, chitosonium lactate, chitosonium formate, chitosonium aceeate, chitosonium gallate, chitosonium glutamate, chitosonium maleate, chitosonium succinamate, chitosonium aspartate, chitosonium glycolate, and combinations thereof. Each is suitable for use in the subject invention.
In general, the amount of chitosan derivative employed in the compositions of this invention will vary depending upon the particular pharmaceutical or therapeutic active being delivered, whether diluent is present, the type of additives, and the like. In practice, however, it has been found that a concentration of the chitosan derivative in the composition can range up to about 20, preferably between about 0.05 and 10, weight percent, based on the total weight of the composition.
The delivery systems of the present invention contain pharma-ceutical and therapeutic actives that can be applied topically either singularly or in combination. Examples of these actives include, but are not limited to compounds such as the following:
Anti-inflammatory analgesics such as salicylic acid, salicylate esters and salts, acetylsalicylic acid, diflunisal, acetaminophen, phenylbutazone, oxyphenbutazone, sulf inpyrazone, indomethacin, sulindac, fenoprofen, flurbiprofen, ibuprofen, ketoprofen, naproxen, mefenamic acid, floctafenine, tolmetin, zomepirac, diclofenac, piroxicam, and the like.
Loca~ anaesthetics such as cocaine, benzocaine, tetracaine, lidocaine, bupivacaine, their hydrochloride salts, and the like.
Antibiotic agents such as penicillins, cephalosporins, vancomycin, bacitracin, cycloserine, polymyxins, colistin, nystatin, amphoterlcin B, mupirocim, tetracyclines, chloramphenicol, 2~2~62 erythromycin, neomycin, streptomycin, kanamycin, gentamicin, tobramycin, amikacin, netilmicin, spectinomycin, clindamycin, rifampin, nalidixic acid, flucytosine, griseofulvin, and the like.
Sulf anilamide antibacterial agents such as sulf anilamide, sulfacetamide, sulfadiazine, sulfisoxazole, sulfamethoxazole, trimethoprim, pyrimethamine, and the like.
Antiviral agents such as vidarabine, acyclovir, ribavirin, amantadine hydrochloride, rimantadine, idoxyuridine, interferons, and the like.
Antiseptic agents such as acridine dyes, alcohols, bronopol, chlorhexidine, phenols, hexachlorophene, organic mercurials, organic peroxides, i.e., benzoyl peroxide, quaternary ammonium compounds, and the like.
Vitamin and vitamin defivatives such as Vitamin A, retinol, retinoic acid ~both cis and trans), alpha-tocopherol (Vitamin E), 7-dehydrocholesterol (Vitamin D), Vitamin K, thiamine, riboflavin, niacin, wridoxine, biotin, pantothenic acid, ascorbic acid, choline, inositol, and the like.
Anti-inflammatory corticosteroids such as progesterone, hydroco~tisone, prednisone, fluorocortisone, triamcinolone, dexamethasone, betamethasone, fluocinolone, and the like.
Anti-fungal agents such as miconazole, tolnaftate, naftifine hydrochloride, loceryl, undecylic acid and iB salB, and other hetero-cyclic compounds including morpholine, imidazoles and derivatives thereof.
Vasodilators such as niacin, nicotinate esters and salts, nitro-glycerine, amyl nitrite, prazosln, minoxidil and diazoxide and calcium channel blockers such as nifedipine, diltiazem, indomethacin, and the like.
Gonadal hormones such as gonadotropin-releasing hormone, human chorionic gonadotropin, gonadotropins, 17-beta-estriol, ethinyl estradiol, diethyl stibestrol, norethindrone, norethynodrel, medroxyprogesterone acetate, d-norgestrel, testosterone, .. , . ~
-:
.
202~962 fluoxymesterone, androstenedione, norethandrolone, nandrolone phenpropionate, methylandros~enediol, and the like.
Anti-histamines such as diphenhydramine, chlorpheniramine, chlorcyclizine, promethazine, cimetidine, ranitidine, and the like.
Autacoids such as prostaglandins, prostacyclin, thromboxanes, leukotrienes, angiotensins (captopril), as well as other pharmaceuti-cally active peptides such as serotonin, endorphins, vasopressin, oxytocin, and the like.
Kerolytic agents such as benzoyl peroxide, salicylic acid, trichloroacetic acid, and piroctone, and wart treatment compounds such as salicyclic acid, trichloroacetic acid and lactic acid, singularly or in combination with anti-viral agents.
Anti-diarrhea agents such as bismuth salts (especially the subsalicylate), opium and its derivatives, diphenoxylate, difenoxin, loperamide, nufenoxole, lidamine and the like.
Anti-alopecia agents such as niacin, nicotinate esters and salts, and minoxidil.
Moisturizing agents such as lactic acid, pyrrolidone carboxylic acid, glycolic acid, glycerine, propylene glycol, sorbitol, other alpha-hydroxy carooxylic acids, and various salts of these esters and salts, and the like.
As indicated above, this list of pharmaceutical and therapeutic actives is not inclusive, but is presented merely to demonstrate the scope of the invention. A wide variety of other actives can be employed either alone or in combination.
Glycosaminoglycans (GAGS) comprise a class of polysaccharides that occur in the connective tissue of mammals, and include byaluronic acid, chondroitin su~tate, and heparin, and which can be included in delivery systems of the invention. Some of these polysaccharides, hyaluronic acid in particular, have been used suc-cessfully for wound healing and tissue regeneration in both humans and laboratory animals. The exact mechanism of tissue regeneration is not known, but oligomeric metabolites of N-acetylglucosamines and ~' `~
~' , , -- , - -- ~.
2020~62 glucosamine functionality present in glycosaminoglycans such as hyaluronic acid is present in chitin and chitosan, and similar wound healing and tissue regeneration properties have been reported for chitin and chitosan.
Preferably, hyaluronic acid is added only to delivery systems containing covalent derivatives of chitosan. Hyaluronic acid inter-acts with chitosonium salts and may cause precipitation thereof.
The amount of active employed will be that amount necessary to deliver a pharmaceutically or therapeutically effective amount to achieve the desired result at the site of application. In particular, an effective amount depends, lnter alia, upon the particular active, the severity of the condition, and other factors. In general, the concen-tration of the actives in the delivery systems can vary from as little as 0.001 up to 50 percent or higher, by weight of the delivery system.
More typically, the active concentration is between about 0.01 and 10 wt percent of the delivery system. Skilled practitioners will be able to adjust the quantity of active in the delivery system.
If desired, the delivery systems of this invention can contain one or more pharmaceutically acceptable diluents or vehicles in addi-tion to the chitosan derivative, the active component, and the deliv-ery enhancer. In many instances, the chitosan derivative itself can be about 0.5 to about 20 weight percent of the system with the remain-der being diluent and optionally, other additives. Suitable diluents include among others, water, ethanol, aqueous ethanol, isopropanol, glycerine, din.ethylether, polyethylene glycol, ethoxylated or propoxylated glucose, sorbitol derivatives, and the like.
Additives for the enhanced percutaneous absorption of various pharmaceutical or therapeutic actlves also may be utilized. Such percutaneous enhancers include propylene glycol, glycerol, urea, diethyl sebecate, sorbitan ethoxylates, nicotinate esters (such as hexyl nicotinate), oleic acid, pyrrolidone ~arboxylate esters, (such as dodecyl pyrrolidone carboxylate), N-methyl pyrrolidone, N,N-diethyl-m-toluamide, dimethyl sulfoxide, decyl methyl sulfoxide, ;
- , - , .
2020~2 ah~cyl methyl sulfoxides, N,N-dimethyl formamide, cis-ll-octadecenoic acid, l~odecylazacycloheptan-2-one, and 1,3-dioxacyclopentane or 1,2-dioxacyclohexane containing at least one aliphatic group of four to eighteen carbon atoms.
It has been discovered that incorporation of delivery enhancers into delivery systems of the present invention unexpectedly improves absorption of the active at the application site. Delivery enhancers are useful whenever the active is to be delivered through the stratum corneum. The improved efficiency of delivery can be utilized in a number of ways. For example, it affords the opportunity to deliver, in a topical system, an unexpectedly high concentration of active. A
high concentration of active could be utilized to reduce the number of times the treatment must be applied during a given period. Skilled practitioners recognize other manners of utilizing the unexpected results obtained herein.
Delivery enhancers of the invention preferably are not com-pletely hydrophobic or oleophobic. Rather, they are both hydrophilic and oleophllic to varying degrees. Thus, delivery enhancers of the invention may be at least slightly soluble in aqueous solutions and in a non-aqueous component.
Some delivery enhancers also can act as an emulsifier between the oil phase and the aqueous phase. Addition of such an emulsifying delivery enhancer before the emulsion is formed typically causes the drop size of the oil phase to be smaller. Smaller drop size may con-tribute to increasing delivery efficiency.
The delivery enhancers of the invention are distinct from the above-described percutaneous enhancers. The percutaneous enhanc-ers typically act as humectants, lubricants, softening agents, moistur-izers, debris removers, and impart cleansing and other effects. These enhancers therefore prepare the application site to receive active by ensuring that the site is sof tened, free of debris, and amenable to pen-etration. In contrast, the delivery enhancers of the subject invention do not serve such functions. Rather, the delivery enhancers of the E~-16246 ' ' ' .
. '.
-.
.
-` 2020~62 invention serve to provide a path or bridge through the skin, reduce the hydrophobicity of the skin, or otherwise delivering the active more efficiently.
Benzyl alcohol is a preferred delivery enhancer. Other deliv-ery enhancers include dimethyl sulfoxide and AZONE. In particular, benzyl alcohol is a preferred delivery enhancer for steroids.
Certain compositions serve to further enhance the effect of the delivery enchancers. For example, propylene glycol, described above as a percutaneous enhancer, further improves the delivery of steroids when benzyl alcohol is utilized as a delivery enhancer.
Propylene glycol thus is a preferred percutaneous enhancer in con-junction with benzyl alcohol as a delivery enhancer. Hexylene glycoland cis-octadecen-11-oic acid also are ~ompositions which enhawe delivery.
An example of the unexpected results obtained by using deliv-ery enhancers include delivery of steroid products. It has been dis-covered that benzyl alcohol is an especially suitable delivery enhancer for steroids. In particular, benzyl alcohol may be a delivery enhancer for steroids such as Amcinonide Betamethasone Dipropionate Betamethasone Valerate Clobestasol Propionate Desonide Desoximetasone Diflorasone Diacetate Fluocinolone Fluocinolone Acetonide Fluocinonide Halcinonide Hydrocortisone Hydrocortisone Valerate Mometasone Furoate Triamcinolone Triamcinolone Acetonide Triamcinolone Acetonide USP
Tridesilon Desonide :, ~' ~............................... .
: . .- : . . ~ , .
- . . ~ . ~
. 202~62 The delivery systems of the ,oresent invention are particularly efficient for delivery of steroids. The chitosan salt forms a film over the application site, ensuring that the steroid and delivery enhancer do not migrate and are not removed from the site, e.g., by perspira-tion or contact with clothing. Further, the delivery enhancer, espe-cially benzyl alcohol, promotes efficient introduction of the steroid into the treatmen~ site. This increased efficiency, together with the excellent site protection afforded by the chitosan film which forms over the site, afford the opportunity to deliver to a site an increased quantity of steroid per application. Therefore, instead of requiring three or more applications of steroid daily, as typically is required by known delivery systems, the delivery system of the present invention may be applied only once daily. This decreased application frequency provides several benefits, including increased consumer acceptance and improved treatment derived, inter alia, from an easily understood and executed treatment schedule.
Known methods for topically delivering actives such as steroids typically re~uire repeated applications during a 24-hour period to ensure that a sufficient quantity of active is delivered to the site.
Repeated application is at best inconvenient, and at worst leads to uneven treatment, such as lack of treatment because the scheduled application time fell during a period of sleep, or at a time when appli-cation was impossible.
Repeated application of known topical treatments is necessary because the treatments cannot deliver a sufficient quantity of active in one application, e.g., without feeling greasy or delivering the active at an uneven rate. However, the delivery system of the inven-tion affords an even delivery rate over a long period.
Delivery systems of the invention typically comprise solutions, lotions, dispersions, or oil-in-water emu~sions. Oil-in-water emulsions feel relatively "non-greasy~ when applied, whereas water-in-oil emul-sions tend to have a greasy or oily feel. Therefore, oil-in-water emul-sions are preferred by consumers.
D-162~6 .
;-. ' -- 2020~2 Emulsion-type delivery systems of the invention are made by the lldirectl' method or by the ~inversion~ method. In the lldirectl' method, the oil phase is dispersed into the continuous aqueous phase to form the oil-in-water emulsion directly. An oil-in-water emulsion is made by the ~inversion~ method by emulsifying the aqueous phase into a continuous oil phase. At first, a wate~in-oil emulsion is formed, but, as the quantity of aqueous phase is increased, the emul-sion becomes l'invertedll and forms an oil-in-water emulsion. Either preparation method can be used to prepare emulsion-type delivery systems of the invention.
The delivery enhancer may be part of either fraction of the delivery system. The delivery enhancer may be added tO the system either as part of one of the fractions, or as a separate component after the remainder of the delivery system is formed. In the latter technique, the delivery enhancer is distributed by agitation.
The quantity of delivery enhancers should not exceed the mini-mum quantity which will produce delivery enhancement. Addition of an excess quantity is not economically or therapeutically efficient.
Therefore, the quality of delivery enhancer is up to about 20 wt pe~
cent of the delivery system, preferably between about 0.25 and 10 wt percent, and more preferably between about 0.5 and S wt percent.
In practice, the delivery systems of the invention are readily formulated by mixing a delivery enhancer with a solution or suspen-sion of the chitosan derivative. The active or actives are dissolved or suspended either in the aqueous solution or, if it is present, in a non-aqueous fraction, or in a component of a fraction. For example, a water~oluble active may be incorporated directly into the aqueous fraction or may first be dissolved in a water-soluble non-aqueous com-ponent in which it is soluble, such as propylene glycol or isopropanol.
The non-aqueous fraction then is mixed with a solution or suspension of the desired chitosan derivative. An emulsion is formeci if the non^aqueous fraction is not soluble in the aqueous phase: a suitable ~ emulsifier maybe used. Other adjuvant ingredients such as glycerine, ; ~ D-16246 ~ .
. : :........ , , . . . ~
.
.: , . :
- ~
.
" ' . ~ ' , ' :
.
- 2020~62 propylene glycol, sorbitol, preservatives, steari~ acid, cetyl alcohol, other high molecular weight alcohols, surfactants, menthol, eucalyp-tus oil, other essential oils, fragrances, penetration enhancers, and the like to give stable delivery systems, such as cremes, ointments, lotions, and aerosols, may also be included.
Alternatively, solutions or mixtures of the actives with the chitosan derivatives may be fabricated into films, rods, sheets, sponges, or fibers for use as suppositories, medicated sutures, medi-cated sheets, medicated bandages, patches, and the like.
The following examples are intended to further illustrate the invention, not to limit it in any way. The scope of the lnvention is limited only to the scope of the appended claims.
Example 1 is directed to the preparation of delivery systems of the present invention using derivatives prepared by the acid decrystallization method as well as known derivatives prepared by methods disclosed in the literature. Unless otherwise indicated the solution viscosity of the chitosan polymers is between about 5 and 5000 cP at 1% and 20C, as measured using a Brookfield viscometer model LVT, spindle #2.
EXAMPLES
Throughout the Examples, all parts are parts by weight, unless ~ otherwise identified.
,~ ~ ExamDle 1 This example illustrates various comparative compositions and delivery systems of the invention wherein the active is a steroid.
A solution of triamcinolone acetonide (TA) in propylene glycol was prepared by stirring 0.55 parts TA into 100 parts prowlene glycol for about lS minutes. This solution was utilized in the preparations of this Example. In each case, benzyl alcohol was the delivery enhancer.
A. Lotion-tvDe DeliverY SYstem of the lnvention A delivery system of the invention in the form of a lotion was prepared by blending 20.11 parts of the TA solution, ~ parts of chitosan lactate (viscosity of 1 percent solution is 5 cP), 52.39 parts ~`
, .
.
. ~ ~
., .
, 2~
bolled dlst~ed water ~ olutlon oS chito~an l~ctat~), 20 parto Isopropyl alcohol, and 0.5 parts benzyl alcohol.
B, Emulslon-tvpe Dellverv Svstem ot ehe rnve~tlon A dell~lery system Or the invention usln~ low molecular welght chltosan lactate was prepared in accordance wlth the method of tne invention.
The aqueous phase was prepared by blending 7.02 partS low molecular weight chltosan lactate (vlscos~ty of 1 percent solutlon is 5 cP) in 56.87 parts bo~led distllled water (as solutlon of chltosan lac-tate), together with 20.11 parts or the TA solution. This n~ixture was heated to about 50-55C. then 3.0 parts Myr~ 52 (polyoxyethylene (40) stearate, ICI Amerlcas, ~nc.) was added.
The oll pha~e was prepared by blending 7.5 part~ Prom~g~n D, (cetearyl alcohol, a blend of cetyl alcohol and stearyl alcohol, and c~teareth 20 from Amerchol) 4.0 parts white petrolatum, and 0.5 parts glycerol monostearate. The emulslon then was ~ormed by addin~
the oll phase to the water phase, both at 75C.
The temperature o~ the emulslon was ad~usted to S0C, at which tlme ~.0 part ben2yl aJcohol was added. Aglta~lon was di~con-tlnued after the temperature was decre~sed below 40C.
C. Emulsion-tv~e ~2eliverv S~tstem of the Inventlon A dellvery system ot the invention us~ng both low and high molecu~ar welght chltosan lactates w~s prepare~ by the dlrect method.
The aqueous pha~e was pr~pared ~y mlxlng 10 parts or a 10%
- aqueou~ solutlon ot low molecular welght chitosan lactato (vlscosityof 1 percent solution Is 5 cP) an~ 30 parts ot a 4 percent solutlon ot hlgher molecular weieht chitosan lactate ~viscos~ty Or 1 percent &olu-tlon ~s 230 cP) wlth 20.11 parts ot TA solutlon and 4 parts bollod d~s-tllled water. The temperature or the mixture ~s ad~usted to SSC, and 3 parts Myr~ 52 was added.
The remainder o~ the preparation was as described in Example lB.
;1 ;~
~ . :
, ' -24- 2020~2 D. DeliverY SYstem of the Invention The direct method was utilized to prepare a delivery system of the invention. The aqueous phase was prepared as in Example lC, except that 4 parts water was omitted.
The oil phase was prepared by mixing 7.5 parts Promulgen D, 4.0 parts white petrolatum, O.S parts glycerol monostearate, and S
parts benzyl alcohol.
The oil phase then was emulsified at a temperature of about 75C. Afitation was continued during cooling until the temperature was below about 40C.
* * ~ * J
Each of the delivery systems lA-lD was compared to two commercially-available triamcinolene acetonide products (Aristocort creme and ointment; Lederle Laboratories Div. of American Cyana-mide Co., Wayne, NJ). In two blind tests by an independent labora-tory, Examples lA, lC, and lD scored higher than the commercially-available product. Example lB scored higher in one test.
* ~ ~ ~
Although preferred embodiments of the invention have been discussed herein, those skilled in the art will appreciate that changes and modifications may be made without departing from the spirit of this invention, as defined in and limited only by the scope of the appended claims.
':~
'`
. ' ~ '
Claims (31)
1. A biocompatible, substantive, gas permeable film-form-ing delivery system for delivery of pharmaceutical or therapeutic actives to a desired topical site of a subject, said system comprising at least one pharmaceutical or therapeutic active, at least one aminopolysaccharide selected from the group consisting of chitosonium polymers and covalent chitosan derivatives, and at least one delivery enhancer for delivering the active through the topical site; and wherein said system, after delivery to said site, provides a substantive, gas permeable film from which the actives are available for treatment of said subject at said site.
2. The delivery system of claim 1 wherein said chitosan derivative is a chitosonium polymer.
3. The delivery system of claim 1 wherein said chitosan is a covalent chitosan derivative.
4. The delivery system of claim 1 wherein said chitosan derivative is chitosonium pyrrolidone carboxylate.
5. The delivery system of claim 1 wherein said chitosan derivative is chitosonium niacinate.
6. The delivery system of claim 1 wherein said chitosan derivative is chitosonium itaconate.
7. The delivery system of claim 1 wherein said chitosan derivative is chitosonium salicylate.
8. The delivery system of claim 1 wherein said chitosan derivative is chitosonium lactate.
9. The delivery system of claim 1 wherein said chitosan derivative is chitosonium glycolate.
10. The delivery system of claim 3 wherein said chitosan derivative is blended with hyaluronic acid.
11. The delivery system of claim 1 which contains a phar-maceutically acceptable diluent.
12. The composition of claim 1 which is in the form of a film.
13. The composition of claim 1 which is in the form of a gel.
14. The composition of claim 1 which is in the form of a patch.
15. The composition of claim 1 which is in the form of an aerosol.
16. The composition of claim 1 which is in the form of a suppository.
17. The composition of claim 1 which is in the form of a fibre.
18. The composition of claim 1 which is in the form of a rod.
19. The composition of claim 1 which is in the form of microspheres.
20. The composition of claim 1 which is a device selected from the group of a pad, sponge and suture.
21. The composition of claim 1 which is in the form of a suture.
22. The composition of claim 1 which is in the form of an aqueous solution.
23. The composition of claim 1 which is in the form of a lotion.
24. The composition of claim 1 which is in the form of a suspension or an emulsion.
25. The composition of claim 1 wherein the active com-prises a steroid.
26. The composition of claim 25 wherein the delivery enhancer is benzyl alcohol.
27. The composition of claim 26, further comprising propylene glycol.
28. A method for the preparation of a delivery system for use in the administration of pharmaceutical and therapeutic actives to a topical site of a subject, said method comprising blending at least one pharmaceutical or therapeutic active; at least one chitosan derivative selected from the group con-sisting of chitosonium polymers and chitosan derivatives; and at least one delivery enhancer for delivering the active through the topical site to form a delivery system.
29. The method of claim 28 wherein said chitosan derivative is dissolved in a solvent before blending.
30. The method of claim 28 wherein said active component is dissolved or suspended in a diluent before blending.
31. A method for the topical administration of a pharma-ceutical or therapeutic active to a subject, which comprises adminis-tering to said subject at a designated site, a pharmaceutically or ther-apeutically effective amount of the delivery system of claim 1.
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| US37883489A | 1989-07-12 | 1989-07-12 | |
| US7-378,834 | 1989-07-12 |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CA2020962A1 true CA2020962A1 (en) | 1991-01-13 |
Family
ID=23494719
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CA 2020962 Abandoned CA2020962A1 (en) | 1989-07-12 | 1990-07-11 | Enhanced delivery systems for pharmaceutical or therapeutic actives |
Country Status (1)
| Country | Link |
|---|---|
| CA (1) | CA2020962A1 (en) |
-
1990
- 1990-07-11 CA CA 2020962 patent/CA2020962A1/en not_active Abandoned
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