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Title:  Parenteral formulations of a peptide for the treatment of systemic lupus erythematosus
United States Patent: 
7,294,687
Issued: 
November 13, 2007

Inventors: 
Cohen-Vered; Sharon (Kfar Sava, IL), Naftali; Esmira (Rosh HaAyin, IL), Weinstein; Vera (Mevaseret Zion, IL), Gilbert; Adrian (Ra'anana, IL), Klinger; Ety (Tel Aviv, IL)
Assignee: 
TEVA Pharmaceutical Industries, Ltd. (Petach-Tikva, IL)
Appl. No.: 
10/758,572
Filed: 
January 14, 2004


 

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Abstract

The subject invention provides a pharmaceutical composition comprising an aqueous carrier; from 0.1 mg/ml to 20 mg/ml of the composition of a pharmaceutically acceptable salt of a peptide having the structural formula NH.sub.2-Gly Tyr Tyr Trp Ser Trp Ile Arg Gln Pro Pro Gly Lys Gly Glu Glu Trp Ile Gly-COOH; and a substituted .beta.-cyclodextrin in an amount effective to dissolve the peptide in the aqueous carrier, wherein the composition has a pH between 4 and 9, a process for preparation, and a method of alleviating symptoms of systemic lupus erythematosus (SLE) in a human subject comprising administering to the human subject the pharmaceutical composition.

SUMMARY OF INVENTION

The subject invention provides a pharmaceutical composition comprising an aqueous carrier; from 0.1 mg/ml to 20 mg/ml of the composition of a pharmaceutically acceptable salt of a peptide having the structural formula NH.sub.2-Gly Tyr Tyr Trp Ser Trp Ile Arg Gln Pro Pro Gly Lys Gly Glu Glu Trp Ile Gly-COOH (SEQ ID NO:1);and a substituted .beta.-cyclodextrin in an amount effective to dissolve the peptide in the aqueous carrier, wherein the composition has a pH between 4 and 9.

The subject invention also provides a pharmaceutical composition comprising an aqueous carrier; from 0.1 mg/ml to 20 mg/ml of the composition of an acetate salt of a peptide having the structural formula NH.sub.2-Gly Tyr Tyr Trp Ser Trp Ile Arg Gln Pro Pro Gly Lys Gly Glu Glu Trp Ile Gly-COOH (SEQ ID NO:1); and from 70 mg/ml to 170 mg/ml of the composition of hepta-(sulfobutyl ether)-.beta.-cyclodextrin, wherein the peptide and the hepta-(sulfobutyl ether)-.beta.-cyclodextrin are dissolved in the aqueous carrier; and wherein the solution has a pH between 6.5 and 8.5.

The subject invention also provides a method of alleviating symptoms of systemic lupus erythematosus (SLE) in a human subject comprising administering to the human subject any of the above pharmaceutical compositions in an amount effective to alleviate the symptoms of SLE in the human subject.

The subject invention also provides a process for manufacturing the above pharmaceutical composition comprising the steps of: a) preparing a solution of a substituted .beta.-cyclodextrin in an aqueous carrier at a predetermined concentration; b) adding predetermined amount of a pharmaceutically acceptable salt of the peptide NH.sub.2-Gly Tyr Tyr Trp Ser Trp Ile Arg Gln Pro Pro Gly Lys Gly Glu Glu Trp Ile Gly-COOH (SEQ ID NO:1) to the solution of step a); c) adjusting the pH of the solution of step b) until the peptide dissolves in the solution; and d) if necessary, adjusting the pH of the solution of step c) to a pH of 4-9, thereby manufacturing the pharmaceutical composition.

The subject invention also provides a process of lyophilizing the above pharmaceutical composition, comprising the steps of: a) lowering the temperature of the pharmaceutical composition to -40.degree. C.; b) holding the temperature at -40.degree. C. for a predetermined time; c) raising the temperature of the solution to 20.degree. C.; d) holding the temperature at 20.degree. C. for a predetermined time; and e) reducing the pressure to 10 .mu.bar, thereby lyophilizing the pharmaceutical composition.

The subject invention also provides a process of lyophilizing the above pharmaceutical composition, comprising the steps of: a) lowering the temperature of the pharmaceutical composition to -45.degree. C.; b) holding the temperature at -45.degree. C. for a predetermined time; c) raising the temperature of the solution to -20.degree. C.; d) raising the temperature of the solution to 25.degree. C.; and e) holding the temperature at 25.degree. C. for a predetermined time, thereby lyophilizing the pharmaceutical composition.

DETAILED DESCRIPTION OF THE INVENTION

The subject invention provides a pharmaceutical composition comprising an aqueous carrier; from 0.1 mg/ml to 20 mg/ml of the composition of a pharmaceutically acceptable salt of a peptide having the structural formula NH.sub.2-Gly Tyr Tyr Trp Ser Trp Ile Arg Gln Pro Pro Gly Lys Gly Glu Glu Trp Ile Gly-COOH (SEQ ID NO:1); and a substituted .beta.-cyclodextrin in an amount effective to dissolve the peptide in the aqueous carrier, wherein the composition has a pH between 4 and 9.

In one embodiment, the concentration of the acetate salt of the peptide is at least 0.5 mg/ml.

In one embodiment, the concentration of the salt of the peptide is from 0.5 mg/ml to 10 mg/ml.

In another embodiment, the concentration of the salt of the peptide is from 0.5 mg/ml to 2.5 mg/ml.

In another embodiment, the concentration of the salt of the peptide is from 2.5 mg/ml to 5 mg/ml.

In another embodiment, the concentration of the salt of the peptide is from 5 mg/ml to 7 mg/ml.

In another embodiment, the concentration of the salt of the peptide is from 7 mg/ml to 8.5 mg/ml.

In another embodiment, the concentration of the salt of the peptide is from 8.5 mg/ml to 10 mg/ml.

In another embodiment, the concentration of the salt of the peptide is from 9 mg/ml to 10 mg/ml.

In another embodiment, the concentration of the salt of the peptide is from 10 mg/ml to 15 mg/ml.

In another embodiment, the concentration of the salt of the peptide is from 15 mg/ml to 20 mg/ml.

In another embodiment, the concentration of the salt of the peptide is 1.0 mg/ml.

In another embodiment, the concentration of the salt of the peptide is 2.5 mg/ml.

In another embodiment, the concentration of the salt of the peptide is 5 mg/ml.

In another embodiment, the concentration of the salt of the peptide is 10 mg/ml.

In another embodiment, the concentration of the salt of the peptide is 15 mg/ml.

In another embodiment, the concentration of the salt is from 0.1 mg/ml to 0.5 mg/ml.

In another embodiment, the concentration of the salt is from 0.1 mg/ml to 0.2 mg/ml.

In another embodiment, the concentration of the salt is from 0.2 mg/ml to 0.3 mg/ml.

In another embodiment, the concentration of the salt is from 0.3 mg/ml to 0.4 mg/ml.

In another embodiment, the concentration of the salt is from 0.4 mg/ml to 0.5 mg/ml.

In a further embodiment, the composition has a pH between 6.5 and 8.5.

In a further embodiment, the composition has a pH between 7.5 and 8.5.

In a further embodiment, the composition has a pH between 4 and 5.

In a further embodiment, the composition has a pH between 5 and 6.

In a further embodiment, the composition has a pH between 6 and 7.

In a further embodiment, the composition has a pH between 7 and 8.

In a further embodiment, the composition has a pH between 8 and 9.

In another embodiment, the pharmaceutically acceptable salt is an acetate salt.

In another embodiment, the substituted .beta.-cyclodextrin is a hydroxypropyl, a sulfobutyl ether, or a sulfopropyl ether substituted .beta.-cyclodextrin.

In a further embodiment, the substituted .beta.-cyclodextrin is a sulfobutyl ether substituted .beta.-cyclodextrin.

In a further embodiment, the pharmaceutically acceptable salt is an acetate salt, and the substituted .beta.-cyclodextrin is hepta-(sulfobutyl ether)-.beta.-cyclodextrin.

In another embodiment, the composition further comprises a pharmaceutically acceptable buffer in an amount and of a type suitable to make the pH of the pharmaceutical composition in the range of 4-9. The buffer may be acetate buffer, citrate buffer, or sodium carbonate.

The subject invention also provides a pharmaceutical composition comprising an aqueous carrier; from 0.1 mg/ml to 20 mg/ml of the composition of an acetate salt of a peptide having the structural formula NH.sub.2-Gly Tyr Tyr Trp Ser Trp Ile Arg Gln Pro Pro Gly Lys Gly Glu Glu Trp Ile Gly-COOH (SEQ ID NO:1); and from 70 mg/ml to 170 mg/ml of the composition of hepta-(sulfobutyl ether)-.beta.-cyclodextrin, wherein the peptide and the hepta-(sulfobutyl ether)-.beta.-cyclodextrin are dissolved in the aqueous carrier; and wherein the composition has a pH between 6.5 and 8.5.

In one embodiment, the concentration of the acetate salt of the peptide is at least 0.5 mg/ml.

In one embodiment, the concentration of the acetate salt of the peptide is from 0.5 mg/ml to 10 mg/ml.

In a further embodiment, the concentration of the acetate salt of the peptide is from 0.5 mg/ml to 2.5 mg/ml.

In another embodiment, the concentration of the salt is from 0.1 mg/ml to 0.5 mg/ml.

In another embodiment, the concentration of the salt is from 0.1 mg/ml to 0.2 mg/ml.

In another embodiment, the concentration of the salt is from 0.2 mg/ml to 0.3 mg/ml.

In another embodiment, the concentration of the salt is from 0.3 mg/ml to 0.4 mg/ml.

In another embodiment, the concentration of the salt is from 0.4 mg/ml to 0.5 mg/ml.

In another embodiment, the concentration of the salt of the peptide is from 5 mg/ml to 7 mg/ml.

In another embodiment, the concentration of the salt of the peptide is from 7 mg/ml to 8.5 mg/ml.

In another embodiment, the concentration of the salt of the peptide is from 8.5 mg/ml to 10 mg/ml.

In another embodiment, the concentration of the salt of the peptide is from 9 mg/ml to 10 mg/ml.

In another embodiment, the concentration of the salt of the peptide is from 10 mg/ml to 15 mg/ml.

In another embodiment, the concentration of the salt of the peptide is from 15 mg/ml to 20 mg/ml.

In a further embodiment, the concentration of acetate salt of the peptide is 1.0 mg/ml.

In a further embodiment, the concentration of acetate salt of the peptide is 2.5 mg/ml.

In another embodiment, the concentration of the salt of the peptide is 5 mg/ml.

In another embodiment, the concentration of the salt of the peptide is 10 mg/ml.

In another embodiment, the concentration of the salt of the peptide is 15 mg/ml.

In another embodiment, the concentration of hepta-(sulfobutyl ether)-.beta.-cyclodextrin is 120 mg/ml and the pH of the composition is between 7.5 and 8.5.

The subject invention also provides a method of alleviating symptoms of systemic lupus erythematosus (SLE) in a human subject comprising administering to the human subject any of the above pharmaceutical compositions in an amount effective to alleviate the symptoms of SLE in the human subject.

The subject invention also provides the above pharmaceutical compositions for use in treating SLE in a human subject.

The subject invention also provides a process for manufacturing any of the above pharmaceutical compositions comprising the steps of: a) preparing a solution of a substituted .beta.-cyclodextrin in an aqueous carrier at a predetermined concentration; b) adding predetermined amount of a pharmaceutically acceptable salt of the peptide NH.sub.2-Gly Tyr Tyr Trp Ser Trp Ile Arg Gln Pro Pro Gly Lys Gly Glu Glu Trp Ile Gly-COOH (SEQ ID NO:1) to the solution of step a); c) adjusting the pH of the solution of step b) until the peptide dissolves in the solution; and d) if necessary, adjusting the pH of the solution of step c) to a pH of 4-9, thereby manufacturing the pharmaceutical composition.

In one embodiment of the process, the resulting final concentration of the substituted .beta.-cyclodextrin in the pharmaceutical composition is from 70 mg/ml to 170 mg/ml.

In one embodiment of the process, the predetermined concentration of the substituted .beta.-cyclodextrin is such which results in a final concentration of substituted .beta.-cyclodextrin in the pharmaceutical composition of from 80 mg/ml to 170 mg/ml.

In one embodiment of the process, the predetermined concentration of the substituted .beta.-cyclodextrin is such which results in a final concentration of substituted .beta.-cyclodextrin in the pharmaceutical composition of from 90 mg/ml to 170 mg/ml.

In one embodiment of the process, the predetermined concentration of the substituted .beta.-cyclodextrin is such which results in a final concentration of substituted .beta.-cyclodextrin in the pharmaceutical composition of from 100 mg/ml to 170 mg/ml.

In one embodiment of the process, the predetermined concentration of the substituted .beta.-cyclodextrin is such which results in a final concentration of substituted .beta.-cyclodextrin in the pharmaceutical composition of from 110 mg/ml to 170 mg/ml.

In one embodiment of the process, the predetermined concentration of the substituted .beta.-cyclodextrin is such which results in a final concentration of substituted .beta.-cyclodextrin in the pharmaceutical composition of from 120 mg/ml to 170 mg/ml.

In one embodiment of the process, the predetermined concentration of the substituted .beta.-cyclodextrin is such which results in a final concentration of substituted .beta.-cyclodextrin in the pharmaceutical composition of from 130 mg/ml to 170 mg/ml.

In one embodiment of the process, the predetermined concentration of the substituted .beta.-cyclodextrin is such which results in a final concentration of substituted .beta.-cyclodextrin in the pharmaceutical composition of from 140 mg/ml to 170 mg/ml.

In one embodiment of the process, the predetermined concentration of the substituted .beta.-cyclodextrin is such which results in a final concentration of substituted .beta.-cyclodextrin in the pharmaceutical composition of from 150 mg/ml to 170 mg/ml.

In one embodiment of the process, the predetermined concentration of the substituted .beta.-cyclodextrin is such which results in a final concentration of substituted .beta.-cyclodextrin in the pharmaceutical composition of from 160 mg/ml to 170 mg/ml.

In one embodiment of the process, the predetermined concentration of the substituted .beta.-cyclodextrin is such which results in a final concentration of substituted .beta.-cyclodextrin in the pharmaceutical composition is 120 mg/ml.

In another embodiment, the predetermined amount of peptide is such which results in a final concentration of peptide in the pharmaceutical composition is at least 0.1 mg/ml.

In another embodiment, the predetermined amount of peptide is such which results in a final concentration of peptide in the pharmaceutical composition is at least 0.5 mg/ml.

In another embodiment, the predetermined amount of peptide is such which results in a final concentration of peptide in the pharmaceutical composition is 2.5 mg/ml, 2.0 mg/ml, 1.0 mg/ml, 0.5 mg/ml or 0.1 mg/ml.

In another embodiment, the predetermined amount of peptide is such which results in a final concentration of peptide in the pharmaceutical composition is 5 mg/ml, 10 mg/ml or 15 mg/ml.

In another embodiment of the process, step b) further comprises mixing the solution for 1 hour.

In another embodiment, in step c) the pH is adjusted using HCl or NaOH 1.0N.

In another embodiment, the process further comprises filtering the solution of step d) through a cellulose acetate filter.

In another embodiment of the above process, the predetermined concentration of the substituted .beta.-cyclodextrin is such which results in a final concentration of substituted .beta.-cyclodextrin in the pharmaceutical composition is 120 mg/ml; the predetermined amount of peptide is such which results in a final concentration of peptide in the pharmaceutical composition is 2.5 mg/ml, 2.0 mg/ml, 1.0 mg/ml, 0.5 mg/ml or 0.1 mg/ml; step b) further comprises mixing the solution for 1 hour; and in step c) the pH is adjusted using HCl or NaOH 1.0N, and the process further comprises filtering the solution of step d) through a cellulose acetate filter.

The subject invention also provides a composition prepared by the above process.

The subject invention also provides a process of lyophilizing the above pharmaceutical composition, comprising the steps of: a) lowering the temperature of the pharmaceutical composition to -40.degree. C.; b) holding the temperature at -40.degree. C. for a predetermined time; c) raising the temperature of the solution to 20.degree. C.; d) holding the temperature at 20.degree. C. for a predetermined time; and e) holding the temperature at 25.degree. C. for a predetermined time, thereby lyophilizing the pharmaceutical composition.

In one embodiment of the process, step a) is performed within 2 hours.

In another embodiment, step b) is performed within 3 hours.

In a further embodiment, step c) is performed over 13 hours.

In a further embodiment, step c) is performed at a pressure of 110 .mu.bar.

In a further embodiment, step d) is performed over 13 hours.

In a further embodiment, step d) is performed at a pressure of 110 .mu.bar.

In a further embodiment, in step e) the pressure is reduced to 10 .mu.bar.

In a further embodiment, step e) is performed over 5 hours.

In another embodiment of the process, step a) is performed within 2 hours; step b) is performed within 3 hours; step c) is performed over 13 hours and at a pressure of 110 .mu.bar; step d) is performed over 13' hours and at a pressure of 110 .mu.bar; and step e) is performed over 5 hours and the pressure is reduced to 10 .mu.bar.

The subject invention also provides a lyophilized pharmaceutical composition prepared by the above process.

The subject invention also provides a process of lyophilizing the above pharmaceutical composition, comprising the steps of: a) lowering the temperature of the pharmaceutical composition to -45.degree. C.; b) holding the temperature at -45.degree. C. for a predetermined time; c) raising the temperature of the solution to -20.degree. C.; d) raising the temperature of the solution to 25.degree. C.; and e) holding the temperature at 25.degree. C. for a predetermined time, thereby lyophilizing the pharmaceutical composition.

In one embodiment, step a) is performed within 6 hours.

In another embodiment, step b) is performed within 3 hours.

In another embodiment, step c) is performed over 19 hours.

In another embodiment, step c) is performed at a pressure of 150 .mu.bar.

In another embodiment, step d) is performed over 13 hours.

In another embodiment, step d) is performed at a pressure of 150 .mu.bar.

In another embodiment, step e) is performed over 8 hours.

In another embodiment, step e) is performed at a pressure of 150 .mu.bar.

In another embodiment of the process, step a) is performed within 6 hours; step b) is performed within 3 hours; step c) is performed over 19 hours and at a pressure of 150 .mu.bar; step d) is performed over 13 hours and at a pressure of 150 .mu.bar; and step e) is performed over 8 hours and at a pressure of 150 .mu.bar.

The subject invention also provides a lyophilized pharmaceutical composition prepared by any of the above processes.

In one embodiment of the above lyophilized pharmaceutical composition, the water content of the composition is less than 5%.

In another embodiment, the water content of the composition is less than 4.0%.

In another embodiment, the water content of the composition is less then 3.5%.

The subject invention also provides a lyophilized pharmaceutical composition comprising a pharmaceutically acceptable salt of a peptide having the structural formula NH.sub.2-Gly Tyr Tyr Trp Ser Trp Ile Arg Gln Pro Pro Gly Lys Gly Glu Glu Trp Ile Gly-COOH (SEQ ID NO:1); and a substituted .beta.-cyclodextrin.

The subject invention also provides a packaged pharmaceutical composition comprised of: a packaging material; and a predetermined amount of the above lyophilized pharmaceutical composition.

The preparations of the present invention may be given parenterally, topically, or rectally. They are of course given by forms suitable for each administration route. For example, they are administered by injection, inhalation, ointment, suppository, etc. administration by injection, infusion or inhalation; topical by lotion or ointment; and rectal by suppositories.

The phrases "parenteral administration" and "administered parenterally" as used herein means modes of administration other than enteral and topical administration, usually by injection, and includes, without limitation, intravenous, intramuscular, intraarterial, intrathecal, intracapsular, intraorbital, intracardiac, intradermal, intraperitoneal, transtracheal, subcutaneous, subcuticular, intraarticular, subcapsular, subarachnoid, intraspinal and intrasternal injection and infusion.

The phrases "systemic administration," "administered systematically," "peripheral administration" and "administered peripherally" as used herein mean the administration of a compound, drug or other material other than directly into the central nervous system, such that it enters the patient's system and, thus, is subject to metabolism and other like processes, for example, subcutaneous administration.

Details of general formulation procedures and information on additional excipients may be found in Remington: The Science and Practice of Pharmacy, 20.sup.th Edition.
 

Claim 1 of 25 Claims

1. A pharmaceutical composition comprising an aqueous carrier; from 0.1 mg/ml to 2.5mg/ml of the composition of an acetate salt of a peptide having the structural formula NH.sub.2-Gly Tyr Tyr Trp Ser Trp Ile Arg Gln Pro Pro Gly Lys Gly Glu Glu Trp Ile Gly-COOH (SEQ ID NO:1); and from 70 mg/ml to 170 mg/ml of the composition of hepta-(sulfobutyl ether)-.beta.-cyclodextrin or a salt of hepta-(sulfobutyl ether)-.beta.-cyclodextrin, wherein the peptide and the hepta-(sulfobutyl ether)-.beta.-cyclodextrin or a salt of hepta-(sulfobutyl ether)-.beta.-cyclodextrin are dissolved in the aqueous carrier; and wherein the pharmaceutical composition has a pH between 6.5 and 8.5.

____________________________________________
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