United States Patent [19]
`United States Patent [191
`Brode et al. (cid:9)
`Brode et al.
`
`[54] CONTRACEPTIVE COMPOSITIONS
`[54] CONTRACEPTIVE COMPOSITIONS
`
`[75] Inventors: George L. Brode, Bridgewater, N.J.;
`[75] Inventors: George L. Brode, Bridgewater, N.J.;
`Gustavo F- Doncel, Norfolk, Va’;
`Gustavo F. Doncel, Norfolk, Va.;
`Henry L. Gabelnick, N. Bethesda,
`
`Bethesda, Henry L. Gabelnick, Md.; Russell L. Kreeger, Flennngton;
`
`Md.; Russell L. Kreeger, Flemington;
`George A. Salensky, White House
`George A. salensky, white House
`Station’ both of N_]_
`Station, both of N.J.
`
`[73] Assignees: Medical College of Hampton Roads,
`[73] Assignees: Medical College of Hampton Roads,
`Arlington, Va.; Biomaterials
`Arlington, Va.; Biomaterials
`Corporation, Plainsboro, N.J.
`Corporation, Plainsboro, NJ.
`
`(cid:9) (cid:9)
`
`111111111111111111111111111101A1)!!9!p11111111111111111111111111
`HllllllllllllllllllllIlllllllllllllllllllIllllllllllllllllllllllllllllllll
`US00559598OA
`5,595,980
`[11] Patent Number:
`5,595,980
`[11] Patent Number: (cid:9)
`Jan. 21, 1997
`[45] Date of Patent: (cid:9)
`[45] Date of Patent:
`Jan. 21, 1997
`
` 424/433
`4,707,362 11/1987 Nuwayser (cid:9)
`4,707,362 11/1987 Nuwayser ............................. .. 424/433
` 526/200
`4,845,175 7/1989 Lo (cid:9)
`4,845,175
`7/1989 Lo ............ ..
`. 526/200
`5/1990 (cid:9) Partain et al. (cid:9)
` 536/20
`4,929,722
`4,929,722
`5/1990 Pal‘t?in et al- --
`-- 536/20
`8/1990 (cid:9) Partain et al. (cid:9)
` 514/777
`4,946,870
`4,946,870
`8/1990 Partain et a1. ........................ .. 514/777
`FOREIGN PATENT DOCUMENTS
`PATENT
`0189935 8/1986 European Pat. Off. .
`0189935 8/1986 European Pat. O?. .
`2078110 1/1982 United Kingdom .
`2078110
`1/1982 United Kingdom .
`OTHER PUBLICATIONS
`OTHER PUBLICATIONS
`The Elfects of Frequent Nonoxynol-9 Use On The Vaginal
`The Effects of Frequent Nonoxynol-9 Use On The Vaginal
`and Cervical Mucosa Somchai Niruthisard, MD et al., pp.
`and Cervical Mucosa Somchai Nirllthisard, MD et al., pp.
`176-179, 1991.
`176—179, 1991.
`Comparison of Vaginal Tolerance Test of Sperrnicidal Prepa
`Comparison of Vaginal Tolerance Test of Spermicidal Prepa-
`rations in Rabbits and Monkeys P. Eckstein et al., pp. 85-93,
`rations in Rabbits and Monkeys P. Eckstein et al., pp. 85-93,
`1969'
`1969.
`HEC Cellosize Hydroxyethyl Cellulose—Union Carbide
`grcporggggflgs g???“ Cellubse Um“ Carblde
`Corporation, pp. 1-32, 1991.
`
`primary Examiner_Michae1 G_ wityshyn
`Primary Examiner—Michael G. Wityshyn
`Assistant Examiner—Francisco C. Prats
`Assistant Exami"er~Fmn9iSc° C- Prat?
`Attorney, Agent, or Finn—Banner & Witcoff Ltd.
`Atmmey' Agent’ 0’ F‘""—Ba“ner & Wltw? Ltd
`[57]
`ABSTRACT
`ABSTRACT
`[57] (cid:9)
`
`Improved contraceptive compositions are disclosed which
`Improved contraceptive compositions are disclosed which
`comprise a spermicide or virucide, a polymeric delivery
`comprise a spermicide or virucide, a polymeric delivery
`component and optionally a cosmetic ingredient. The
`component and optionally a cosmetic ingredient. The
`improvement is directed to the use of certain hydrophobi-
`improvement is directed to the use of certain hydrophobi
`cally modi?ed polysaccharides as the polymeric delivery
`cally modified polysaccharides as the polymeric delivery
`component. Quite advantageously, the hydrophobically
`component. Quite advantageously, the hydrophobically
`modi?ed polysaccharides of the present invention can alter
`modified polysaccharides of the present invention can alter
`sperm motility. Moreover, the hydrophobically modified
`sperm motility- Moreover, the hydrophobically modi?ed
`polysaccharides can provide reduced irritation potential
`polysaccharides can provide reduced irritation potential
`when used in combination with spermicides such as, for
`when used in combination with spermicides such as, for
`example, nonoxynol-9, which may reduce the potential for
`example, nonoxynol-9, which may reduce the potential for
`infection of sexually transmitted diseases such as HIV and
`infection of sexually transmitted diseases such as HIV and
`herpes_
`herpes.
`
`8 Claims, No Drawings
`8 Claims, No Drawings
`
`[21] App]. No; 418,834
`[21] Appl. No.: 418,884
`
`[22] Filed:
`[22] Filed: (cid:9)
`
`Apr. 7, 1995
`Apr. 7, 1995
`Related US. Application Data
`Related U.S. Application Data
`
`[63] Continuation of Ser. No. 129,253, Sep. 29, 1993, abandoned.
`[63] Continuation of SerNo. 129,253, Sep. 29, 1993, abandoned.
`[51] Int. CI.' (cid:9)
` A61K 31/72
`[51] Int. cl.6 ................................................... .. A61K 31/72
`[52] US. Cl. .
`. 514/57; 514/59; 514/55;
`[52] U.S. Cl.
` 514/57; 514/59; 514/55;
`514/814; 514/843; 514/935; 514/944; 514/945;
`514/814; 514/843; 514/935; 514/944; 514/945;
`536/44; 536/55.l; 536/99; 424/DIG. 14
`536/44; 536/55.1; 536/99; 424/DIG. 14
`[58] Field of Search ................................... .. 514/814, 843,
` 514/814, 843,
`[58] Field of Search (cid:9)
`514/55, 57, 59, 935, 944, 945; 536/99,
`514/55, 57, 59, 935, 944, 945; 536/99,
`44, 55_1; 424/D1G_ 14
`44, 55.1; 424/DIG. 14
`
`[56]
`[56]
`
`References Cited
`References Cited
`
`U.S. PATENT DOCUMENTS
`U'S- PATENT DOCUMENTS
`4,228,277 10/1980 Landoll (cid:9)
` 536/90
`4,228,277 10/1980 Landoll ................................... .. 536/90
` 424/325
`4,242,359 12/1980 Cooper et al. (cid:9)
`4,242,359 12/1980 Cooper et a1. ..... ..
`424/325
`4,284,003 5/1983 Kazmiroski et al. (cid:9)
` 424/341
`4,284,003
`5/1983 Kazmiroski et al.
`424/341
` 424/329
`4,321,277 3/1982 Saurino (cid:9)
`4,321,277
`3/1982 Saurino ......... ..
`424/329
`4,387,094 6/1983 Bagros (cid:9)
` 424/180
`4,337,094
`6/1983 Bagms
`424/130
`4,459,289 7/1984 Maltz (cid:9)
` 424/180
`4,459,289
`7/1984 Maltz ..
`424/180
`4,474,769 10/1984 Smith (cid:9)
` 424/180
`4,474,769 10/1984 Smith .... ..
`424/180
`4,551,148 11/1985 Riley et al. (cid:9)
` 604/890
`4,551,148 ll/1985 Riley et al. ..
`604/890
`4,663,159 5/1987 Brode et al. (cid:9)
` 424/70
`4,663,159
`5/1987 Brode et a1. ............................ .. 424/70
`
`Par Pharm., Inc., et al.
`Exhibit 1009
`Page 001
`
`(cid:9)
`(cid:9)
`

`

`5,595,980
`5,595,980
`
`2
`2
`can be improved. In addition, the improved contraceptive
`can be improved. In addition, the improved contraceptive
`compositions of the present invention are substantive to the
`compositions of the present invention are substantive to the
`mucosal lining of the vagina and can provide a reduced
`mucosal lining of the vagina and can provide a reduced
`degree of vaginal irritation which may lower the risk of
`degree of vaginal irritation which may lower the risk of
`contracting sexually transmitted diseases.
`5 contracting sexually transmitted diseases.
`
`1
`1
`CONTRACEPTIVE COMPOSITIONS
`CONTRACEPTIVE COMPOSITIONS
`
`This invention was made with government support under
`This invention was made with government support under
`Cooperative Agreement DPE-3044-A-00-6063-00 between
`Cooperative Agreement DPE-3044-A-00-6063-00 between
`the United States Agency for International Development and
`the United States Agency for International Development and
`the Medical College of Hampton Roads. The government
`the Medical College of Hampton Roads. The government
`has certain rights in this invention.
`has certain rights in this invention.
`This application is a continuation of application Ser. No.
`This application is a continuation of application Ser. No.
`08/129,253, ?led Sep. 29, 1993, now abandoned.
`08/129,253, filed Sep. 29, 1993, now abandoned.
`
`HELD OF THE INVENTION
`FIELD OF THE INVENTION
`
`The present invention generally relates to contraceptive
`The present invention generally relates to contraceptive
`compositions, and more speci?cally relates to improved
`compositions, and more specifically relates to improved
`contraceptive compositions comprising certain hydrophobi
`contraceptive compositions comprising certain hydrophobi-
`cally modi?ed polysaccharides as polymeric delivery com
`cally modified polysaccharides as polymeric delivery com-
`ponents.
`ponents.
`
`DETAILED DESCRIPTION OF THE
`DETAILED DESCRIPTION OF THE
`INVENTION
`INVENTION
`
`The contraceptive compositions of the present invention
`The contraceptive compositions of the present invention
`are suitable for use in mammals. As used herein, the term
`are suitable for use in mammals. As used herein, the term
`"mammals" means any class of higher vertebrates that
`“mammals” means any class of higher vertebrates that
`nourish their young with milk secreted by mammary glands,
`nourish their young with milk secreted by mammary glands,
`e.g., humans, rabbits and monkeys.
`e.g., humans, rabbits and monkeys.
`The spermicides useful in accordance with the present
`The spermicides useful in accordance with the present
`invention are known to those skilled in the art. Typical
`invention are known to those skilled in the art. Typical
`spermicides include, for example, benzalkonium chloride,
`spermicides include, for example, benzalkonium chloride,
`octoxynol-9, ricinoleic acid, phenol mercuric acetates and
`octoxynol-9, ricinoleic acid, phenol mercuric acetates and
`nonoxynol-9, etc. Nonoxynol-9 and benzalkonium chloride
`nonoxynol-9, etc. Nonoxynol-9 and benzalkonium chloride
`are preferred spermicides for use in accordance with the
`are preferred spermicides for use in accordance with the
`present invention.
`present invention.
`The virucides suitable for use in the contraceptive com-
`The virucides suitable for use in the contraceptive com
`positions of the present invention are known to those skilled
`positions of the present invention are known to those skilled
`in the art. Typical virucides include, for example, acyclovir,
`in the art. Typical virucides include, for example, acyclovir,
`idoxyurnidine, ribavirin, nonoxynol-9, vidarabine and
`idoxyurnidine, ribavirin, nonoxynol-9, vidarabine and
`rimantadine.
`rimantadine.
`Thus, the contraceptive compositions of the present
`Thus, the contraceptive compositions of the present
`invention may typically comprise one or more spermicide or
`invention may typically comprise one or more spermicide or
`one or more virucide or both. Some ingredients such as, for
`one or more virucide or both. Some ingredients such as, for
`example, nonoxynol-9, may function both as spermicide and
`example, nonoxynol-9, may function both as spermicide and
`virucide.
`virucide.
`The total amount of spermicide and virucide, or mixtures
`The total amount of spermicide and virucide, or mixtures
`thereof, will typically range from about 0.1 to 50 weight
`thereof, will typically range from about 0.1 to 50 weight
`percent based on the weight of the contraceptive composi
`percent based on the weight of the contraceptive composi-
`tion. Preferably, the amount of spermicide or virucide
`tion. Preferably, the amount of spermicide or virucide
`employed will be that amount necessary to achieve the
`employed will be that amount necessary to achieve the
`desired spermicidal or virucidal results. Appropriate
`desired spermicidal or virucidal results. Appropriate
`amounts can be determined by those skilled in the art.
`amounts can be determined by those skilled in the art.
`Preferably, the total concentration of the spermicide or
`Preferably, the total concentration of the spermicide or
`virucide, or mixtures thereof, will comprise from about 1 to
`virucide, or mixtures thereof, will comprise from about 1 to
`25 weight percent, and more preferably from about 1 to 5
`25 weight percent, and more preferably from about 1 to 5
`weight percent, based on the weight of the contraceptive
`weight percent, based on the weight of the contraceptive
`composition.
`composition.
`The polymeric delivery components suitable for use in the
`The polymeric delivery components suitable for use in the
`contraceptive compositions of the present invention com-
`contraceptive compositions of the present invention com
`prise one or more hydrophobically modified polysaccharides
`prise one or more hydrophobically modi?ed polysaccharides
`selected from the group consisting of cellulosics and chito-
`selected from the group consisting of cellulosics and chito
`sans. Such polysaccharide starting materials from which the
`sans. Such polysaccharide starting materials from which the
`hydrophobically modi?ed polysaccharides of the present
`hydrophobically modified polysaccharides of the present
`invention can be made are known to those skilled in the art.
`invention can be made are known to those skilled in the art.
`Typical cellulosics include, for example, hydroxyethyl cel
`Typical cellulosics include, for example, hydroxyethyl cel-
`lulose, hydroxypropyl cellulose, methyl cellulose, hydrox
`lulose, hydroxypropyl cellulose, methyl cellulose, hydrox-
`ypropylmethyl cellulose, hydroxyethyl methyl cellulose,
`ypropylmethyl cellulose, hydroxyethyl methyl cellulose,
`and the like. Preferred cellulosics include hydroxyethyl
`and the like. Preferred cellulosics include hydroxyethyl
`cellulose and hydroxypropyl cellulose. Typical chitosans
`cellulose and hydroxypropyl cellulose. Typical chitosans '
`include, for example, the following chitosan salts; chitosan
`include, for example, the following chitosan salts; chitosan
`lactate, chitosan salicylate, chitosan pyrrolidone carboxy
`lactate, chitosan salicylate, chitosan pyrrolidone carboxy-
`late, chitosan itaconate, chitosan niacinate, chitosan formate,
`late, chitosan itaconate, chitosan niacinate, chitosan formate,
`chitosan acetate, chitosan gallate, chitosan glutamate, chi-
`chitosan acetate, chitosan gallate, chitosan glutamate, chi
`tosan maleate, chitosan aspartate, chitosan glycolate and
`tosan maleate, chitosan aspartate, chitosan glycolate and
`quatemary amine substituted chitosan and salts thereof, etc.
`quaternary amine substituted chitosan and salts thereof, etc.
`Chitosan lactate and chitosan pyrrolidone carboxylate and
`Chitosan lactate and chitosan pyrrolidone carboxylate and
`are preferred chitosans. The polymeric delivery component
`are preferred chitosans. The polymeric delivery component
`may comprise mixtures of polysaccharides between classes
`may comprise mixtures of polysaccharides between classes
`of the group, e.g., cellulosics and chitosans, or within a class,
`of the group, e.g., cellulosics and chitosans, or within a class,
`e.g., two cellulosics.
`e.g., two cellulosics.
`
`10
`10
`
`15
`15
`
`20
`
`25
`25
`
`30
`30
`
`35
`35
`
`BACKGROUND OF THE INVENTION
`BACKGROUND OF THE INVENTION
`Contraceptive compositions typically comprise an active
`Contraceptive compositions typically comprise an active
`ingredient, such as, for example, nonoxynol-9, a polymeric
`ingredient, such as, for example, nonoxynol-9, a polymeric
`delivery component for delivering the active ingredient,
`delivery component for delivering the active ingredient,
`such as, for example, hydroxyethyl cellulose or carboxym
`such as, for example, hydroxyethyl cellulose or carboxym-
`ethyl cellulose, cosmetic ingredients, such as, for example,
`ethyl cellulose, cosmetic ingredients, such as, for example,
`water, sorbitol and propylene glycol, and optionally other
`water, sorbitol and propylene glycol, and optionally other
`ingredients, such as, for example, stabilizers, fragrances,
`ingredients, such as, for example, stabilizers, fragrances,
`viscosity adjusters, and the like.
`viscosity adjusters, and the like.
`One important attribute of contraceptive compositions is
`One important attribute of contraceptive compositions is
`that the active ingredients should be effective as a spermi-
`that the active ingredients should be e?ective as a spermi
`cide. In addition, the other ingredients present in the con-
`cide. In addition, the other ingredients present in the con
`traceptive compositions should not interfere with the effec-
`traceptive compositions should not interfere with the effec
`tiveness of the active ingredient. Many existing
`tiveness of the active ingredient. Many existing
`contraceptive compositions possess these properties. How
`contraceptive compositions possess these properties. How-
`ever, such existing contraceptive compositions typically do
`ever, such existing contraceptive compositions typically do
`not have a high degree of substantivity to the mucosal lining
`not have a high degree of substantivity to the mucosal lining
`of the vagina. Moreover, existing polymeric delivery com
`of the vagina. Moreover, existing polymeric delivery com-
`ponents generally do not provide any functional effect with
`ponents generally do not provide any functional effect with
`respect to altering sperm motility.
`respect to altering sperm motility.
`Spermicides such as nonoxynol-9 and benzalkonium 40
`Spermicides such as nonoxynol-9 and benzalkonium
`chloride have been used effectively as active ingredients in
`chloride have been used effectively as active ingredients in
`contraceptive compositions for many years. However, it has
`contraceptive compositions for many years. However, it has
`been found that such ingredients can be irritating to the
`been found that such ingredients can be irritating to the
`mucosal lining of the vagina and cause an increased risk of
`mucosal lining of the vagina and cause an increased risk of
`vaginal irritation. Along with such increased risks of vaginal
`vaginal irritation. Along with such increased risks of vaginal 45
`45
`irritation, there may be increased risks of contracting sexu-
`irritation, there may be increased risks of contracting sexu
`ally transmitted diseases of bacterial, fungal or viral origin,
`ally transmitted diseases of bacterial, fungal or viral origin,
`such as, for example, HIV and herpes.
`such as, for example, HIV and herpes.
`Accordingly, improved contraceptive compositions are
`Accordingly, improved contraceptive compositions are
`desired which are substantive and which can provide a low
`desired which are substantive and which can provide a low
`degree of irritation to the mucosal lining of the vagina. In
`degree of irritation to the mucosal lining of the vagina. In
`addition, improved contraceptive compositions are desired
`addition, improved contraceptive compositions are desired
`wherein polymeric delivery components are provided which
`wherein polymeric delivery components are provided which
`can alter sperm motility.
`can alter sperm motility.
`
`50
`50
`
`55
`55
`
`SUMMARY OF THE INVENTION
`SUMMARY OF THE INVENTION
`
`In accordance with the present invention, improved con-
`In accordance with the present invention, improved con
`traceptive compositions comprising a spermicide or viru
`traceptive compositions comprising a spermicide or vim-
`cide, a polymeric delivery component for the spermicide or 60
`cide, a polymeric delivery component for the spermicide or
`60
`virucide and cosmetic ingredients are provided wherein the
`virucide and cosmetic ingredients are provided wherein the
`polymeric delivery component comprises a hydrophobically
`polymeric delivery component comprises a hydrophobically
`modi?ed polysaccharide. By virtue of the present invention
`modified polysaccharide. By virtue of the present invention
`it is now possible to provide contraceptive compositions
`it is now possible to provide contraceptive compositions
`wherein the polymeric delivery component can enhance
`wherein the polymeric delivery component can enhance 65
`65
`effectiveness of the spermicide. As a result, the overall
`effectiveness of the spermicide. As a result, the overall
`spenrricidal effectiveness of the contraceptive compositions
`spermicidal effectiveness of the contraceptive compositions
`
`Par Pharm., Inc., et al.
`Exhibit 1009
`Page 002
`
`

`

`5,595,980
`5,595,980
`
`4
`
`R5
`R6 —N8 —R8 [A28]
`R7
`
`3
`3
`The hydrophobically modi?ed polysaccharides of the
`The hydrophobically modified polysaccharides of the
`present invention comprise a hydrophobic substituent con-
`present invention comprise a hydrophobic substituent con
`taining a hydrocarbon group having from about 8 to 18
`taining a hydrocarbon group having from about 8 to 18
`carbon atoms, preferably from about 10 to 18 carbon atoms
`carbon atoms, preferably from about 10 to 18 carbon atoms
`and more preferably from about 12 to 15 carbon atoms. The 5
`and more preferably from about 12 to 15 carbon atoms. The
`hydrocarbon group of the hydrophobic substituent may
`hydrocarbon group of the hydrophobic substituent may
`comprise an alkyl or arylalkyl con?guration. As used herein
`comprise an alkyl or arylalkyl configuration. As used herein
`the term "arylalkyl group" means a group containing both
`the term “arylalkyl group” means a group containing both
`aromatic and aliphatic structures. Procedures for hydropho
`aromatic and aliphatic structures. Procedures for hydropho-
`bically modifying the above mentioned polysaccharides are
`bically modifying the above mentioned polysaccharides are
`known to those skilled in the art. See, for example, U.S. Pat.
`known to those skilled in the art. See, for example, U.S. Pat.
`Nos. 4,228,277 issued Oct. 14, 1980 and 4,663,159 issued
`Nos. 4,228,277 issued Oct. 14, 1980 and 4,663,159 issued
`May 5, 1987.
`May 5, 1987.
`The degree of substitution of the hydrophobic substituent
`The degree of substitution of the hydrophobic substituent
`on the polysaccharide is typically from about 0.05 to 0.5,
`on the polysaccharide is typically from about 0.05 to 0.5,
`preferably from about 0.08 to 0.25, more preferably 0.08 to
`preferably from about 0.08 to 0.25, more preferably 0.08 to
`0.16 and most preferably from greater than about 0.11, e.g.,
`0.16 and most preferably from greater than about 0.11, e.g.,
`0.12, to less than 0.16, e.g., 0.15, moles of the hydrophobic
`0.12, to less than 0.16, e.g., 0.15, moles of the hydrophobic
`substituent per mole of polysaccharide. The hydrophobic
`substituent per mole of polysaccharide. The hydrophobic
`substituent may be anionic, cationic, nonionic or amphot-
`substituent may be anionic, cationic, nonionic or amphot
`eric. More than one particular hydrophobic substituent can
`eric. More than one particular hydrophobic substituent can
`be substituted onto the polysaccharide provided that the total
`be substituted onto the polysaccharide provided that the total
`substitution level is within the ranges set forth above.
`substitution level is within the ranges set forth above.
`A preferred hydrophobic substituent is a cationic, quater-
`A preferred hydrophobic substituent is a cationic, quater
`nary, nitrogen-containing radical having the formula:
`nary, nitrogen-containing radical having the formula:
`
`10 (cid:9)
`
`wherein
`wherein
`each R5, R, and R7 are CH3 or C2H5;
`each R5, R6 and R7 are CH3 or CZHS;
`R8 is CH2 CHOHCH2 or CH2CH2; and
`R8 is CH2 CHOHCH2 or CHZCHZ; and
`A2 is a halide ion.
`A2 is a halide ion.
`Preferably, at least one of R5, R6 and R7 are CH3.
`Preferably, at least one of R5, R6 and R7 are CH3.
`Preferably R8 is CH2CHOHCH2. Preferably, A2 is a chloride
`Preferably R8 is CHZCHOHCHZ. Preferably, A2 is a chloride
`anion.
`anron.
`A preferred cationic substituent for chitosans is an ammo-
`A preferred cationic substituent for chitosans is an ammo
`15 nium group containing radical having the formula:
`nium group containing radical having the formula:
`
`M1363 A36)
`NH3e A30
`
`35 (cid:9)
`35
`
`45 (cid:9)
`45
`
`wherein A3 is an organic acid counter ion. Preferably, A3 is
`wherein A3 is an organic acid counter ion. Preferably, A3 is
`20 lactate pyrrolidone carboxylate, acetate or combinations
`lactate pyrrolidone carboxylate, acetate or combinations
`20
`thereof.
`thereof.
`In addition to the above described hydrophobically modi-
`In addition to the above described hydrophobically modi
`?ed polysaccharides, the contraceptive compositions may
`fied polysaccharides, the contraceptive compositions may
`contain other polysaccharides, or derivatives thereof, such
`contain other polysaccharides, or derivatives thereof, such
`as, for example; hydroxyethyl cellulose, carboxymethyl
`25 as, for example; hydroxyethyl cellulose, carboxymethyl
`25
`cellulose, dextran sulfate and hyaluronic acid. Such other
`cellulose, dextran sulfate and hyaluronic acid. Such other
`polysaccharides may or may not be hydrophobically modi-
`polysaccharides may or may not be hydrophobically modi
`fied. Such other polysaccharides, when present in the com-
`?ed. Such other polysaccharides, when present in the com
`position, may comprise from about 0.1 to 25%, based on the
`position, may comprise from about 0.1 to 25%, based on the
`weight of the contraceptive compositions. One preferred
`30 weight of the contraceptive compositions. One preferred
`30
`contraceptive composition in accordance with the present
`contraceptive composition in accordance with the present
`invention comprises a cationic hydrophobically modified
`invention comprises a cationic hydrophobically modified
`hydroxyethyl cellulose in combination with chitosan lactate
`hydroxyethyl cellulose in combination with chitosan lactate
`as the polymeric delivery component.
`as the polymeric delivery component.
`Preferably, the hydrophobically modi?ed polysaccharides
`Preferably, the hydrophobically modified polysaccharides
`of the present invention are water soluble. As used herein,
`of the present invention are water soluble. As used herein,
`the term "water soluble" means that at least 1 gram and
`the term “water soluble” means that at least 1 gram and
`preferably at least 2 grams of the hydrophobically modified
`preferably at least 2 grams of the hydrophobically modi?ed
`polysaccharide are soluble in 100 grams of distilled water at
`polysaccharide are soluble in 100 grams of distilled water at
`40 25° C. and 1 atmosphere. The degree of water solubility can
`25° C. and 1 atmosphere. The degree of water solubility can
`40
`be controlled by varying the amount of ether substitution,
`be controlled by varying the amount of ether substitution,
`hydrophobe substitution and cation substitution on the
`hydrophobe substitution and cation substitution on the
`polysaccharide, the details of which are known to those
`polysaccharide, the details of which are known to those
`skilled in the art.
`skilled in the art.
`The molecular weight of the polysaccharides suitable for
`The molecular weight of the polysaccharides suitable for
`use in accordance with the present invention typically ranges
`use in accordance with the present invention typically ranges
`from about 10,000 to 500,000 grams per gram mole and
`from about 10,000 to 500,000 grams per gram mole and
`preferably ranges from about 20,000 to 200,000 grams per
`preferably ranges from about 20,000 to 200,000 grams per
`gram mole. As used herein, the term "molecular weight"
`gram mole. As used herein, the term “molecular weight”
`5o means weight average molecular weight. Methods for deter-
`means weight average molecular weight. Methods for deter
`50
`mining weight average molecular weight of polysaccharides
`mining weight average molecular weight of polysaccharides
`are known to those skilled in the art. One preferred method
`are known to those skilled in the art. One preferred method
`for determining molecular weight is low angle laser light
`for determining molecular weight is low angle laser light
`scattering. The viscosity of the polysaccharides typically
`scattering. The viscosity of the polysaccharides typically
`55 ranges from about 5 to 5000 centipoise, preferably from
`ranges from about 5 to 5000 centipoise, preferably from
`55
`about 10 to 500 centipoise. Unless otherwise indicated, as
`about 10 to 500 centipoise. Unless otherwise indicated, as
`used herein the term "viscosity" refers to the viscosity of a
`used herein the term “viscosity” refers to the viscosity of a
`2.0 weight percent aqueous solution of the polymer mea-
`2.0 weight percent aqueous solution of the polymer mea
`sured at 25° C. with a Brookfield viscometer. Such viscosity
`sured at 25° C. with a Brook?eld viscometer. Such viscosity
`60 measuring techniques are known to those skilled in the art.
`measuring techniques are known to those skilled in the art.
`60
`Typically, the amount of the polymeric delivery compo-
`Typically, the amount of the polymeric delivery compo
`nent will range from about 0.1 to 99.9 weight percent,
`nent will range from about 0.1 to 99.9 weight percent,
`preferably, from about 0.5 to 50 weight percent and more
`preferably, from about 0.5 to 50 weight percent and more
`preferably from about 1 to 10 weight percent, based on the
`preferably from about 1 to 10 weight percent, based on the
`weight on the contraceptive composition.
`65 weight on the contraceptive composition.
`65
`The balance of the contraceptive compositions of the
`The balance of the contraceptive compositions of the
`present invention, i.e., typically from about 0.1 to 99.8% and
`present invention, i.e., typically from about 0.1 to 99.8% and
`
`R1
`
`R2—N®—R4
`R3
`
`[A181
`
`wherein:
`wherein:
`each R1 and R2 are CH3 or C2H5;
`each R1 and R2 are'CH3 or CZHS;
`R3 is CH2CHOHCH2 or CH2CH2;
`R3 is CHZCHOHCH2 or CHZCHZ;
`R4 is an alkyl or arylalkyl group having about 8 to 18
`R4 is an alkyl or arylalkyl group having about 8 to 18
`carbon atoms; and
`carbon atoms; and
`Al is a halide ion.
`A1 is a halide ion.
`Preferably, R1 and more preferably, both R1 and R2 are
`Preferably, R1 and more preferably, both R1 and R2 are
`CH3. Preferably, R3 is CH2CHOHCH2. Preferably, R4 is
`CH3. Preferably, R3 is CH2CHOHCH2. Preferably, R4 is
`C„H(2n+1), where n is from 8 to 18. An especially preferred
`C,,H(2n+l), where n is from 8 to 18. An especially preferred
`hydrophobic group, i.e., R4 has the formula C12H25. Chlo-
`hydrophobic group, i.e., R4’ has the formula C12H25. Chlo
`rine is a preferred halide ion.
`rine is a preferred halide ion.
`Other preferred hydrophobic substituents include those
`Other preferred hydrophobic substituents include those
`prepared from hydrophobe containing reagents such as
`prepared from hydrophobe containing reagents such as
`glycidyl ethers, e.g., nonylphenylglycidyl ether or dode-
`glycidyl ethers, e.g., nonylphenylglycidyl ether or dode
`cylphenylglycidyl ether, alphaole?n epoxides, e.g., 1,2
`cylphenylglycidyl ether, alphaolefin epoxides, e.g., 1,2
`epoxy hexadecane and their respective chlorohydrins, alkyl
`epoxy hexadecane and their respective chlorohydrins, alkyl
`halides, e.g., dodecylbromide, and mixtures thereof.
`halides, e.g., dodecylbromide, and mixtures thereof.
`The ionic character of the hydrophobically modified
`The ionic character of the hydrophobically modi?ed
`polysaccharides of the present invention is not critical and
`polysaccharides of the present invention is not critical and
`can be anionic, cationic, nonionic or amphoteric. However,
`can be anionic, cationic, nonionic or amphoteric. However,
`cationic polysaccharides are preferred for use in accordance
`cationic polysaccharides are preferred for use in accordance
`with the present invention. Thus, in a preferred aspect of the
`with the present invention. Thus, in a preferred aspect of the
`invention, the polysaccharides are also substituted with an
`invention, the polysaccharides are also substituted with an
`ionic substituent in addition to the hydrophobic substituent.
`ionic substituent in addition to the hydrophobic substituent.
`The amount of ionic substituent typically ranges from about
`The amount of ionic substituent typically ranges from about
`0.05 to 0.9, preferably from 0.10 to 0.25, moles of the ionic
`0.05 to 0.9, preferably from 0.10 to 0.25, moles of the ionic
`substituent per mole of the polysaccharide for cellulosics
`substituent per mole of the polysaccharide for cellulosics
`and preferably from about 0.5 to 0.9 moles of the ionic
`and preferably from about 0.5 to 0.9 moles of the ionic
`substituent per mole of the polysaccharide for chitosan
`substituent per mole of the polysaccharide for chitosan
`derivatives. More than one particular ionic substituent can
`derivatives. More than one particular ionic substituent can
`be substituted onto the polysaccharide provided that the total
`be substituted onto the polysaccharide provided that the total
`substitution level is within the ranges set forth above.
`substitution level is within the ranges set forth above.
`A preferred cationic substituent for cellulosics is a cat-
`A preferred cationic substituent for cellulosics is a cat
`ionic quaternary nitrogen containing radical having the
`ionic quaternary nitrogen containing radical having the
`formula:
`formula:
`
`Par Pharm., Inc., et al.
`Exhibit 1009
`Page 003
`
`

`

`5,595,980
`5,595,980
`
`6
`6
`ably 5 weight percent, for at least one hour, preferably at
`ably 5 weight percent, for at least one hour, preferably at
`least 24 hours. Preferably, there are appropriate levels of the
`least 24