Note: Descriptions are shown in the official language in which they were submitted.
~ ~ ` 2 ~
EMULSIONS COMPRlSING AMINOPOLYSACCHARIDES
FELD OF THE INVENTION
This invention relates, in general, to novel delivery systems
use~ul for the topical delivery of emulsions which may contain pha~
maceutical or therapeutic actives. In one aspect, this invention
relates to delivery systems containing certain aminopolysaccharides
and derivatives thereof which are effective systems for the delivery
of emulsions which may contain a variety of pharmaceutical and
therapeutic actives. In a further aspect, this invention is directed to
the preparation and use of such systems.
BACKCROUND OF THE INVENTION
Tradinonally, pharmaceutical and therapeutic actives can be
administered to the body by a number of routes, including ingestion,
in~ection, inhalation, and topical application. Absorption of an active
by ingestion, injection, or inhalation generally gives systemic distri~
bution of the active throughout the body. Systemic distribution or
the active ~may be unsatisractory rOr three reasons. First, these
modes Or administration ~produce non-specific distribution. The
active ~s distributed through the entire body and not localized.~ Sec-
ond, there may be undesirable effects such as toxic or irritating reac-
tions on non-target organs or regions. Final~y, to achieve the desired
erlect at the target organ or region, a higher dosage than might oth-
er~rise be desired must be administered to compensate for systemic
dilution of the active.
In contrast to systemic delivery, topical delivery is application
Or~an~aotive in a manner so that it acts primarily at the site of appli-
cation. This type Or application is used typically for dermatological
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disorders. The above-described deficiencies of systemic dellvery are
not encountered when an active is applied topically. Rather, topical
application affords the opportunity to minimize the dosage and con- ~ `
fine the active to the region of the body to which it is applied. Thus,
systemic distribution of the active throughout the body is obviated.
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 membranes and
tissues, such as the hair, skin, eyes, ears, mouth, nose, throat, rec-
tum, vagina, and urethra.
However, despite these advan~ages 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 sub~ect 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 o~ 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 minimize undesir-
abb 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 Sormula-
tions 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 o~ the above-described crite-
ria. For example, a delivery system which does not ensure that the
active efriciently penetrates the application site is not satisfactory
because it requires that an excess of active be incorporated into the
.:
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delivery system to ensure deliverg 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 fite. or to crystallize before it penetrates the site, is
wasted. Further, a delivery system which satisfies each criterion will
be ad~udged 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
comprising emulsions of an aqueous solution of an
aminopGlysaccharide derivative and a non-aqueous phase. The inven-
tion also relates to a method for preparing the delivery systems, to a
method for their application to a subject, and to a method of testing
their substantivity.
The delivery system of the present invention is a
biocompatible, substantive, film-forming system for the delivery of
pharmaceutical or therape~tic actives to a desired topical site of a
subject or host. The system comprises:
A) at least one pharmaceutical or therapeutic active;
B) an aqueous fraction comprtsing at least one
ah~inopolysaccharide derivative selected from the group consisting of
chitosonium polymers and covalent chitosan derivatives; and
C) a non-aqueous fraction which is no~ soluble in the aque-
ous fraction.
The system efflciently!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.
, ' '",
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DET~ILED DESCRIPTION OF THE IN~ENTION
This invention is based on the discovery that a delivery System
for pharmaceutical or therapeutical actives comprising:
A) at least one pharmaceutical or therapeutic active;
B) an aqueous fraction comprising at least one
aminopolysaccharide derivative selected from the group consisting of
chitosonium polymers and covalent chitosan derivatives; and
C) a non-aqueous fraction which is not soluble in the aque-
ous fraction;
is, unexpectedly, substantive to proteinaceous sub-
strates, such as hair, skin, and mucosa.
The aqueous fraction of the delivery system of this invention
encompasses divers aminopolysaccharides, particularly chitosan
derivatives. The non-aqueous fraction encompasses at least one com-
ponent which is not water-soluble so that an emu~sion is formed.
Each fraction can contain other components solub~e therein.
Together, the two fractions possess a variety of useful characteristics
which make these materials superior for the delivery of pharmaceuti-
cal and therapeutic actives.
~ s used throughout the specification and claims, the phrase
~pharmaceuti~al active~' is considered to be a drug, i.e., a substance
which, when applied to or introduced into the body, alters body func-
tions in some way. The phrase ~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 considered a drug. For example, mineral oil does alter
thè skin in at least a cosmeti~ manner or in some cases may be thera-
peutic. Therefore, mineral oil is considered to be a ~Itherapeutic
active" for purpo6es of the present invention.
There are several features which make the delivery systems of
the present invention superior delivery vehicles. In the first
instance, surprisingly, the delivery systems of this invention are sub-
stantive with hair, skin, and mucous membrane. ~hroughout the
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specification and claims, the term l~substantivell 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 appropriate hydrophobic
groups or combinations thereof may be used. Thus, the delivery sys-
tems 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 ~he application site from insult or injury.
Cationically-charged chitosan derivatives exhibit su~stantive
properties to ketatin and other protein 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 106s or migration of the film and the active.
Any two-phase form of the delivery system, such as creme, ointment
spray (aerosol, for examp~e) comprising the two fractions conve-
niently may be utilized to form the subject delivery system.
Application Or an active- and aminopolysaccharide-containing
delivery system whidh forms a film provides uniform distribution of
the active on the eissue and prevents migration or loss of the active
from the site of application. The reservoir of active In the lilm helps
to control the dosage at a constant level, thus controlling the rate of
release. Also, chitosan derivatives which are free of naturally-asso
ciated proteins, heavy metals, and the like, are biocompatible and
~ . .
~ D-16248
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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 of -
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, publlshed 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, salicylic, benzoic, itaconic, malic, nicotinic,
glutamic, aspartic, and thé acid form o~ other amino acids such as
N-acetyl methionine, N-acetyl tyrosine, N-acetyl glycine, N-benzoyl
sefine, and thelike.
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 ~eagents such as
~, -:
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~,
~%~ 8
-- 7 --
ethylene oxide, proWlene oxide, glycidol, alkyl halides (from Cl to
C24), glycidyl triaL~cylammonium salts (alkyl groups from Cl 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
deivative, 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 poly-
mer 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 ?n amount sufficient to protonate the reac-
tivesitesof thedeacetylated aminopolysaccharide; and ! ' ~ ' :
(2) water in an amount up to about 65 weightpercent 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
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(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 decrystallization 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 from
other known methods in several respects. First, 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 soluble before the solu-
tion becomes too viscous to be easily handled. If the solution is fur-
ther diluted to reduce the viscosity, the concentration of chitosan is
reduced even further. The dilute nature of such a solution makes
chemical reaction to derivatize the molecule inefficient and econom-
ically unattractive.
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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 hydrochlo-
ric 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 marfinal 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,
nitrogen, and sulfur. Combinations of such acids also may be utilized.
Pre~erred acids are the mono- and di-carboxylic acids composed of
carbon, hydrogen, oxygen, and nitrogen, which are at least partially
:
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water soluble and biologically and/or pharmaceutically acceptable lor
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, N-acetylglycine, acetylsali-
cylic, fumaric, gallic, glycolic, iminodiacetic, itaconic, DL-lactic,
maleic, DL-malic, methacrylic, 2-pyrrolidone-S-carboxyliC, salicylic,
succinamic, succinic, ascorMc, aspartic, adipic, glutamic, glutaric,
malonic, nicotinic, pyruvic, sulfonyldiacetic, 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 employed include acetone, methanol,
ethanol, n-propanol, isopropanol, tertiary butyl alcohol, acetonitrile,
tetrahydrofuran, dioxane, 2-ethoxyethanol, dimethoxyethane, and the
lilce.
The second component of the diluent medium i6 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 from 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 formation 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.
The sequence of mixing the diluent medium and the
deacetylated chltosan is not critical. However, it has been observed
that excellent results are obtained if the diluent medium is prepared
~162~8
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. . .
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from the water and organic compound together with the acid and
then the chitosan added.
Chitosan, which is a deacetylated form of chitin, has a very
rigid structure, as illustrated in the following formula:
OH . a~
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 to be soluble in water, they
should be prepared from starting materials which have a relatively
large number oI free primary amine groups, i.e., y should be larger
than about 0.5. Preferably, the degree of deacetylation of chitosan
used herein i~ in excess of 60 percent, and more preferably in excess
ot 70 percent. The molecular weight range of chitosan employed in
the present invention can range from about 5000 tO over a million
and more prererably from about 10,000 to about 500,000. Particularly
preferred is chitosan having a! molecular weight of I from about 20~000
to about 250,000.
The above~described mon~ and di-carboxylic acids or other
combinations can be employed in the preparation o~ derivatives of
c~itosan useful in this invention. Thus, derivatives of chitosan suit-
abb for use in the present invention include chitosan salts o~
carboxylic acids (R~COOH) having the formula:
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2 0 L~ ~3 8 1 8
-- 12-
OH ot
(~ ~0
HO~, O~) HO~O~) (II)
Rcoo- 5~ o o.o-o-S
For example, pyrrolidone carboxylic acid (PCA) is an effective mois-
turizing agent which hæ a low order of irritation. Chitosonium
wrrolidone 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 wch as aqueous
isopropanol or other suitable solvent that will dissolve PCA and swell
the chitosan wrrolidone 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 free of its naturally associated proteins, chitin or
chitosan is not antigenic to human tissue, and may be used on or
lnserted under the skin, or placed in contact with body fluids without
harm. Chitin in the body is slowly attacked by lysozyme and is
absorbed. In addition, chitin and chitosan may be safely ingested by
humans, for example, common foods such as bread, beer, wine,
shrimp, cra~s, 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
present invention can be comprised of chitosan derivatives prepared
by known methods.
::
16248
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- 13-
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
Nicotinic (Niacin)
2,3-Pyridinedicarboxylic
2-Pyrrolidone-5-carboxylic .
Pyruvic ~ ~
Salicyclic ~-
Succinamic , ~-
Succinic
Sulfanilic
Sulfonyldiacetic
L-Tartaric ;
Thioacetic
Thiolactic ,~
Vanillic
Com jbinations 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 75C to effect dissolu-
tion, a~ter which they remain soluble. The products from the reaction
; of acrylic, citric, gallic, ~-hydroxybenzoic, and vanillic acids, when
6248
2~2~
. .
- 14--
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 acetate, 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 invention comprise a non-aqueous
fraction which is not soluble in the aqueous fraction. Thus, delivery
systems of the invention are emulsions. The non-aqueous,
water-insoluble phase can be an active agent, e.g., mineral oil. This
phase also may contain an active agent or a dlluent.
The delivery systems of the present invention contain pharma-
ceutical and therapeutic actives that can be applied topically either p
singularly or in combination. Examples of these actives include, but
are not limited to compounds such as the following:
Anti-inflamm?toryj analgesics such as salicylic acid, salicylate
esters and salts, acetylsalicylic acid, ditlunisal, acetaminophen,
phenylbutazone, oxyphenbutazone, sulfinwrazone, indomethacin, -
sulindac, tenoprofen, flurbiprofen, ibuprofen, ketoprofen, naproxen,
mefenamic acid, floctafenine, tolmetin, zomepirac, diclofenac,
piroxicam, and the like.
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Local 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,
amphotericin B, mupirocim, tetracyclines, chloramphenicol, erythro-
mycin, neomycin, streptomycin, kanamycin, gentamicin, tobramycin,
amikacin, netilmicin, spectinomycin, clindamycin, rifampin, nalidixic
acid, flucytosine, griseofulvin, and the like.
Sulfanilamide antibacterial agents such as sulfanilamide,
sulfacetamide, sulfadiazine, sulfisoxazole, sulfamethoxazole,
trimethoprim, wrimethamine, and thelike.
Antiviral agents such as vidarabine, acyclovir, ribavirin,
amantadine hydrochloride, rimantadine, idoxyuridine, interferons, and
the lL~ce.
Antiseptic agents such as acridine dyes, alcohols, bronopol,
chlorhexidine, phenols, hexachlorophene, organic mercuria~s, organic
peroxides, i.e., benzoyl peroxide, quaternary ammonium compounds,
and the like.
Vitamin and vitamin derivatives such as Vitamin A, retinol,
retinoic acid (both cis and trans~, alpha-tocopherol (Vitamin E),
7-dehydrocholesterol (Vitamin D), Vitamin K, thiamine, riboflavin,
niacin, pyridoxine, biotin, pantothenic acid, ascorbic acid, choline,
inositol, and the like.
Anti-inflammatory corticosteroids such as progesterone,
hydrocortisone, prednisone, fluorocortisone, triamcinolone,
dexamethasone, betamethasone, fluocinolone, and the like.
Anti-fungal agents such as miconawle, tolnaftate, naftifine
hydrochloride, loce~, undecylic acid and its salts, and other hetero-
cyclic compounds including morpholine, imidazoles and derivatives
thereof.
VasodlUators such as niacin, nicotinate esters and salts, nitro-
glyoerine, amyl nitrite, prazosin, minoxidil and diazoxide; and calcium
~. ~
16248
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channel blockers such as nifedipine, diltiazem, indomethacin, and the
lil~e.
Gonadal hormones such as gonadotropin-releasing hormone,
human chorionic gonadotropin, gonadotropins, l~-beta~triol, ethinyl
estradiol, diethyl stibestrol, norethindrone, norethynodrel,
medroxyprogesterone acetate, d-norgestrel, testosterone,
fluoxymesterone, androstenedione, norethandrolone, nandrolone
phenpropionate, methylandrostenediol, 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, vaisopressint
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 i -
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.
Steroids such as amcinonide, betamethasone dipropionate,
betamethasone valerate, clobestasol propionate, desonide,
desoximetasone, diflorasone diacetate, fluocino~one, flucinolone
acetonide, fluocinonide, halcinonide, hydrocortisone, hydrocortisone
valerate, mometasone furoate, triamcinolone, triamcinolone
acetonide, triamcinolone acetonide USP, and tridesilon desonide.
Moisturizing agents such as lactic acid, pyrrolidone carboxylic
acid, glycolic acid, glycerine, propylene glycol, sorbitol, other alpha-
hydroxy carboxylic acids, and various salts of these esters and salts,
and the lllce.
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As indicated above, this ~ist 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, such as
permethrin for veterinary applications, can be employed, either alone
or in combination. Similarly, omentum may be delivered by a delivery
system of theinvention.
Omentum products, also known as omental lipid materials, are
found to be useful as cosmetics for skin creams and such for topical
use as sldn softeners having an emollient, softening, and smoothing
effect. Omentum is safe to use in the presence of cuts and abrasions
and in skin conditions such a kertosis and irritations.
Mammalian omental extracts are said to be useful in the soft-
ening, moisturizing, and smoothing of skin, and reduction of calluses
and white spots thereon, and, therefore, useful as a skin cream or
lotion. It is also said to be useful in accelerating the rate of tanning,
thus reducing the time required in the sun tn achieve the tanning
effect. Since such sun exposure is well known to lead to skin condi-
tions such as melanoma or other skin cancers, omentum can be said to
be useful to prevent such conditions.
Omental materials also are said ~o be used in wound healing, as
described above, in angiogenesis for myocardial conditions such as
myocardial infarcts, angina, vascular or coronary inplants,
angioplasty, and bone healing.
Glycasaminoglycans (GAGS) comprise a class oI
polysaccharides that occur in the connective tissue of mammals, and
include hyaluronic acid, chondroitin sulfate, 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-
cess~ully for wound healing and tissue regeneration in both humans
and laboratory animals. The exact mechanism of tissue regenerstion
is not known, but oligomeric metabolites of N-acetylglucosamines and
glucosamine functionality present in glycasaminoglycans such as
hyaluronic acid is present in chitin and chitosan, and similar wound
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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 precipation 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, inter 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 concentration of a pharmaceutical active is
between about 0.01 and 10 wt percent of the delivery system, while
that of a therapeutic active typically is between about 0.1 and 50 pe~
- cent. 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
non-aqueous water-insoluble fraction. In many instances, the
chitosan derivative itself can be about 0.5 to about 20 weight percent
of the system with the remainder being diluent and optionally, other
additives. Suitable diluents include among others, water, ethanol,
aqueous ethanol, isopropanol, glycerine, dimethylether, polyethylene
glycol, ethoxylated or propoxylated glucose, sorbitol derivatives, and
the lL~ce.
I ~Additlves for the enhanced percutaneous absorption of various
ph?rmaceutlcal or therapeutic actives 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 carboxylate esters, (such as
dodecyl wrrolidone carboxylate), N-methyl wrrolidone,
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N,N-diethyl-m-toluamide, dimethyl sulfoxide, decyl methyl sulfoxide,
alkyl methyl sulfoxides, N,N-dimethyl formamide, cis-ll-octadecenoic
acid, l-dodecylazacycloheptan-2-one, and 1,3-dioxacyclopentane or
1,2-dioxacyclohexane containing at least one aliphatic group of four
to eighteen carbon atoms. ;
Incorporation of delivery enhancers into delivery systems of
the present invention improves absorption of the active at the appli-
cation slte. 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 unexpect-
edly 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 fiven period. Skilled practitioners recognize other
manners of utilizing the unexpected results obtained herein.
- Delivery enhancers preferably are not completely hydrophobic
or oleophoblc. Rather, they are both hydrophilic and oleophilic to
varying degrees. Thus, delivery enhancers 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 water-insoluble, non-aqueous fraction and the aqueous fraction.
AWtlon of such an emulsifying delivery enhancer before the emulsion
is formed typically causes the drop size of the oil phase to be sma~er.
Smaller drop size may contribute to increased delivery efficiency.
Benzyl alcohol, dimethyl sulfoxide, and AZONE are suitable.~ ~ ~
Delivery enhancers are distinct f rom the above-described ; ~ -
percutaneous enhancers. The percutaneous enhancers typically act as
humectants, lubricants, softeding agents, moisturizers, debris remov- i- -
ers, and impart cleansing and other effects. ~hese enhancers there- `~ ;
fore prepare the application site to receive active by ensuring that
the site is softened, free of debris, and amenable to penetration. In
contrast, delivery enhancers do not serve such functions. Rather,
delivery enhancers serve to provide a path or bridge through the skin, -
D-162~8
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reduce the hydrophobicity ol the skin, or otherwise deliver the active
more efficiently.
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 also is utilized as a delivery enhancer.
Propylene glycol thus is a preferred percutaneous enhancer in con-
~unction with benzyl alcohol as a delivery enhancer. Hexylene glycol
and cis-octadecen-11-oic acid also are compositions which enhance
delivery.
As defined herein, mineral oil is a therapeutic active, because
it serves as an excellent emollient. However, the oil typically
imparts an unpleasant ~oily~ feeling to the skin if applied directly in a
known delivery system. However, if applied as part of a delivery sys-
tem of the invention, the oily feeling on the skin is not present.
- Delivery systems of the invention also are suitable for veteri-
nary uses, as described above. For example, permethrin insecticide is
delivered together with an emollient by a system of the invention.
Another example of the unexpected results obtained by using a
delivery system of the invention includes delivery of omentum prod-
ucts. Because additional carriers, such as a blend of the benzoates of
C12-Cls alcohols (Fine Solv TN), can be added to the delivery system,
omentum can be delivered more conveniently at concentrations
bigher than those acbieved by known methods.
The delivery systems of the present invention are particularly
efficient. The chitosan salt forms a substantive film over the app11-
catlon site, ensuring that tbe active does not migrate and is not
removed ftom thé s~ite, e.g., by`perspiration or contact with clothing
The excellent site protection prwided by the cbito6an film affords
the opportunity to deliver to a site an incteased quantity of active per
application. Thetefore, instead of tequiring, e.g., three or more
applications daily, as may be utilizeid with known delivery systems,
the delivery system of the present invention may be applied only once
. .
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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 typically
require repeated applications during a 24-hour period to ensure that a
sufficient quantity of active is delivered to the site. Repeated appli-
catian is at best ir.convenient, and at worst leads to uneven treat-
ment, such as lack of treatment because the scheduled application
time fell during a period of sleep, or at a time when application 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 comprise oil-in-water emul-
sions. Oil-in-water emulsions feel relatively ~non-greasy~ when
applied, whereas water-in-oil emulsions tend to have a greasy or oily
feel. Therefore, oil-in-water emulsions are preferred by consumers.
Emulsion-type delivery systems of the invention are made by
the ~direct~ method or by the ~inversion~ method. In the l~directl~
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 water-in-oil emulsion is
formed, but, as the quantity of aqueous pbase is increased, the emul-
sion becomes "inverted" and forms an oil-in-water emulsion. Either
preparation method can be used to prepare emulsion-type delivery
systemsof theinvention.
An active may be part of either fraction of the delivery sys-
tem. The active may be added to the system either as part of one of
the fractions, or as a separate component after the remainder of the
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delivery syseem is formed, In the latter technique, the active is dis-
tributed by agitation. ~,
In practice, the delivery systems of the invention are readily ~ ~ -
formulated by mixing a non-aqueous fraction with a solution or sus-
pension of the chitosan derivative. The active or actives are dis-
solved or suspended in either fraction, in a component of a fraction,
or comprise the fraction, as in the case of an emollient where the
active is mineral oil, a non-aqueous water-insoluble composition. For
example, an active may be incorporated into the aqueous fraction by
first dissolving it in a wate~soluble non-aqueous component, such as
propylene glycol or isopropanol. The non-aqueous fraction is mixed
with a solution or suspension of the desired chitosan derivative. An
emulsion is formed if another non-aqueous fraction is not soluble in
the aqueous phase; a suitable emulsifier may be used. Other adjuvant
ingredients such as glycerine, propylene glycol, sorbitol, preserva-
tives, stearic acid, cetyl alcohol, other high molecular weight
alcohols, surfactants, menthol, eucalyptus 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.
The substantivity of delivery systems of the invention and
other systems is illustrated by ESCA (Electron Spectroscopy for
Chemical Analysis) testing on an artiticial skin substitute to which a
delivery system of the invention is applied. Intormation gathered
from these tests compares tavorably with ESCA testing of the
substantivity of chitosonium lactate solutions with human skin, as
descri!bed herein,! , ,
ESCA is a known technique for qualitative and quantitative
surface analysis for simple compositions of matter, such as whether -
silicone is present on a substrate. Electronspectrochemical analysis ;
has been uti~ized to determine whether hair conditioner builds up on
the surtace of hair. However, the substantivity of many topical deliv-
ery systems cannot be directly determined in this traditional, exterior
' .,
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surface-measuring technique, because the thickness of the film
formed on the skin by delivery systems of the invention may exceed
100 Angstroms. Typically, a maximum depth of about 100 ~ngstroms
can be analyzed by the technique.
It has been discovered that the substantivity of topical prepa-
rations, including films formed by delivery systems of the invention,
can be measured by applying the delivery system to a substrate,
applying tape to the treated area, peeling off the tape, and analyzing
both the material which remains on the substrate (where possible) and
the material which is transferred to the tape. Skilled practitioners
recognize that when testing substantivity on living tissue it is not
possible to test the substrate.
When testing tape is removed from living tissue, the analysis
focuses on the C-O, O-C-O, and quaternary ammonium bonds present
in the chitosonium salt, and the presence of polymer on the tape,
whether at or beneath the surface thereof, illustrates the
substantivity of the polymer. For example, on tests of tapes stripped
from human skin to which a delivery system of the invention has been
applied, the concentration of C-O type carbon (which includes the
O-C-O type) was 8.0 atom-percent on an untreated control, 18.7
atom-percent immediately after treatment, and 13.7 atom percent
after a 24 hour period during which the treatment area had been
washed. Data on the quaternary nitrogen concentration indicated 0.2
atom-percent on the control, 1.1 atom-percent immediately after
treatment, and 0.6 atom-percent after 24 hours.
When an artificial substrate is utilized, it is possible to analyze
the surface of the substrate. Thus, the analysis also focuses on a moi-
ety uniquely present, in~ the substrate. For example, herein, the sub-
strate was a vinyl film containing predominantly polyvinylchloride,
with a small percentage of carboxyl groups, which impart a negative
surface potential to simulate the anionic nature of the skin. There-
fore, chlorine is a moiety present in the substrate but not ~n the deliv-
ery system. Analysis of the tape-stripped surface of the substrate
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will, therefore, be high in chlorine (i.e., approximately equal to the
chlorine concentration in the substrate) if the delivery system has
been completely removed, i.e., is not substantive, and will be lower if
the delivery system is substantive. Further, presence of chitosan
polymer at the surface of both stripped substrate and stripping tape
(note that these surfaces were adjacent before stripping) indicates
that the polymer film itself failed and thus provides further evidence
that the delivery system is substantive.
The following examples are intended to further illustrate the
invention, not to limit it in any way. The scope of the invention is
limited only by the scope of the appended claims.
Examples 1 to 3 are 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. Example 4 illustrates substantivity testing on
both commercially-available emollients and delivery systems of the
invention.
EXAMPLES
Throughout the Examples, all parts are parts by weight, unless
otherwlse identiSied.
ExamDle 1
An emo~ent was made in accordance with the method of the
invention by the direct method of emulsification. The aqueous phase
was prepared by m~cingi 3.18 parts chitosan lactate salt (viscqsity
about 5 cP at 1 percent) in 77 parts water, heating the mixture to ~ ~ -
7SC, then add~u 3 parts Myr~ 52 (polyoxyethylene (40) stearate; ICI
~mericas, Inc.). The non-aqueous phase was a blend of 4 parts light
mineral oil, ~ parts Ceraphyl 424 (myristyl myristate; Van Dyk,
Bellev~e, NJ), S parts stearyl alcohol, and l.S parts Acetulan (an
acetylated lanolin alcohol and cetyl alcohol product from Amerchol).
' ~
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. ...
The non-aqueous phase was emulsified at 75C into the water
phase to form an oil-in-water emulsion. Then, 0.5 parts Cellosize
PCG 10 (hydroxyethyl cellulose, Union Carbide Corp.) was added at
75C and blended with the emulsion for 10 minutes. The emulsion
was cooled to 50C and 1 part benzyl alcohol (preservative) was added
and thoroughly blended into the emulsion.
When applied to human skin, the emollient formed an essen-
tially imperceptible film which was non-greasy and substantive. The
emollient film remained on the skin after the skin was washed under
conditions which essentially completely removed
commercially-available llhand creme~ products.
Examde 2
This example provides a side-by-side comparison of a delivery
system of the invention and an otherwise identical system without a
carrier for the water-insoluble non-aqueous fraction.
- The aqueous phase was a solution of 29 parts of a 7 percent
chitosan lactate (viscosity of 1 percent solution is 5 cP), 12 parts puri-
fied water, and 5.6 parts Tween 80 (surfactant from ICI Americas,
Inc.: polyoxyethylene (20) sorbitan mono-oleate).
The non-aqueous phase of the comparative composition was 50
parts Omentum (a proprie~ary formulation of Angio Medical Corp.,
Van Vuys, CA), and 2.4 parts Span 80 (polyoxyethylene (20) sorbitan
mono-oleate from ICI Americas, ~nc.).
The non-aqueous phase Or the delivery system of the invention
.
was 50 parts Omentum, 2.4 parts Span 80, and 5 parts Fine Solv TN
(benzoate or C12-C15 alcohols; Finetex, Inc., Elmwood Park, NJ). ;
Each emulsion was formed by heating each phase to 75C, then
directly forming the emiJlsioh by adding the non-aqueous phæ to the
aqueous phase with good mixing.
Each emulsion was cooled to 50C and 1 part benzyl alcohol
was added. Equal portions of the delivery system without the carrier
and the deltvery system with the carrier were applied to a human
hand. ~fter 3 minutes, the delivery system without the carrier felt
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greasy and imparted a greasy look to the sldn. Without Fine Solv TN
or an equivalent carrier, at 50 percent Omentum, the system was
cosmetically unpleasant. However, after the same period, the site to
which the delivery system which incorporated a carrier was applied
was non-greasy and both tactilely and visually pleasant.
ExamPle 3
A perme~hrin insecticide intended for veterinary use was made
in accordance with the method of the invention.
One hundred parts of analytical grade isopropyl alcohol con-
taining 5.25 parts of permethrin were added slowly to 369.75 parts of
a 3 percent solution of chitosan wrrolidone carboxylate at a tempera-
ture of 50C. Slow addition, i.e., over a 30-minute period, was neces-
sary to avoid precipitation of the chitosan pyrrolidone carboxylate.
Then, the temperature was raised to 72C.
A mixture of 22.5 parts Promulgen D (cetearyl alcohol, a blend
of cetyl alcohol and stearyl alcohol, and ceteareth 20~ and 2.5 parts
glycerol monwtearate at 80C was emulsified into the chitosan-con-
taining solution. The temperature was reduced to 50C, at which
time 2.5 parts of benzyl alcohol were added. Stirring was continued
until the temperature was about 40C.
This delivery system of the invention was effective as an emol-
lient and permethrin delivery system.
,ExamDle4
To test the substantivity of topica~y-applied su~stances,
including dellvery systems of the invention, a small quantity of sub-
stance is rubbed onto a carboxyl group-containing polyvinylchloride
polymer film, much as it would be applied to the skin by a consumer
The treated substrates were examined both directly after application
of the formulation and after washing the treated area with a 1 per-
cent solution of sodium lauryl sulfate for three minutes, followed by a
ten-minute rinse in running tap water. Several commercially avail-
able emollients were also examined under identical sample prepara-
tion conditions.
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ESCA analyses were performed using a Surface Science Instru-
ments SSX-100 ESCA spectrometer. Analyses were performed on
each sample using a 1 mm diameter analysis area. In most cases, two
analyses from different areas of the samples were performed. All
measured Mnding energies were charge-corrected to the principal Cls
photolectron line at 284.6eV. Angular-resolved measurements were
performed using a tilt stage aceessory supplied by Surface Science
Instruments.
A. Comparison of Delivery
System of the Invention to
Commercial Emollient
A composition of the invention (emollient) comprising
chitosonium lactate and silicone was compared to a fatty acid- and
silicone-containing commercial emollient (COMPLEX 15). The ESCA
data in Table 1 illustrate the presence of the silicone ingredient in
both preparations.
The data in Table 1 illustrate that, for the commercial emol-
lient, no chlorine from the substrate was detected immediately after
application, indicating that the thickness of the emollient exceeded
the 50-100 Angstrom sampling depth of the ESCA technique. The
as-applied system of the invention allowed detection of a small
amount of chloride. However, an angular-resolved ESCA experiment
on this sample (Table 2) showed a smooth decline in the amount of
chlorine detected as the sampling depth was made shallower. This
data indicated that the chlorine observed in the as-applied sample of
the invention was the result of a continuous layer of the delivery
system which was thinner than the sampling depth, rather than a
discontinuous coating. A discontinuous coating, in which bare
patches of substrate were present, would not be expected to show the
smooth decline in chloride concentration.
D-16248
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TABLE 1
SURFACE COMP0SITION: VINYL SUBST ATES
Atom. % -
Sample C Cl O N Si S Other
Control 69.7 19.3 8.4 0.8 1.0 -- 0.9 Na
7 0 .1 17 . 4 9 . 40 . 71.3 -- 1.1 Na
Control 73.6 13.210.9 1.0 1.2
Washed 72.6 13.311.6 1.2 1.2 -- --
COMPLEX lS 56.5 -- 23.0 -- 20.5 --
60.1 -- 20.7 -- 19.1 -- -- -~
COMPLEX lS/ 74.0 14.111.0 -- 0.4 0.3 --
Washed 74.1 14.7 9.8 -- 1.4 -- -- .
Invention 59 . 4 3.520.3 -- 16.9
59.0 5.320.1 -- 15.6 -- --
~:_ Invention 69.2 15.014.0 1.2 0.4 0.2 --
- Washed 65.3 7.621.6 2.9 1.6 O.S Na,Ca
. ~ ,
_ABLE 2
ANGULAR RESOLVED ESCA OF
AS-TREATED SAMPLE OP INVENTION
Angle~ C Cl O Si Other
62.4 7.6 18.4 11.3 0.3~ N
59.9 4.1 19.9 16.1 --
57.3 2.9 22.1 17.7 -- `
Sur~ace s~nsltlvity ln,creases as this angle decreases. -~
The washed samples show radical differences from the
as-applied samples in b~th instances. COMPLEX 15 appeared to be
almost compbtely removed by the wash procedure. The surface
chlotine level rose from nondetectable to slightly above that detected ~ -
on the untreated con~rol vinyl following the wash step. There were
lndications in the carbon high resolution data of possibly some slight ~,~
D~16248
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retention of a fatty acid/ester type material. However, based on the
ESCA data, there was no evidence of substantial retention of any
component of this product by this vinyl substrate.
The situation was demonstrably Wferent in the case Or the
delivery system of the invention. While the silicone component was
again readily removed by the surfactant wash, the chitosonium salt
remained substantive. This conclusion was based on the detection of
the marker functional groups, quaternary ammonium and C-O, on the
washed substrates. As shown in Table 1, relatively high levels of
nitrogen were detected on this sample. More importantly, nitrogen
high resolution spectra clearly showed that the additional nitrogen
observed on the washed treated sample was in the quaternary form.
The nitrogen observed in the high resolution spectra did not show the
expected ratio of quaternary to amide type nitrogen for the
chitosonium polymer. The quaternary form should be the predomi-
nant nitrogen species if all the nitrogen is due to chitosonium. The
data indicate that an aWtional nitrogen species is present, possibly
due to contamination in the wæh procedure. This possibility is sug-
gested by the daea Irom the wæhed vinyl control which also showed a
nitrogen species with~a binding energy similar to that given by the
amide. However, it must be emphasized that this effect in no way
diminishes the ability to conclusively identify the chitosonium since
the quaternary nitrogen series is unique to that molecule.
Further evidence for chitosonium retention was found in the
oxygen content, which also tracked with the nitrogen level as would
be expected for the chitosonium structure, and a carbon high resolu-
tion spectrum, which showed the high level of ether-type ~C-O and
O-C-O) carbonieXpected for"this molecule. The ohlorine level wæ
also inversely related to the nitrogen content, again consistent with
increæed amounts of chitosonium polymer yielding more complete
masking of the substrate. Finally, low levels of sulfur were detected
on both areas of this sample, with a higher sulfur level correlating
with the higher nitrogen level. It seems reasonable tO attribute this
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to residual sulfate surfactant retained by the cationic chitosonium.
Similar retention of sodium dodecylsulfate by cationic cellulosi~s has
been previously documented by ESCA.
Clear evidence for the presence of the polymer was observed
in locations examined. This was particularly noteworthy in compari- ~
son to COMPLEX 15, for which a thicker film of the emollient was ;
initially deposited on the vinyl and yet was readily removed. A very ~ -
thin film (less than 100 Angstrom) of the delivery system of the
invention was initially deposited, yet retention of at least the
chitosonium component of the formulation was achieved, even after
the relatively strenuous washing and rinsing conditions employed.
B. Comparison of Delivery System of the Invention to
Commercial Emollients
A second siloxane- and chitosonium lactate-containing deliv-
ery system (emollient) of the invention was compared to commercial
emollients. The data in Table 3 ~llustrate the results of the test.
TABLE 3
SURPACE COMPOSITION: VINYL SUBSTRATES
Atom ~ Composition
Sample C Cl O N Si S Otber
Control 74.317.5 8.2 -- -- -- -- -
Washed control 71.S18.3 8.7 0.6 0.9 -- --
MOISTUREL 52.1 -- 23.2 -- 24.7 -- --
Washed MOISTUREL 82.7 9.5 6.~0.1 1.-
Wash~d MOISTUREL 79.2 9.2 9.3 -- 2.- -- --
NUTRADERM 86.0 -- 12.6 0.4 -- O.7 0.3~Na
Washed NUTRADERM 72.8 18.7 8.20.2 -- -- -- ~ -
LAC.HYDRIN 83.90.1 1~.7 1.3 -- -- --
Washed LAC.HYDaIN 72.0 20.2 7.8 -- -- -- --
EUCERIN 98.6 -- 1.4 -- -- -- --
Wash~d EUCERIN 99.10.4 0.3 -- 0.2 -- --
Invention 61.20.320.7 -- 17.8 -- --
Washed Inventlon 67.7 0.3 23.2.2 ~.1 2.3 --
10-~ashed Invention 69.10.6 16.0 1.1 2.2 0.7 trace Cu
'
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The high chlorine levels of the washed NUTRADERM and
LAC.HYDRIN samples, which are essentially identical to the washed
control chlorine levels, indicate that neither product is substantive.
The essential absence of chlorine in the as-applied test and the high
chlorine level of the as-washed sample illustrate the initiial presence
and non-substantive nature of the products. It is worth noting that
LAC.HYDRIN does contain a quaternary nitrogen species as a compo-
nent. This species was readily detected on the as-dried surface.
However, in this material, the quaternary nitrogen species is the
ammonium anion which serves as a counterion to an anionic lactate
group. While this cationic ammonium might possibly be expected to
be retained due to ionic interaction with the substrate, it cannot
serve to anchor any component of the formulation. Indeed, the ESCA
data indicated that the washing conditions used in these experiments
were sufficient to remove the ammonium as well.
- EUCERIN was relatively unaffected by the wash procedure
used. EUCERIN is a wate~in-oil ointment which leaves a greasy sur-
face which does not wash off. As can be seen from the data, this
particular material is essentially a hydrocarbon ointment which
resisted the surfactant washing quite well. MOISTUREL showed some
substantivity, as the chlorine content of the washed sample is inter-
mediate those of the as-applied and control samples. As applied, it
gave essentially a pure polydimethylsiloxane surface due to the sili-
cone oil in the formulation. The polydimethylsiloxane was almost
totally removed by the surfactant wash but some component of the
formulation was retained. Therefore, this sample was examined using
the angula~resolved technigue. The results of this analysis (Table 4)
showed enhanced carbon concentration at the immediate surface
indicating that the material retained from this formulation was a
hydrocarbon oil. Petrolatum is the major component of the ~ormula-
tion and, in all ~kelihood, this is the material retained, s1milar to the
hydrocarbon retention observed in the EVCERIN sample.
... .
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TABLE 4 ~:
ANGULAR-RESOLVED ESCA ANALYSIS 0~ WASHED MOISTUREL SAMPLE
Atom
Angle~ C OCl N Si Mg
73.910.5 10.0 0.5 3.31.5
82.2 7.9 7.8 -- 2.1 -- ;: -.
85.1 6.7 5.8 -- 2.3
;`-` '''"'' ;.
~Surface sensitivity increases as this angle decreases.
The chitosonium lactate-containing sample of the invention
was clearly substantive. As in Example 4A, the data from the washed ~-
sample indicated substantial heterogeneity; however, the chitosan
polymer was clearly identified in both areas analyzed. (The washed
sample was visibly heterogeneous as well, with areas of the surface
covered by a white Iilm and others which appeared very clean. The
data in the Table 4 were taken from both regions, with the higher
chlorine content observed in the "cleanl' area of the washed sample.)
The carbon and nitrogen high resolution data from a washed sample
showed the C-O, O-C-O, and quaternary nitrogen groups, including
the expected quaternary-to-amide nitrogen ratio, quite distinctly.
Table S contains data on the compositions of the su~strate
surface and of the tape surface after the su~strate was stripped with
tape as described in the specificaeion.
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TABLE 5
SUR~ACE COMPOSITIONS FOLLOWING TAPE STRIPPING
Atom %
Sample C O Cl Si N Other
Washed MOISTUREL
sample:
Vinyl Interface
Surface 75.1 10.8 11.0 3.2 -- -- :
Tape Interface
Surface 85.3 1~.7 -- --
As Dried Invention : -
sample 4B: : :
Vinyl Interface
Surface 67.2 20.2 0.5 11.~0.8 --
Tape Interface
Surface 59.1 23.6 0.3 17.20.1 --
Washed Invention
~ sample ~B:
- Vinyl Interface
Surface -68.3 21.2 2.9 ~.2 1.8 --
Tape Interface
Surface 69.7 23.~ 0.~ 2.8 2.1 --
Adhesive Tape
Sur~ace 8q.2 15.a -- -- -- --
Tape stripping did not remove a significant amount of the
deposited MOISTUREL components. As noted above, this material is
believed to deposit a hydrocarbon film on the vinyl substrate. Com-
parison of the relative leve~s of carbon and oxygen on the tape sur-
face stripped from the MOISTUREL sample and the control data for
the tape adhesive, surface,alone showed a slight transfer of hydrocar-
bon to the tape. Essentially, therefore, the tape adhesive shows no
ability to remove this film. If only the tape surface were available ~;for analysis, as would be the case for an experiment utilizing a human
subject, no deposition of the material would be detected.
The sample of the invention showed transfer of the siloxane
component to the tape and, as evidenced by the nitrogen detected.
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transfer of some of the chitosonium polymer as well. The presence
of the chitosonium on both interface surfaces was again confirmed by
the high resolution data. The combination of the tape stripping
results with the data on the as-treated substrate (Table 3) of this
sample illustrated that the delivery system of the invention forms a
layered structure upon application, with the chitosonium polymer
present at or near the vinyl interface and the siloxane polymer form-
ing a film over this at the air interface.
The data from the washed sample of the delivery system of the
invention are virtually identical. The only difference is the level of
chlorine detected; this level would be expected to be higher on the
vinyl substrate surface. The chitosonium polymer is readily detected
on both interfaces. The delivery system has such good substantivity
that tape stripping essentially produces cohesive failure within the
deposited chitosonium film. This is dramatically different from the
situation observed on the MOISTUREL sample, and further empha-
sizes the differences not only degrees of retention, but also that this
technique, i.e., the tape stripping method, an effective way to deter- `
mine substantivity on living tissues.
* * * ~ ::
Although particular embodiments of the invention have been
discussed herein, those slcil~ed in the art will appreciate that changes
and modifications may be made without departing from the spirit of
the invention, as defined in and limited only by the scope of the
appended claims.
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