CA2078133A1 - Calcitonin suppository formulations - Google Patents
Calcitonin suppository formulationsInfo
- Publication number
- CA2078133A1 CA2078133A1 CA002078133A CA2078133A CA2078133A1 CA 2078133 A1 CA2078133 A1 CA 2078133A1 CA 002078133 A CA002078133 A CA 002078133A CA 2078133 A CA2078133 A CA 2078133A CA 2078133 A1 CA2078133 A1 CA 2078133A1
- Authority
- CA
- Canada
- Prior art keywords
- polypeptide
- leu
- thr
- gly
- ser
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Abandoned
Links
Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/02—Suppositories; Bougies; Bases therefor; Ovules
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K38/00—Medicinal preparations containing peptides
- A61K38/16—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
- A61K38/17—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
- A61K38/22—Hormones
- A61K38/23—Calcitonins
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
- A61K47/08—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing oxygen, e.g. ethers, acetals, ketones, quinones, aldehydes, peroxides
- A61K47/14—Esters of carboxylic acids, e.g. fatty acid monoglycerides, medium-chain triglycerides, parabens or PEG fatty acid esters
Abstract
Disclosed are rectal and vaginal suppository formulations comprising calcitonin and caprylic acid monoglyceride in a pharmaceutically acceptable suppository vehicle.
Description
W O 91/13601 2 ~ 7 813 3 PCT/US90/01373 , , .
'~ .
.:
CALCITONIN SUPPOSITORY FORMULATIONS
Backqround of the Invention .,' :
., - ,~, . l. Pield of the Inventio~
The present invention relates to a novel method of adminlstering calcltonin to patients and to formulatlons adapted for rectal and vaginal administration. More particularly, the - present invention relates to calcitonin-containing pharmaceutical ~ formulations containing therein caprylic acid monoglyceride which ; promotes absorpt~on of calcitonin and thereby enhances its bioavailability.
.~' .
'~ .
.:
CALCITONIN SUPPOSITORY FORMULATIONS
Backqround of the Invention .,' :
., - ,~, . l. Pield of the Inventio~
The present invention relates to a novel method of adminlstering calcltonin to patients and to formulatlons adapted for rectal and vaginal administration. More particularly, the - present invention relates to calcitonin-containing pharmaceutical ~ formulations containing therein caprylic acid monoglyceride which ; promotes absorpt~on of calcitonin and thereby enhances its bioavailability.
.~' .
2. Desc~i~tion of the Pripr Art ... .
~ he method of administration of pharmaceutlcally active calcitonin is predominantly by injection, although efforts were made in the prior art to use other modes of administration.
While administration by injection is acceptable for short-term therapy, adminlstration by injection to patients in need of long-term calcitonin therapy has serious problems. Not only is it costly to patients to have physicians do the administration for extended periods of time, but ~t is also painful and inconvenient. Nor can calcitonin be given orally to patients since oral administration will result in degradation of calcitonin.
' - - . .. . ,~ . . . .
. : , . ,i. , . . :. : . :
. ; .. : ~ -, , ., . .. : .
. , . ~.. , ,., ., . ~ ', :
wo 9l/l3601 2 0 78 1 ~ 3 PCT/US90/0137-~`
Recently, the prior art has found that calcitonin may also be administered via the rectal route; however, it was also found that certain absorption promoters enhance absorption of calcitonin through the rectal mucosa and as such may be used to advantage in calcitonin suppositories. Absorption promoters that provided increased absorption include certain surface active agents, amino acid derivatives, and certain nonsurfactant adjuvenants, such as, ethylacetoacetate, dimethylethoxymethyl-enemalonate, sodium salicylate and the liXe.
. . ~
, , : .: , : : . . . : . . -:
.
~ ' ' . ~ ' ' ." ' ' ~ ' ' :. ' :
WO 91/13601 2 0 7 8 ~ 3 3 PCT/US90/01373 S~MARy OF THE INVErlTION
This invention relates to a suppository formulation comprising: from about o.ooo4% w/w to about 0.20~ w/w, and preferably from about 0.005% w/w to about 0.05% w~w of calcitonin having a potency of about 25 to 6,000 IU/mg of peptide or higher as hereinafter defined; from about 2.5% w/w to about 50.0% w/w and preferably from about 10% w/w to about 40~ w/w of caprylic acid monoglyceride and a pharmaceutically acceptable suppository vehicle. The invention also relates to a method for increasing the absorption of calcitonin through the rectal and/or vaginal mucosa by utilizing caprylic acid monoglyceride in the suppository formulations. Hereinafter the invention will be described with reference to rectal administration; however, it is to be noted that, vaginal administration is intended to be covered as well.
According to the invention, there is also provided a method for the treatment oS human patients suffering from diseases of hyperparathyroidism, idiopathic hypercalcemia of infancy, Paget's disease, vitamin D intoxication, or osteolytic bone metastases.
Said d~seases are characterized by hypercalcemia and high phosphate concentrations and their treatment is effected by decreasing serum calcium and phosphate concentrations in the blood by rectal application of a calcitonin containing composition to effect control of said diseases by trans~ucosal action.
.
The term calcitonin as used herein ~eans not only ! polypeptides having a structure corresponding to one of the naturally occurring ~.~rmones, and which may be naturally or synthetically produced, but also analogs thereof and related synthetic peptides haYing calcitonin activity.
:. ~ ' ' ' '.' ~ ' ~' ' ' '"' ; ' ~ : . .. ~ , .
WO 91/13601 2 ~ 7 8 1 3 ~ PCT/US90/0137 ~
.~ DETAILED DESCRIPI'ION OF T~E INVENTION
In accordance with the present invention, suppository pharmaceutical formulations are provided in which caprylic acid monoglyceride is incorporated for enhancing the absorption of calcitonin through the rectal mucosa. The composition of the formulations are described hereunder.
:
Calcitonin Calcitonin is a polypeptide hormone involved in the control of calcium metabolism in the body. All known natural calcitonin peptides contain an amino acid sequence of 32 amino acids, of which the seven at the amino terminal end of the peptide chain are held in a cyclic configùration by a sulphur or carbon bridge and the carboxyl terminal residue consists of proline amide. The natural calcitonins include the salmon, eel, bovin, porcine, ovine, rat and human calcitonins. ~he detailed structure within the peptide chain of the hormone varies among different species and while the hormones, and their derivatives and analogues found in various species are of interest for use in the present nvention, salmon calcitonin is of special interest in view of its relatively hydrophobic character and its stability. Salmon calcitonin has the following formula:
H-Cys-Ser-Asn-Leu-Ser-Thr-Cys-Val-Leu-l 2 3 4 5 6 7 8 9 - Gly-Lys-Leu-Ser-Gln-Glu-Leu-His-Lys-Leu-ll 12 13 14 lS 16 17 18 19 Gln-Thr-Tyr-Pro-Arg-Thr-Asn-Thr-Gly-, 20 21 22 23 24 25 26 27 28 Ser-Gly-Thr-pro-NH2 ~'.
W O 91il3601 2 ~ 7 813 ~ pC~r/US90/01373 In ~.S. Pat. Nos. 3,926,93a, 4,062,815, 3,929,758, 4,033,940, 4,336,187, 4,388,235, 4,391,747 and 4,401,593 are disclosed improved synthesis of calcitonins including the salmon calcitonin referred to above.
Human, salmon and porcine calcitonins have been available for therapeutic use for several years. For example, synthetic salmon calcitonin is marXeted by Armour 2harmaceutical Co. under the tradename CALCIMAR in a sterile, lyophilized form reconstitutable for subcutaneous or intravascular injection for the treatment of bone diseases.
.
The level of hypocalcemic activity of calcitonins varies from species to species. Salmon and chicken calcitonin have a potency of about 4,000 to 6,000 MCR (Medical Research Council) U/mg peptide; eel calcitonin about 2,000 to 4,000 MRC U/mg peptide: rat 400 MRC U/mg; while beef, sheep, hog and man about 100 to 200 MRC U/mg peptide.
Calcitonin used by the present invention may be obtained from Armour Pharmaceutical co., from natural sources, or by synthetic routes known in the art. The synthesis can be performed by classical peptide synthesis as well as by solid phase synthesis.
In addition to the above-described calcitonins, the present invention encompasses synthetic calcitonin peptides having biological activity of the same type as those above-desCribed.
Such synthetic calcitonins are disclosed, along with processes for preparation thereof in the following U.S. Pat. Nos.
4,388,235 4,604,23a 4,391,747 4,605,514 4,397,780 4,605,51S
, .: : , ~ W O 91/13601 2 0 7 8 ~ 3 ~ P~/US90/0137--q,401,593 4,606,856 4,414,149 4,622,386 4,444,6~1 4,622,3a7 4,451,395 4,622,3a8 4,469,636 4,632,978 ~,497,731 4,639,509 4,497,732 4,639,510 4,528,132 4,639,511 4,537,716 4,650,854 4,597,900 4,659,804 4,604,236 4,732,969 4,604,237 4,746,728 Synthetic calciton~n analogues disclosed in these patents are incorporated herein by reference as if set out in full herein. This list is not intended to be exhaustive of all U.S.
Patents covering synthetic calcitonin analogues, but is representative of the analogues useful in the present invention;
nor is the invention limited to the compounds disclosed in the listed patents.
. .
In accordance for the foregoing, the following analogues of -~ calcitonin constitute specific active ingredients used in the various suppository formulations of the present invention:
1. Des Asparagine-3-Calcitonins having the structures:
(a) H-Cys-Ser-Leu-Ser-Thr-Cys-Val-Leu-Gly-Lys-Leu-Ser-Gln-Glu-Leu-His-Lys-Leu-Gln-Thr-Tyr-Pro-Arg-Thr-Asn-Thr-Gly-Ser-Gly-Thr-Pro-NH2; and (b) Cys-Ser-Leu-Ser-Thr-cys-Val-Leu-Gly-Lys-Leu-Ser-Gln-Glu-Leu-His-Lys-Leu-Gln-Thr-Tyr-Pro-Arg-Thr-Asp-Val-Gly-Ala-Gly-Thr-Pro-NH2.
' ` WO 9l/13601 2 0 7 ~13 ~ PCT/US90/01373 2. ~16-Alanine] Calcitonins having the following.structures:
(a) cys-ser-Asn-Leu-ser-Thr-cys-val-Leu-Gly-Lys-Leu-Ser-Gln-Glu-Ala-His-Lys-Leu-Gln-Thr-Tyr-Pro-Arg-Thr-Asn-Thr-Gly-Ser-Gly-llhr-Pro-NH2 (Salmon);
-: (b) Cys-Ser-Asn-Leu-Ser-Thr-cys-Val-Leu-Gly-Lys-Leu-Ser-Gln-Glu-Ala-His-Lys-Leu-Gln-Thr-Tyr-pro-Arg-Thr-Asp-val-Gly-Ala-G
Thr-Pro-NH2 (Eel); and (c) Cys-Gly-Asn-Leu-Ser-~hr-Cys-Met-Leu-Gly-Thr-Tyr-Thr-Gln-Asp-Ala-Asn-Lys-Phe-His-Thr-Phe-Pro-Gln-Thr-Ala-Ile-Gly-Val-Gly-Ala-Pro-NH2 (Human~.
.
~ he method of administration of pharmaceutlcally active calcitonin is predominantly by injection, although efforts were made in the prior art to use other modes of administration.
While administration by injection is acceptable for short-term therapy, adminlstration by injection to patients in need of long-term calcitonin therapy has serious problems. Not only is it costly to patients to have physicians do the administration for extended periods of time, but ~t is also painful and inconvenient. Nor can calcitonin be given orally to patients since oral administration will result in degradation of calcitonin.
' - - . .. . ,~ . . . .
. : , . ,i. , . . :. : . :
. ; .. : ~ -, , ., . .. : .
. , . ~.. , ,., ., . ~ ', :
wo 9l/l3601 2 0 78 1 ~ 3 PCT/US90/0137-~`
Recently, the prior art has found that calcitonin may also be administered via the rectal route; however, it was also found that certain absorption promoters enhance absorption of calcitonin through the rectal mucosa and as such may be used to advantage in calcitonin suppositories. Absorption promoters that provided increased absorption include certain surface active agents, amino acid derivatives, and certain nonsurfactant adjuvenants, such as, ethylacetoacetate, dimethylethoxymethyl-enemalonate, sodium salicylate and the liXe.
. . ~
, , : .: , : : . . . : . . -:
.
~ ' ' . ~ ' ' ." ' ' ~ ' ' :. ' :
WO 91/13601 2 0 7 8 ~ 3 3 PCT/US90/01373 S~MARy OF THE INVErlTION
This invention relates to a suppository formulation comprising: from about o.ooo4% w/w to about 0.20~ w/w, and preferably from about 0.005% w/w to about 0.05% w~w of calcitonin having a potency of about 25 to 6,000 IU/mg of peptide or higher as hereinafter defined; from about 2.5% w/w to about 50.0% w/w and preferably from about 10% w/w to about 40~ w/w of caprylic acid monoglyceride and a pharmaceutically acceptable suppository vehicle. The invention also relates to a method for increasing the absorption of calcitonin through the rectal and/or vaginal mucosa by utilizing caprylic acid monoglyceride in the suppository formulations. Hereinafter the invention will be described with reference to rectal administration; however, it is to be noted that, vaginal administration is intended to be covered as well.
According to the invention, there is also provided a method for the treatment oS human patients suffering from diseases of hyperparathyroidism, idiopathic hypercalcemia of infancy, Paget's disease, vitamin D intoxication, or osteolytic bone metastases.
Said d~seases are characterized by hypercalcemia and high phosphate concentrations and their treatment is effected by decreasing serum calcium and phosphate concentrations in the blood by rectal application of a calcitonin containing composition to effect control of said diseases by trans~ucosal action.
.
The term calcitonin as used herein ~eans not only ! polypeptides having a structure corresponding to one of the naturally occurring ~.~rmones, and which may be naturally or synthetically produced, but also analogs thereof and related synthetic peptides haYing calcitonin activity.
:. ~ ' ' ' '.' ~ ' ~' ' ' '"' ; ' ~ : . .. ~ , .
WO 91/13601 2 ~ 7 8 1 3 ~ PCT/US90/0137 ~
.~ DETAILED DESCRIPI'ION OF T~E INVENTION
In accordance with the present invention, suppository pharmaceutical formulations are provided in which caprylic acid monoglyceride is incorporated for enhancing the absorption of calcitonin through the rectal mucosa. The composition of the formulations are described hereunder.
:
Calcitonin Calcitonin is a polypeptide hormone involved in the control of calcium metabolism in the body. All known natural calcitonin peptides contain an amino acid sequence of 32 amino acids, of which the seven at the amino terminal end of the peptide chain are held in a cyclic configùration by a sulphur or carbon bridge and the carboxyl terminal residue consists of proline amide. The natural calcitonins include the salmon, eel, bovin, porcine, ovine, rat and human calcitonins. ~he detailed structure within the peptide chain of the hormone varies among different species and while the hormones, and their derivatives and analogues found in various species are of interest for use in the present nvention, salmon calcitonin is of special interest in view of its relatively hydrophobic character and its stability. Salmon calcitonin has the following formula:
H-Cys-Ser-Asn-Leu-Ser-Thr-Cys-Val-Leu-l 2 3 4 5 6 7 8 9 - Gly-Lys-Leu-Ser-Gln-Glu-Leu-His-Lys-Leu-ll 12 13 14 lS 16 17 18 19 Gln-Thr-Tyr-Pro-Arg-Thr-Asn-Thr-Gly-, 20 21 22 23 24 25 26 27 28 Ser-Gly-Thr-pro-NH2 ~'.
W O 91il3601 2 ~ 7 813 ~ pC~r/US90/01373 In ~.S. Pat. Nos. 3,926,93a, 4,062,815, 3,929,758, 4,033,940, 4,336,187, 4,388,235, 4,391,747 and 4,401,593 are disclosed improved synthesis of calcitonins including the salmon calcitonin referred to above.
Human, salmon and porcine calcitonins have been available for therapeutic use for several years. For example, synthetic salmon calcitonin is marXeted by Armour 2harmaceutical Co. under the tradename CALCIMAR in a sterile, lyophilized form reconstitutable for subcutaneous or intravascular injection for the treatment of bone diseases.
.
The level of hypocalcemic activity of calcitonins varies from species to species. Salmon and chicken calcitonin have a potency of about 4,000 to 6,000 MCR (Medical Research Council) U/mg peptide; eel calcitonin about 2,000 to 4,000 MRC U/mg peptide: rat 400 MRC U/mg; while beef, sheep, hog and man about 100 to 200 MRC U/mg peptide.
Calcitonin used by the present invention may be obtained from Armour Pharmaceutical co., from natural sources, or by synthetic routes known in the art. The synthesis can be performed by classical peptide synthesis as well as by solid phase synthesis.
In addition to the above-described calcitonins, the present invention encompasses synthetic calcitonin peptides having biological activity of the same type as those above-desCribed.
Such synthetic calcitonins are disclosed, along with processes for preparation thereof in the following U.S. Pat. Nos.
4,388,235 4,604,23a 4,391,747 4,605,514 4,397,780 4,605,51S
, .: : , ~ W O 91/13601 2 0 7 8 ~ 3 ~ P~/US90/0137--q,401,593 4,606,856 4,414,149 4,622,386 4,444,6~1 4,622,3a7 4,451,395 4,622,3a8 4,469,636 4,632,978 ~,497,731 4,639,509 4,497,732 4,639,510 4,528,132 4,639,511 4,537,716 4,650,854 4,597,900 4,659,804 4,604,236 4,732,969 4,604,237 4,746,728 Synthetic calciton~n analogues disclosed in these patents are incorporated herein by reference as if set out in full herein. This list is not intended to be exhaustive of all U.S.
Patents covering synthetic calcitonin analogues, but is representative of the analogues useful in the present invention;
nor is the invention limited to the compounds disclosed in the listed patents.
. .
In accordance for the foregoing, the following analogues of -~ calcitonin constitute specific active ingredients used in the various suppository formulations of the present invention:
1. Des Asparagine-3-Calcitonins having the structures:
(a) H-Cys-Ser-Leu-Ser-Thr-Cys-Val-Leu-Gly-Lys-Leu-Ser-Gln-Glu-Leu-His-Lys-Leu-Gln-Thr-Tyr-Pro-Arg-Thr-Asn-Thr-Gly-Ser-Gly-Thr-Pro-NH2; and (b) Cys-Ser-Leu-Ser-Thr-cys-Val-Leu-Gly-Lys-Leu-Ser-Gln-Glu-Leu-His-Lys-Leu-Gln-Thr-Tyr-Pro-Arg-Thr-Asp-Val-Gly-Ala-Gly-Thr-Pro-NH2.
' ` WO 9l/13601 2 0 7 ~13 ~ PCT/US90/01373 2. ~16-Alanine] Calcitonins having the following.structures:
(a) cys-ser-Asn-Leu-ser-Thr-cys-val-Leu-Gly-Lys-Leu-Ser-Gln-Glu-Ala-His-Lys-Leu-Gln-Thr-Tyr-Pro-Arg-Thr-Asn-Thr-Gly-Ser-Gly-llhr-Pro-NH2 (Salmon);
-: (b) Cys-Ser-Asn-Leu-Ser-Thr-cys-Val-Leu-Gly-Lys-Leu-Ser-Gln-Glu-Ala-His-Lys-Leu-Gln-Thr-Tyr-pro-Arg-Thr-Asp-val-Gly-Ala-G
Thr-Pro-NH2 (Eel); and (c) Cys-Gly-Asn-Leu-Ser-~hr-Cys-Met-Leu-Gly-Thr-Tyr-Thr-Gln-Asp-Ala-Asn-Lys-Phe-His-Thr-Phe-Pro-Gln-Thr-Ala-Ile-Gly-Val-Gly-Ala-Pro-NH2 (Human~.
.
3. Des 2-Glycine 8-Des 22-Calcitonins having the structures:
(a) H-Cys-Asn-Leu-Ser-Thr-cys-Gly-Leu- :
Gly-Lys-Leu-Ser-Gln-Glu-Leu-~is-Lys-Leu-Gln-Thr-Pro-Arg-Thr-Asn-Thr-Gly-Ser-Gly-~hr-Pro-NH2 (Salmon); and (b) H-Cys-Asn-Leu-Ser-Thr-cys-Gly-Leu-Gly-Lys-Leu-Ser-Gln-Glu-Leu-His-Lys-Leu-Gln-Thr-Pro-Arg-Thr-~Asp~
Val-Gly-Ala-Gly-Thr-Pro-Nh2 (Eel).
(a) H-Cys-Asn-Leu-Ser-Thr-cys-Gly-Leu- :
Gly-Lys-Leu-Ser-Gln-Glu-Leu-~is-Lys-Leu-Gln-Thr-Pro-Arg-Thr-Asn-Thr-Gly-Ser-Gly-~hr-Pro-NH2 (Salmon); and (b) H-Cys-Asn-Leu-Ser-Thr-cys-Gly-Leu-Gly-Lys-Leu-Ser-Gln-Glu-Leu-His-Lys-Leu-Gln-Thr-Pro-Arg-Thr-~Asp~
Val-Gly-Ala-Gly-Thr-Pro-Nh2 (Eel).
4. Des-13-Serine-Calcitonins haYing the following structures:
(a) Cys-Ser-Asn-Leu-Ser-Thr-cys-Val-Leu-Gly- - -Lys-Leu-Gln-Glu-Leu-His-Lys-Leu-Gln-.
25'~i3~
W O 91/13601 PCT/US90/0137?~
; Thr-Tyr-Pro-Arg-Thr-Asn-Thr-Gly-Ser-Gly-Thr-Pr-NH2;
(b) Cys-Ser-Asn-Le~-Ser-Thr-Cys-Val-Leu-Gly-- Lys-Leu-Gln-Glu-Leu-His-Lys-Leu-Gln-Thr-Tyr-Pro-Arg-Thr-Asp-Val-Gly-Ala-- Gly-Thr-Pro-NH2; and (c) Cys-Gly-Asn-Leu-Ser-Thr-Cys-Met-Leu-Gly-Thr-Tyr-Gln-Asp-Phe-Asn-Lys-Phe-His-The-Phe-Pro-Gln-Thr-Ala-Ile-Gly-Val-Gly-Ala-Pro-NH2.
; 5. Des-2l-~hreonine-Calcitonins having the following structures:
(a) Cys-Ser-Asn-Leu-Ser-Thr-Cys-Val-Leu-Gly-Lys-Leu-Ser-Gln-Glu-Leu-His-Lys-Leu-Gln- :~
. Tyr-Pro-Arg-Thr-Asn-Thr-Gly-Ser-Gly-Thr-Pro-NH2 (Salmon);
(b) Cys-Ser-Asn-Leu-Ser-Thr-Cys-Val-Leu-Gly-Lys-Leu-Ser-Gln-Glu-Leu-His-Lys-Leu-Gln-Tyr-Pro-Arg-Thr-Asp-Val-Gly-Ala-Gly-Thr-Pro-NH2, (Eel); and . .
(c) Cys-Gly-Asn-Leu-Ser-Thr-C!ys-Met-Leu-Gly-Thr-Tyr-Thr-Gln-Asp-Phe-Asn-Lys-Phe-His- :
Phe-Pro-Gln-Thr-Ala-Ile-Gly-Val-Gly-Ala-Pro-NH2 (Human).
WO 91/13601 2 0 7 8 .1~ ~ PCT/US90/01373 ":
:
:
6. [Gly2, Sar3, Gly8, des-Tyr22] Calcitonins having the following structures:
(a) Cys-Gly-Ser-Leu,Ser-Thr-Cys-Gly-LeU-Gly-Lys-Leu-Ser-Gln-Glu-Leu-His-Lys-Leu-Gln-Thr-Pro-Arg-Thr-Asn-Thr-Gly-Ser-Gly-Thr-Pro-NH2: and, (b) Cys Gly-Ser-Leu-Ser-Thr-Cys-Gly-Lue-Gly-Lys-Leu-Ser-Gln-Glu-Leu-His-Lys-Leu-Gln-Thr-Pro-Arg-Thr-Asp-Val-Gly-Ala-Gly-Thr-Pro-NH2 .
7. Des-4-Leucine-calcitonins having the following structures:
(a) Cys-Ser-Asn-Ser-Thr-Cys-Val-Leu-Gly-Lys-Leu-Ser-Gln-Glu-Leu-His-Lys-Leu-Gln-Thr-Tyr-Pro-Arg-Thr-Asn-Thr-Gly-Ser-Gly-Thr-Pro-NH2 (Salmon);
., j (b) Cys-Ser-Asn-Ser-Thr-Cys-Val-Leu-Gly-Lys-Leu-Ser-Gln-Glu-Leu-His-Lys-Leu-Gln-Thr-Tyr-- Pro-Arg-Thr-Asp-Val-Gly-Ala-Gly-Thr-Pro-NH2 (EelJ; and (c) Cys-Gly-Asn-Ser-Thr-Cys-Met-Leu-Gly-Thr-Tyr-Thr-Gln-Asp-Phe-Asn-Lys-Phe-His-Thr-Phe-Pro-Gln-Thr-Ala-Ile-Gly-Val-Gly-Ala-Pro-NH2 (Human).
, ' ~ ' ............. . , -, . . .
WO 91/13601 ~ 3 3 PCT/US90/0137-~
8. Calcieonin-(1-23)-Peptide Amides having the followi~g structures:
.
(a) Cys-Ser-Asn-Leu-Ser-Thr-Cys-Val-Leu-Gly-Lys-Leu-Ser-Gln-Glu-Leu-His-Lys-Leu-Gln-Thr-Tyr-Pro-NH2; and (b) ll R2 Cys-Ser-Asn-Leu-Ser-Thr-Cys-Val-Leu-Gly-Lys-Leu-Ser-Gln-Glu-Leu-His-Lys-Leu-Gln-l'hr-Tyr-Pro-Nli2.
, 9. [Des-l-Aminc,8-Glycine) Calcitonins having the following structures:
~a) Bmp-Ser-Asn-Leu-Ser-Thr-Cys-Gly-Leu-Gly-Lys-Leu Ser-Gln-Glu-Leu-Hls-Lys-Leu-Gln- : -Thr-Tyr-Pro-Arg-Thr-Asn-Thr-Gly-Ser-Gly-Thr-Pro-NH2 (Salmon); and (b) ~mp-Scr-Asn-Leu-Scr-~hr-Cys-Val-Leu-Gly-Lys-Leu-Scr-Gln-Glu-Leu-His-Lys-Leu-Gln-Thr-Tyr-Pro-Arg-Thr-Asp-Val-Gly-Ala-Gly-Thr-Pro-NH2 (Eel).
10. [1,7-Di-Alanine~ Calcitonins having the following structures:
(a) Ala-Ser-Asn-Leu-Ser-Thr-Ala-Val-Leu-Gly-Lys-Leu-Ser-Gln-Glu-Ala-His-Lys-Leu-Gln-Thr-Tyr-Pro-Arg-Thr-Asn-Thr-Gly-Ser-Gly-Thr-Pro-NH2; and - :: .
~` W O 91J13601 2 ~ 7 ~ PC~r/US90/01373 ~' , 11 ' .
`::
.
(b) ~la-Ser-Asn-Leu-Ser-Thr-Ala-Val-Leu-Gly-Lys-Leu-Ser-Gln-Glu-Ala-His-Lys-Leu-Gln-Thr-Tyr-Pro-Arg-Thr-Asp-Val-Gly-Ala-Gly-Thr-Pro-NH2..
11. 8-Methionine Calcitonins having the following structures:
(a) Cys-Ser-Asn-Leu-Ser-Thr-Cys-Met-Leu-Gly-Lys-Leu-Ser-Gln-Glu-Leu-His-Lys-I,eu-Gln-Thr-Tyr-Pro-Arg-Thr-Asn-Thr-Gly-Ser-Gly-Thr-Pro-N~2; and (b) Cys-Ser-Asn-Leu-Ser-Thr-Cys-~et-Leu-; Gly-Lys-Leu-Ser-Gln-Glu-Leu-His-Lys-Leu-Gln-Thr-Tyr-Pro-Arg-Thr-Asp-Val-Gly-Ala-Gly-Thr-Pro-NH2.
12. Des-2-Serine, 3-Asparagine Calcitonins having the following . structures:
(a) Cys-Leu-Ser-Thr-Cys-Val-Leu-Gly-Lys-Leu-Ser-Gln-GlU-Leu-His-Lys-Leu-Gln-Thr-Tyr-Pro-Arg-Thr-Asn-Thr-Gly-Ser-Gly-Thr-Pro-NH2; and . ~
(b) Cys-Leu-Ser-l'hr-Cys-Val-Leu-Gly-Lys-Leu-Scr-Gln-Glu-Leu-His-Lys-Leu-Gln-Thr-Tyr-Pro-Arg-Thr-Asp-Val-Gly-Ala-Gly-Thr-Pro-N~2 -. .
, -~, ~ . ~ . , , :
..
W O 91/13601 2 ~ 7 ~ ~ 3 ~ PCTtUS90/0137-~
.
13. G-seriner Des-l9-Leucine Calcitonins having the following structures:
. (a) Cys-Ser-Asn-Leu-Ser-Ser-Cys-Val-Leu-Gly-Lys-Leu-Ser-Gln-Glu-Leu-His-Lys-Gln-Thr- -Tyr-Pro-Arg-Thr-Asn-Thr-Gly-Ser-Gly-Thr-Pro-NH2; and (b) Cys-Ser-Asn-Leu-ser-Ser-Cys-Val-Leu-Gly-Lys-Leu-Scr-Gln-Glu-Leu-His-Lys-Gln- :~
Thr-Tyr-Pro-Arg-Thr-Asp-Val-Gly-Ala-Gly-Thr-Pro-NH2 14. ~16,19-Di-Alanine] Calcitonins having the following structures: -. _ , (a) Cys-Ser-Asn-Leu-Ser-Thr-CyS-Val-LeU-Gly-Lys-Leu-ser-Gln-Glu-Ala-His-Lys-Ala-Gln-Thr-Tyr Pro-Arg-Thr-Asn-Thr-Gly-Ser-Gly-Thr-Pro-NH2; and (b) Cys-Ser-Asn-Leu-Ser-Thr-Cys-Val-Leu-Gly-.Lys-Leu-Ser-Gln-Glu-Ala-His-Lys-Ala-Gln-Thr-Tyr-Pro-Arg-Thr-Asp-Val-Gly-Ala-Gly-. Thr-Pro-NH2.
, .
15. (l-S-Acetamidomethyl Cysteine, 7-Alanine) Calcitonins havin~
the following structures:
(a) SCH2NH-C(0)-CH3 Cys-Ser-Asn-Leu-Ser-Thr-Ala-Val-LeU-Gly-Lys-Leu-Ser-Gln-Glu-Leu-His-Lys-Leu-Gln-Thr-Tyr-pro-Arg-I~hr-Asn-Thr-Gly-Ser-Gly-Thr-Pro-~H2; and ,. ' ' ''~ '.' -,.,"- '- , ', ' ' ' '-,' ~. ~ WO91/13601 2 ~ 7 ~ ~ 3 ~ PCT/US90/01373 , ~! tb) - SCH2NH-C (O~ -CH3 Cys-Ser-Asn-Leu-Ser-Thr-Ala-Val-Leu-Gly-Lys-Leu-Ser-Gln-Glu-Leu-His-Lys-Leu-Gln-Thr-Tyr-Pro-Arg-Thr-Asp-Val-Gly-Ala-Gly-Thr-pro-NH2 ~ ~
16. Des-l9-Leucine - Calcitonin Analogs having the following structures:
. .
(a) Cy5 -S er-Asn-Leu-Ser-Thr-Cys-Val-Leu-Gly-Lys-Leu-Ser-Gln-Glu-Leu-His-Lys-Gln-Thr-Tyr-Pro-Arg-Thr-Asn-Thr-Gly-Ser-Gly-Thr-Pro-NH2; and (b) Cys-Ser-Asn-Leu-Ser-Thr-Cys-Val-Leu-Gly-Lys-Leu-Ser-Gln-Glu-Leu-His-Lys-Gln-Thr-Tyr-Pro-Arg-Thr-Asp-Val-Gly-Ala-Gly~Thr-Pro-NH2.
17. (Bis-1,7-S-Acetamidomethyl-L-cysteine) Salmon Calcitonins having the following structures: :
(a) 1l 1 . S-CH2-NH-C-CH3 S-CH2-NH-C-CH3 H-Cys-Ser-Asn-Leu-Ser-Thr-Cys-Val-Leu-Gly-Lys-Leu-Ser-Gln-Glu-Leu-His-Lys-Leu-Gln-Thr-Tyr-Pro-Arg-Thr-Asn-Thr-Gly-ser-Gly-Thr-Pro-NH2: and (b) s-cH2-NH-c-cH2 1S-CH2-NH-C-CH3 H-Cys-Ser-Asn-Leu-Ser-Thr-Cys-Val-Leu-Gly-Lys-Leu-Ser-Gln-Glu-Leu-His-Lys-Leu-Gln-Thr-Tyr-Pro-Arg-Thr-Asp-Val-Gly-Ala-Gly-Thr-Pro-NH2.
- .. .- ~ .
. ~ . ~ :
, . :
: : :
``:`
W O 91/13601 2 ~ 7 8 i ~ ~ PCT/US90/0137 -' -a. 8-Glycine, Des-l9-Leucine-Calcitonins having the followin~ -structures:
(a) Cys-Ser-Asn-Le,u-Ser-Thr-Cys-Gly-Leu-Gly-Lys-Leu-Ser-Gln-Glu-Leu-His-Lys-Gln-hr-Tyr-Pro-Arg-Thr-Asn-Thr-Gly-Ser-Gly-Thr-Pro-NH2 (Salmon);
(b) Cys-Ser-Asn-Leu-Ser-Thr-Cys-Gly-Leu-Gly-Lys-Leu-Ser-Gln-Glu-Leu-His-Lys-Gln-Thr-Tyr-Pro-Arg-Thr-Asp-Val-Gly-Ala-Gly-Thr-Pro-NH2 (Eel); and . ~
(c) Cys-Ala-Ser-LPu-Ser-Thr-Cys-Gly-Leu-Gly-Lys-Leu-ser-Gln-Glu-Leu-His-Lys-Gin-; Thr-Tyr-Pro-Arg-Thr-Asp-Val-Gly-Ala-Gly-Thr-Pro-NH2 ~Chicken).
l9. Des-Leul6-Calcitonins having the following str~ctures:
(a) Cys-Ser-Asn-Leu-Ser-Thr-Cys-Val-Leu-Gly-Lys-Leu-Ser-Gln-Glu-~is-Lys-Leu-Gln-Thr-Tyr-Pro-Arg-Thr-Asn-Thr-Gly-Ser-Gly-Thr-Pro-NH2 (Salmon);
(b) Cys-Ser-Asn-Leu-Ser-Thr-cys-Val-Leu-Gly-Lys-Leu-Ser,Gln-Glu-His-Lys-Leu-Gln-Thr-Tyr-Pro-Arg-Thr-Asp-val-Gly-Ala-Gly-Thr-Pro-NH2 (Eel); and -, (c) Cys-Gly-Asn-Leu-Ser-Thr-Cys-Met-Leu-Gly-Thr-Tyr-Thr-Gln-Asp-Asn-Lys-Phe-His-Thr-Phe-Pro-Glu-Thr-Ala-Ile-Gly-Val-Gly-Ala-Pro-NH2 (Human).
.. . . - . , .
- - : ~: . . ............. : -.;: . . .
WO 91/13601 2 Q 7 ~ 1 3 ~ PCT/US90/01373 .
,:
:
20. Leucine22 - Calcitonins having the following structures: -(a) H-Cys-Ser-Asn-Leu-Ser-Thr-Cys-Val-Leu-Gly-Lys-Leu-Ser-Gln-Glu-Leu-His-Lys-Leu-Gln-Thr-Leu-Pro-Arg-Thr-Asn-Thr-Gly-Ser-Gly-Thr-Pro-N~2 (Salmon); and (b) H-Cys-Ser-Asn-Leu-Ser-Thr-Cys-Val-Leu-Gly-Lys-Leu-Ser-Gln-Glu-Leu-His-Lys-Leu-Gln-Thr-Leu-Pro-Arg-Thr-Asp-Val-Gly-Ala-Gly-Thr-Pro-NH2 (Eel).
21. Glycine - 8 Calcitonins having the following structures:
(a) H-Cys-Ser-Asn-Leu-Ser-Thr-Cys-Gly-LeU-Gly-Lys-Leu-Ser-Gln-Glu-Leu-His-Lys-Leu-Gln-Thr-Tyr-- Pro-Arg-Thr-Asn-Thr-Gly-Ser-Gly-Thr-Pro-NH2; and ~b) Cys-Gly-Asn-Leu-Ser-Thr-Cys-Gly-Leu-Gly-Thr-Tyr-Thr-Gln-Asp-Phe-Asn-Lys-Phe-His-Thr-Phe-Pro-Gln-lhr-Ala-Ile-Gly-Val-Gly-Ala-Pro-N~32.
22. Glycine8-D-Arginine24 Calcitonins having the following stuctures:
(a) H-Cys-Ser-Asn-Leu-Ser-Thr-Cys-Gly-Leu-Gly-Lys-Leu-Ser-Gln-Glu-Leu-His-Lys-Leu-Gln-Thr-Tyr-Pro-D-Arg-Thr-Asn-Thr-Gly-Ser-Gly-Thr-Pro-NH2 (Salmon): and-(b) H-Cys-Ser-Asn-Leu-Ser-Thr-Cys-Gly-Leu-Gly-Lys-Leu-Ser-Gln-Glu-Leu-~is-Lys-Leu-Gln-Thr-Tyr-Pro-D-Arg-Thr-Asp-Val-Gly-Ala-Gly-Thr-Pro-NH2 (Eel).
, : ~
:
W O 91/13601 PCT/US90/0137 ~
~73:L3~
` 16 23. L-Tyrosine21 Calcitonins having the following structures:
(a) H-Cys-Ser-Asn-Leu-Ser-Thr-Cys-Val-Leu-Gly-Lys-Leu-Ser-Gln-Glu-Leu-His-Lys-Leu-Gln-Tyr-Tyr-Pro-Arg-Thr-Asn-Thr-Gly-Ser-Gly-Thr-Pro-NH2 (Salmon); and (b) H-Cys-Ser-Asn-Leu-Ser-Thr-Cys-Val-Leu-'~ Gly-Lys-Leu-Ser-Gln-Glu-Leu-His-Lys-Leu-Gln-Tyr-Tyr-Pro-Arg-Thr-Asp-Val-Gly-Ala-Gly-Thr-Pro-NH2 (Eel).
24. D-Arginine24 Calcitonins having the following structures:
(a) H-Cys-Ser-Asn-Leu-Ser-Thr-cys-Val-Leu-Gly-Lys-Leu-Ser-Gln-Glu-Leu-His-Lys-Leu-Gln-Thr-Tyr-Pro-D-Arg-Thr-Asn-Thr-Gly-Ser-Gly-Thr-Pro-NH2 (Salmon); and ! ~ ' , , .
(b) H-Cys-Ser-Asn-Leu-Ser-Thr-Cys-Val-Leu-Gly-Lys-L~u-Ser-Gln-Glu-Leu-His-Lys-, Leu-Gln-Thr-Tyr-Pro-D-Arg-~hr-Asp-Val-Gly-Ala-Gly-Thr-Pro-NH2 (Eel).
25. Amides Analogues of Calcitonin having the following structures:
(a) Y-Cys-Ser-Asn-Leu-Ser-Thr-Cys-Val-Leu-Gly-1 2 3 4 5 6 7 8 9 lO
Lys-Leu-Ser-Gln-Glu-Leu-His-Lys-Leu-Gln-Thr-Tyr-Pro-Arg-Thr-Asn-Thr-Gly-ser-Gly-Thr-Pro-NH2 wherein Y is N(a) decanoyl and X is N(e) decanoyl.
W O 91/13601 2 ~ 7 ~ 1 3 ~ PC~r/US90/01373 : 17 26. [N-aipha, 1,7-Di-Alanine, Des-19-LeUcine] Calcitonins having the following structures:
i ~ (a) [N-alpha-X, 1, 7 Di-Alanine (8-Y) Des-l9-Leucine]
calcitonins, wherein X is H, free amino or acyl-amino wherein acyl is derived from a carboxylic acid having l-lo caroon atoms, _-lactic acid or half amide of ~ malonic, succinic, glutaric, or adipic acids; Y is . L-valine, glycine, L-methionine, _-alanine, L-leucine or L-isoleucine; and (b) [N-alpha-X, 1, 7-Di-Alanine, Des-l9-Leucine]
calcitonins, wherein X is an acyl derived fro~
. carboxylic acid having 1-5 carbon atoms.
. . .
; 27. 1,7-Di-Alanine, B-Glycine, Des-l9-Leucine Calcitonin having the following structure:
.: H2N-Ala-Ser-Asn-Leu-Ser-Thr-Ala-Gly-Leu-Gly-Lys-Leu-Ser-Gln-Glu-Leu-His-Lys-Gln-Thr-Tyr-Pro-Arg-~, 15 20 Thr-Asn-Thr-Gly-Ser-Gly-Thr-Pro-(C=O)-NH2.
28. N~-Propionyl, 1,7-Di-Alanine, Des-l9-Leucine Calcitonin having the following structure:
CH3-cH2-(c=o)-Hn-Ala-Ser-Asn-Leu-Ser-Thr-Ala-Val-Leu-Gly-Lys-Leu-Ser-Gln-Glu-Leu-His-Lys-Gln-Thr-Tyr-Pro-lS 20 Arg Thr-Asn-Thr-Gly-Ser-Gly-Thr-Pro-(C=0)-NH2 .: - ' -.
: ~ : . .
..
.. ..
.~; .
. . , ~ . ,, . :
wo 9l,l360l 2 ~ 7 ~ ~ 3 ~ PCT/US90/0137 ~
.
CaPrvlic Acid MonoalyCeride Absorption of calcitonin through the rectal mucosa is enhanced by the presence-of caprylic acid monoglyceride in the formulations of the present invention. Caprylic acid monoglyceride or glyceryl caprylate may be obtained by using a state-of-the-art method of preparation, or it may be obtained from commercial suppliers, such as Dynamit Nobel under the tradename Imwitor 308, which contains a mixture of mono-, di- and triglycerides of caprylic acid with a typical ratio of 60:30:10.
As used in co~nection with the specification and claims o-f the -present invention, the term caprylic acid monoglyceride will be used to denote the commercially supplied mixture of mono-, di-and triglycerides of caprylic acid.
The Sup~ositorv Vehicle The biologically/pharmacologically active calcitonin, as hereinbefore defined, and caprylic acid monoglyceride are formulated with a suppository vehicle adapted for rectal administration.
~ he suppository vehicle comprises a suppository base and certain adjuvenants and additives suitable for making such formulations. The suppository base may be an aqueous or a fatty base material, the latter being preferred mainly for ease of formulation and administration. The fatty base material for use in the present invention includes: fatty oils and fats, such as cocoa butter, palm oil, coconut oil, lard; waxes, such as lanolin and vasoline; fatty acids, such as, oleic-, stearic-, and lauric acids. We prefer to use a suppository base consisting essentially of polyethylene qlycols or mixtures of mono-, di-, and triglycerides of fatty acids of Clo to C20 chain length.
These are obtainable as polyethylene glycol l,ooo-a,ooo (PEG
, - ~ r. . , , , ; ; ' ~ :, ' :
'. , . , ~
. ~ ' ' ' ' ~ .
'.: ' '.
.' ' .
WO 91/13601 2 0 7 ~ 1 3 ~ PCT/US90/01373 ' 19 :
,' polymer of ethylene oxide, mol. wt. 1,000-8,000); cocoa butter, NF (fat obtained from the roasted seed of TheobrOma cacao);
Suppocire AIX (semi-synthetic glycerides with ethoxylated fatty acid esters containing 95% mono-, di- and triglycerides and 5%
polysorbate 65~; Witepsoi S 55 (semi-synthetic glycerides with ethoxylated fatty acid esters containing 98~ mono-, di- and triglycerides and z% PEG25 - cetyl stearyl alcohol) and Witepsol E75, supplied by Dynamit Nobel, which is glyceryl esters of saturated fatty acids of chain length Cl0-Cl8 .
The preparations of the present invention may also contain other additives, such as antioxidants, stabilizers, viscosity builders, preservatives, and the like. The concentration of these additives may vary according to the particular additive used and the desired result sought. The use of the kind and concentration of additives are well within the ability of the skilled artisan.
We contemplate three methods by which calcitonin can be incorporated into the s~ppository system, namely, by the use of:
l) a buffer system, 2) a gelatin stabilizer and 3) a bulking agent.
l) According to this method, a buffer system is used as a carrier for the calcitonin which provides stability for the sàme and facilitates its admixture with the suppOsitory vehicle.
l'he buffer system of the present invention preferably contains a sodium or potassium phosphate/phosphoric acid bufSer or a sodium or potassium acetate/acetic acid buffer or a sodium or potassium citrate/citric acid buffer in the range of 0.0l M to 0.5M and preferably in the range of 0.05 M to 0.2 M. The p~
range of these buffers are between 2.0 to 8Ø This ..... . . ~
~ :. . '' , .
- ~ :
. .: ~ , .. ~, - ~ " ";, ' :~ ' .
.:
- , .
W O 91~13601 2 ~ 7 313 ~ PCT/US90/0137 .''.' ' concentration was found effective to provide stability of the dissolved calcitonin in the vehicle.
2) According to this method, the stabilizer system contains from about l to about 32% w/w of a gelatin hydrolized in a o.s% w/w sodium chloride solution or in purified water. The pH
range of the stabilizer system is between 2.0 to ~Ø This stabilizer system has been found very effective in providing ~stability to the dissolved calcitonin.
..
; 3) Accordi~g to this method, a lyophilized or dry mixed bul~ing agent is used as a carrier for calcitonin. The ratio of calcitonin to the bulking powder is about lO to 60,000 IU per mg.
Examples of bulking agents include, but are not limited to gelati~, methionine, dextrose, sucrose, mannitol, sorbitol, lactose, methyl cellulose, povidone, sodium chloride and sodium acetate.
Prepa~atio~ o~ the Formulations : -:
In general the preparation of the formulations of the present inventior. is as follows: the absorption promoter is melted with the suppository base: antioxidants, such as aHA
~butylated hydroxyanisole, USP) and ~HT (butylated - hydroxytoluene, USP) are added thereto and dissolved thereby forming the suppository vehicle: calcitonin is dissolved in a buffer solution or a stabilizer system or homogenously distributed in a bulk powder mix and is blended with the suppository vehicle: and the formulation is then poured into suitable suppository molds and allowed to solidify.
Ingredients and amounts contemplated by the present invention are shown in the general Formulas A, B and C.
, :, :..., - :
~ .
, - -. . . ' :' , `' 2Q7~133 General Formula A
Ingredient Ouantity in mq : Calcitonin 25 - 6,000 I.U. 0.006 - 1.0 0.005 - 1.0 M Acetate buffer, l-lOO~l Imwitor 308 37.5 - 750 B~A
0.015 - 1.5 BHT 0.015 - 1.5 Witepsol S 55 or Suppocire AIX or PEG l,ooo - 8,000 Qs Ad 1,500*
General Formula B
Ingredient Ouantity in ma Calcitonin 25 - 6,000 I.U. 0.006 - 3.0 l-100 ~l per gram of suppository base of:
1 to 32% w/w gelatin solution hydrolized : in 0.9% w/w sodium chloride or purified water; pH adjusted to 2.0 to 8.0 with HCl or NaOH.
Imwitor 308 37.5 _ 750 BHA
0.015 - 1.5 BHT
0.015 - 1.5 Witepsol S 55 or Suppocire AIX or PEG l,OOO - 8,000 Qs Ad 1,500*
* While 1,500 mg quantity suppository units are illustrated in General Formula A, B and C, the quantity per unit may be in the : , 2~7 ~ 3 ~
WO 91/13601 PCT/US90/0137?
'~
; General For~yl~ C
.
. .
, In~redient Ouantity in mq ,;
Calcitonin 25 - 6,000 I.U. 0.006 - 3.0 Mannitol, USP 37 5 750 Imwitor 308 37 5 ~ 750 BHA
O.OlS - l.5 ~HT
0.015 - l.5 Witepsol S 55 or suppocire AIX or l,OOO - 8,000 Qs Ad l,500*
. .
-~ Preparative examples and typical formulations are set forth below. However, it is to be understood that these examples are given by way of illustration only and are not to be construed as limiting the invention either in spirit or in scope as many modifications will be appàrent to those skilled in the art.
.'' . .
:
Imwitor 308 (promoter) is melted with Witepsol S 55 bas~ at approximately 45C. ~he antioxidants, BHA and BHT, are addad and dis~olved. The melted mixture is then allowed to cool to a slightly thicker mass. Calcitonin (powder) is dissolved in O.l M
acetate buffer (pH 4.0? to contain 25 to 6,000 I.U. of salmon calcitonin in 37.5 ~l of the solution. The calcitonin solution is added to ~he blended base and mixed. The mixture is poured into suppository molds and allowed to solidify.
lt While 1,500 mg quantity suppository units are illustrated in General Formula A, ~ and C, the quantity per unit may be in the range of 500 mg to 5,000 mg.
.~
"' ' .' ' ', ' . ': , " . ~
, ~
,: , ' ' ' ' ` " ' ` , ' ' ' ' ' ' ' . " , ' ' ' '', ` . ,`' . , ' ~' `" ' '',' "'. ' `~'`', ;; `' ,'' ' .' '''~ ' ''' " '"' ' ` ' ' ` ` . . ' ' ~ '` . ' '. : , ', . , ` . ' ' ' ' ~ W O 91/13601 2 ~ 7 ~ 1 3 ~ pC~r~US90/01373 Imwitor 308 (promoter) is melted with Suppocire AIX ~ase at approximately 45C. The antioxidants, BHA and BHT, are added and dissolved. ~he melted mixture is then allowed to cool to a slightly thic~er mass. calcitonin powder is dissolved in 0.1 M
acetate buffer (pH 4.0) to contain the desired calcitonin potency in 37.5 ~1 of the solution. The calcitonin solution is added to the blended base and mixed. The mixture is poured into suppository molds and allowed to solidify.
':.
Imwitor 308 (promoter) is melted with PEG 1450 base at approximately 50C. The antioxidants, ~HA and BHT, are added and dissolved. The melted mixture is then allowed to cool to a slightly thicker mass. Calcitonin powder is dissolved in 1-32%
gelatin/0.9~ sodium chloride solution (pH 3.2) to contain the desired I.U. of calcitonin in 37.S ~1 of the solution. ~he calcitonin solution is added to the blended base and mixed. The mixture is poured into suppository molds and allowed to solidify.
EXAM~E 4 Imwitor 308 (promoterJ is melted with Witepsol E 75 or Suppocire AIX base at approximately 50C. The antioxidants, BHA
and BHT, are added and dissolved. Ihe melted mixture is then allowed to cool to a slightly thicXer mass. Calcitonin, as a calcitonin-mannitol lyophilized powder mixture, is added to the suppository vehicle above and suspended uniformly. The suspension is poured into suppository molds and allowed to solidlfy.
2 0 7 .~
W O 91/1360t PCT/US90/0137 ; 24 E~X~1PLE 5 Inqt~edient 0uantity SCT 45 I.U. in 37.5 ~1 of a o.1 M
acetate buffer (pH 4.0) 0.025 mg Imwitor 308 BHA mg ~ .
~HT 0.15 mg Witepsol S 55 QS 0.15 mg 1500 mg :`~
In~redient Ouantitv SCT 500 I.U. in 37.5 ~1 of a 0 acetate buffer (pH 4.0) .1 M 0.1 mg Imwitor 308 100 mg SHT 0.15 mg Suppocire AIX QS 0.15 mg 1500 mg In~edient Ouantity SCT 5,000 I.U. in 37.5 ~1 o~ 0 acetate buffer (pH 4.0) a .1 M 0.050 mg Imwitor 308 700 mg ~HT 0.15 mg Witepsol S 55 QS 0.15 m~
ISoo =g , .
W O 91/13601 2 0 7 ~ ~ 3 ~ PCT/US90/01373 Inq~edient Ouantity SCT 2,000 I.U. 0.075 mg Mannitol, USP 75 r,g Imwitor 308 75 r,g B~A
0.15 ~.g BHT
0.15 r.,g Suppocire AIX QS Ad 1500 r~g `::
Inqredient Q~antlt~
SCT 400 I.U. 0.045 mg Mannitol, USP 225 rug Imwitor 308 750 ~g BHA
. 0.15 ~g ~ BHT
0.15 ~g Witepsol E 75 QS Ad 1500 rg . EXAMPLE l0 In~redient Oua~tity SCT l00 I.U. 0.l r~g Mannitoi, USP 250 mg Imwitor 308 500 mg B~A 0.15 rg : 8HT 0.lS rg Suppocire AIX QS Ad 1500 mg ~. ~
wo 9l~l360- 2 ~ 7 313 ~ PCT/US90/0137 -~
EXA~PLE Il . ' ~ .
Inqredient Quantity : Calcitonin* in a 20% solution of gelatin 0.1 m hydrolized in 0.9% sodium chloride vehicle, : pH adjusted to 3.2 with HCl, 25 ~l/g suppository base Imwitor 308 600 mg BHA
0.15 mg BHT
0.15 mg Suppocire AIX QS Ad 1500 mg * 1,7-Di-Alanine, 8-glycinë, Des-l9-Leucine Calcitonin . .
EXA~ 2 I~gredient Ouantity vine Calcitonin 400 I.U. in a 32% solution O.1 . of gelatin hydrolized in purified water 5uephpocliet pH adjusted to 3.2 with HCl, 25 ~l/g , Imwitor 308 75 mg BHA
0.15 mg BHT
0.15 mg Suppocire AIX QS Ad 1500 mg - , , - : . .. , ,~ , .,, .
- . - . . : . . - ,-, .
,, ' : ' ~ ' ' ' :~
~XAMPLE 13 In~redient Quantitv ., Calcitonin* in a 10% solution of gelatino.l mg hydrolized in 0.9% sodium chloride vehicle, p~ adjusted to 3.2 with ~Cl, 25 ~l/g suppository base Imwitor 308 750 mg Bl~ 0.15 mg BH~ 0.15 mg Witepsol S 55 1500 mg :, ;~ * N~-Propionyl, 1,7-Di-Alanine, Des-l9-Leucine Calcitonin "~ ~
Suppository formulations of the present invention were tested for hypocalcemic effect according to the following procedure:
' Non-promoter and promoter containing salmon calcitonin suppositories were administered rectally into rats and the rectums were sealed to avoid expulsion of the suppositories.
Blood samples were analyzed for serum calcium leveis at base line, 1, 2, 3 and 4 hours and percent serum calcium level depressions from base line values were calculated and expressed as hypocalcemic response. Reduction of serum calcium levels from base line is a measure of salmon calcitonin activity.
~ .
Results obtained are illustrated in ~able I. The formulation used is that described in Example 5 with varying amounts of Imwitor 308.
.
W O 91/13601 2a73i3~ PCT/US90/0137^~
TA8L~ I
Effect of promoter (Imwitor 308) in Rectally,,Administered SCT,Suppository to R~ats .
Imwitor % % Hypocalcemic Effect in Suppository (Post Administration) l Hour 2 Hour 3 Hour 4 Hour O l9 18 ll 9 2.5 23 I6 3 2 .0 28 25 15 8 lO.0 26 34 38 32 25.0 26 34 35 34 ', 50.0 28 35 37 35 While only certain embodiments of our invention have been : ' described in specific detail, it will be apparent to those skilled in the art that many other specific embodiments may be . practiced and many chan~es may be made all within the spirit of the invention and the,scope of the appended claims.
.. , . . ~. . . .
.: . . - ~. . . .
(a) Cys-Ser-Asn-Leu-Ser-Thr-cys-Val-Leu-Gly- - -Lys-Leu-Gln-Glu-Leu-His-Lys-Leu-Gln-.
25'~i3~
W O 91/13601 PCT/US90/0137?~
; Thr-Tyr-Pro-Arg-Thr-Asn-Thr-Gly-Ser-Gly-Thr-Pr-NH2;
(b) Cys-Ser-Asn-Le~-Ser-Thr-Cys-Val-Leu-Gly-- Lys-Leu-Gln-Glu-Leu-His-Lys-Leu-Gln-Thr-Tyr-Pro-Arg-Thr-Asp-Val-Gly-Ala-- Gly-Thr-Pro-NH2; and (c) Cys-Gly-Asn-Leu-Ser-Thr-Cys-Met-Leu-Gly-Thr-Tyr-Gln-Asp-Phe-Asn-Lys-Phe-His-The-Phe-Pro-Gln-Thr-Ala-Ile-Gly-Val-Gly-Ala-Pro-NH2.
; 5. Des-2l-~hreonine-Calcitonins having the following structures:
(a) Cys-Ser-Asn-Leu-Ser-Thr-Cys-Val-Leu-Gly-Lys-Leu-Ser-Gln-Glu-Leu-His-Lys-Leu-Gln- :~
. Tyr-Pro-Arg-Thr-Asn-Thr-Gly-Ser-Gly-Thr-Pro-NH2 (Salmon);
(b) Cys-Ser-Asn-Leu-Ser-Thr-Cys-Val-Leu-Gly-Lys-Leu-Ser-Gln-Glu-Leu-His-Lys-Leu-Gln-Tyr-Pro-Arg-Thr-Asp-Val-Gly-Ala-Gly-Thr-Pro-NH2, (Eel); and . .
(c) Cys-Gly-Asn-Leu-Ser-Thr-C!ys-Met-Leu-Gly-Thr-Tyr-Thr-Gln-Asp-Phe-Asn-Lys-Phe-His- :
Phe-Pro-Gln-Thr-Ala-Ile-Gly-Val-Gly-Ala-Pro-NH2 (Human).
WO 91/13601 2 0 7 8 .1~ ~ PCT/US90/01373 ":
:
:
6. [Gly2, Sar3, Gly8, des-Tyr22] Calcitonins having the following structures:
(a) Cys-Gly-Ser-Leu,Ser-Thr-Cys-Gly-LeU-Gly-Lys-Leu-Ser-Gln-Glu-Leu-His-Lys-Leu-Gln-Thr-Pro-Arg-Thr-Asn-Thr-Gly-Ser-Gly-Thr-Pro-NH2: and, (b) Cys Gly-Ser-Leu-Ser-Thr-Cys-Gly-Lue-Gly-Lys-Leu-Ser-Gln-Glu-Leu-His-Lys-Leu-Gln-Thr-Pro-Arg-Thr-Asp-Val-Gly-Ala-Gly-Thr-Pro-NH2 .
7. Des-4-Leucine-calcitonins having the following structures:
(a) Cys-Ser-Asn-Ser-Thr-Cys-Val-Leu-Gly-Lys-Leu-Ser-Gln-Glu-Leu-His-Lys-Leu-Gln-Thr-Tyr-Pro-Arg-Thr-Asn-Thr-Gly-Ser-Gly-Thr-Pro-NH2 (Salmon);
., j (b) Cys-Ser-Asn-Ser-Thr-Cys-Val-Leu-Gly-Lys-Leu-Ser-Gln-Glu-Leu-His-Lys-Leu-Gln-Thr-Tyr-- Pro-Arg-Thr-Asp-Val-Gly-Ala-Gly-Thr-Pro-NH2 (EelJ; and (c) Cys-Gly-Asn-Ser-Thr-Cys-Met-Leu-Gly-Thr-Tyr-Thr-Gln-Asp-Phe-Asn-Lys-Phe-His-Thr-Phe-Pro-Gln-Thr-Ala-Ile-Gly-Val-Gly-Ala-Pro-NH2 (Human).
, ' ~ ' ............. . , -, . . .
WO 91/13601 ~ 3 3 PCT/US90/0137-~
8. Calcieonin-(1-23)-Peptide Amides having the followi~g structures:
.
(a) Cys-Ser-Asn-Leu-Ser-Thr-Cys-Val-Leu-Gly-Lys-Leu-Ser-Gln-Glu-Leu-His-Lys-Leu-Gln-Thr-Tyr-Pro-NH2; and (b) ll R2 Cys-Ser-Asn-Leu-Ser-Thr-Cys-Val-Leu-Gly-Lys-Leu-Ser-Gln-Glu-Leu-His-Lys-Leu-Gln-l'hr-Tyr-Pro-Nli2.
, 9. [Des-l-Aminc,8-Glycine) Calcitonins having the following structures:
~a) Bmp-Ser-Asn-Leu-Ser-Thr-Cys-Gly-Leu-Gly-Lys-Leu Ser-Gln-Glu-Leu-Hls-Lys-Leu-Gln- : -Thr-Tyr-Pro-Arg-Thr-Asn-Thr-Gly-Ser-Gly-Thr-Pro-NH2 (Salmon); and (b) ~mp-Scr-Asn-Leu-Scr-~hr-Cys-Val-Leu-Gly-Lys-Leu-Scr-Gln-Glu-Leu-His-Lys-Leu-Gln-Thr-Tyr-Pro-Arg-Thr-Asp-Val-Gly-Ala-Gly-Thr-Pro-NH2 (Eel).
10. [1,7-Di-Alanine~ Calcitonins having the following structures:
(a) Ala-Ser-Asn-Leu-Ser-Thr-Ala-Val-Leu-Gly-Lys-Leu-Ser-Gln-Glu-Ala-His-Lys-Leu-Gln-Thr-Tyr-Pro-Arg-Thr-Asn-Thr-Gly-Ser-Gly-Thr-Pro-NH2; and - :: .
~` W O 91J13601 2 ~ 7 ~ PC~r/US90/01373 ~' , 11 ' .
`::
.
(b) ~la-Ser-Asn-Leu-Ser-Thr-Ala-Val-Leu-Gly-Lys-Leu-Ser-Gln-Glu-Ala-His-Lys-Leu-Gln-Thr-Tyr-Pro-Arg-Thr-Asp-Val-Gly-Ala-Gly-Thr-Pro-NH2..
11. 8-Methionine Calcitonins having the following structures:
(a) Cys-Ser-Asn-Leu-Ser-Thr-Cys-Met-Leu-Gly-Lys-Leu-Ser-Gln-Glu-Leu-His-Lys-I,eu-Gln-Thr-Tyr-Pro-Arg-Thr-Asn-Thr-Gly-Ser-Gly-Thr-Pro-N~2; and (b) Cys-Ser-Asn-Leu-Ser-Thr-Cys-~et-Leu-; Gly-Lys-Leu-Ser-Gln-Glu-Leu-His-Lys-Leu-Gln-Thr-Tyr-Pro-Arg-Thr-Asp-Val-Gly-Ala-Gly-Thr-Pro-NH2.
12. Des-2-Serine, 3-Asparagine Calcitonins having the following . structures:
(a) Cys-Leu-Ser-Thr-Cys-Val-Leu-Gly-Lys-Leu-Ser-Gln-GlU-Leu-His-Lys-Leu-Gln-Thr-Tyr-Pro-Arg-Thr-Asn-Thr-Gly-Ser-Gly-Thr-Pro-NH2; and . ~
(b) Cys-Leu-Ser-l'hr-Cys-Val-Leu-Gly-Lys-Leu-Scr-Gln-Glu-Leu-His-Lys-Leu-Gln-Thr-Tyr-Pro-Arg-Thr-Asp-Val-Gly-Ala-Gly-Thr-Pro-N~2 -. .
, -~, ~ . ~ . , , :
..
W O 91/13601 2 ~ 7 ~ ~ 3 ~ PCTtUS90/0137-~
.
13. G-seriner Des-l9-Leucine Calcitonins having the following structures:
. (a) Cys-Ser-Asn-Leu-Ser-Ser-Cys-Val-Leu-Gly-Lys-Leu-Ser-Gln-Glu-Leu-His-Lys-Gln-Thr- -Tyr-Pro-Arg-Thr-Asn-Thr-Gly-Ser-Gly-Thr-Pro-NH2; and (b) Cys-Ser-Asn-Leu-ser-Ser-Cys-Val-Leu-Gly-Lys-Leu-Scr-Gln-Glu-Leu-His-Lys-Gln- :~
Thr-Tyr-Pro-Arg-Thr-Asp-Val-Gly-Ala-Gly-Thr-Pro-NH2 14. ~16,19-Di-Alanine] Calcitonins having the following structures: -. _ , (a) Cys-Ser-Asn-Leu-Ser-Thr-CyS-Val-LeU-Gly-Lys-Leu-ser-Gln-Glu-Ala-His-Lys-Ala-Gln-Thr-Tyr Pro-Arg-Thr-Asn-Thr-Gly-Ser-Gly-Thr-Pro-NH2; and (b) Cys-Ser-Asn-Leu-Ser-Thr-Cys-Val-Leu-Gly-.Lys-Leu-Ser-Gln-Glu-Ala-His-Lys-Ala-Gln-Thr-Tyr-Pro-Arg-Thr-Asp-Val-Gly-Ala-Gly-. Thr-Pro-NH2.
, .
15. (l-S-Acetamidomethyl Cysteine, 7-Alanine) Calcitonins havin~
the following structures:
(a) SCH2NH-C(0)-CH3 Cys-Ser-Asn-Leu-Ser-Thr-Ala-Val-LeU-Gly-Lys-Leu-Ser-Gln-Glu-Leu-His-Lys-Leu-Gln-Thr-Tyr-pro-Arg-I~hr-Asn-Thr-Gly-Ser-Gly-Thr-Pro-~H2; and ,. ' ' ''~ '.' -,.,"- '- , ', ' ' ' '-,' ~. ~ WO91/13601 2 ~ 7 ~ ~ 3 ~ PCT/US90/01373 , ~! tb) - SCH2NH-C (O~ -CH3 Cys-Ser-Asn-Leu-Ser-Thr-Ala-Val-Leu-Gly-Lys-Leu-Ser-Gln-Glu-Leu-His-Lys-Leu-Gln-Thr-Tyr-Pro-Arg-Thr-Asp-Val-Gly-Ala-Gly-Thr-pro-NH2 ~ ~
16. Des-l9-Leucine - Calcitonin Analogs having the following structures:
. .
(a) Cy5 -S er-Asn-Leu-Ser-Thr-Cys-Val-Leu-Gly-Lys-Leu-Ser-Gln-Glu-Leu-His-Lys-Gln-Thr-Tyr-Pro-Arg-Thr-Asn-Thr-Gly-Ser-Gly-Thr-Pro-NH2; and (b) Cys-Ser-Asn-Leu-Ser-Thr-Cys-Val-Leu-Gly-Lys-Leu-Ser-Gln-Glu-Leu-His-Lys-Gln-Thr-Tyr-Pro-Arg-Thr-Asp-Val-Gly-Ala-Gly~Thr-Pro-NH2.
17. (Bis-1,7-S-Acetamidomethyl-L-cysteine) Salmon Calcitonins having the following structures: :
(a) 1l 1 . S-CH2-NH-C-CH3 S-CH2-NH-C-CH3 H-Cys-Ser-Asn-Leu-Ser-Thr-Cys-Val-Leu-Gly-Lys-Leu-Ser-Gln-Glu-Leu-His-Lys-Leu-Gln-Thr-Tyr-Pro-Arg-Thr-Asn-Thr-Gly-ser-Gly-Thr-Pro-NH2: and (b) s-cH2-NH-c-cH2 1S-CH2-NH-C-CH3 H-Cys-Ser-Asn-Leu-Ser-Thr-Cys-Val-Leu-Gly-Lys-Leu-Ser-Gln-Glu-Leu-His-Lys-Leu-Gln-Thr-Tyr-Pro-Arg-Thr-Asp-Val-Gly-Ala-Gly-Thr-Pro-NH2.
- .. .- ~ .
. ~ . ~ :
, . :
: : :
``:`
W O 91/13601 2 ~ 7 8 i ~ ~ PCT/US90/0137 -' -a. 8-Glycine, Des-l9-Leucine-Calcitonins having the followin~ -structures:
(a) Cys-Ser-Asn-Le,u-Ser-Thr-Cys-Gly-Leu-Gly-Lys-Leu-Ser-Gln-Glu-Leu-His-Lys-Gln-hr-Tyr-Pro-Arg-Thr-Asn-Thr-Gly-Ser-Gly-Thr-Pro-NH2 (Salmon);
(b) Cys-Ser-Asn-Leu-Ser-Thr-Cys-Gly-Leu-Gly-Lys-Leu-Ser-Gln-Glu-Leu-His-Lys-Gln-Thr-Tyr-Pro-Arg-Thr-Asp-Val-Gly-Ala-Gly-Thr-Pro-NH2 (Eel); and . ~
(c) Cys-Ala-Ser-LPu-Ser-Thr-Cys-Gly-Leu-Gly-Lys-Leu-ser-Gln-Glu-Leu-His-Lys-Gin-; Thr-Tyr-Pro-Arg-Thr-Asp-Val-Gly-Ala-Gly-Thr-Pro-NH2 ~Chicken).
l9. Des-Leul6-Calcitonins having the following str~ctures:
(a) Cys-Ser-Asn-Leu-Ser-Thr-Cys-Val-Leu-Gly-Lys-Leu-Ser-Gln-Glu-~is-Lys-Leu-Gln-Thr-Tyr-Pro-Arg-Thr-Asn-Thr-Gly-Ser-Gly-Thr-Pro-NH2 (Salmon);
(b) Cys-Ser-Asn-Leu-Ser-Thr-cys-Val-Leu-Gly-Lys-Leu-Ser,Gln-Glu-His-Lys-Leu-Gln-Thr-Tyr-Pro-Arg-Thr-Asp-val-Gly-Ala-Gly-Thr-Pro-NH2 (Eel); and -, (c) Cys-Gly-Asn-Leu-Ser-Thr-Cys-Met-Leu-Gly-Thr-Tyr-Thr-Gln-Asp-Asn-Lys-Phe-His-Thr-Phe-Pro-Glu-Thr-Ala-Ile-Gly-Val-Gly-Ala-Pro-NH2 (Human).
.. . . - . , .
- - : ~: . . ............. : -.;: . . .
WO 91/13601 2 Q 7 ~ 1 3 ~ PCT/US90/01373 .
,:
:
20. Leucine22 - Calcitonins having the following structures: -(a) H-Cys-Ser-Asn-Leu-Ser-Thr-Cys-Val-Leu-Gly-Lys-Leu-Ser-Gln-Glu-Leu-His-Lys-Leu-Gln-Thr-Leu-Pro-Arg-Thr-Asn-Thr-Gly-Ser-Gly-Thr-Pro-N~2 (Salmon); and (b) H-Cys-Ser-Asn-Leu-Ser-Thr-Cys-Val-Leu-Gly-Lys-Leu-Ser-Gln-Glu-Leu-His-Lys-Leu-Gln-Thr-Leu-Pro-Arg-Thr-Asp-Val-Gly-Ala-Gly-Thr-Pro-NH2 (Eel).
21. Glycine - 8 Calcitonins having the following structures:
(a) H-Cys-Ser-Asn-Leu-Ser-Thr-Cys-Gly-LeU-Gly-Lys-Leu-Ser-Gln-Glu-Leu-His-Lys-Leu-Gln-Thr-Tyr-- Pro-Arg-Thr-Asn-Thr-Gly-Ser-Gly-Thr-Pro-NH2; and ~b) Cys-Gly-Asn-Leu-Ser-Thr-Cys-Gly-Leu-Gly-Thr-Tyr-Thr-Gln-Asp-Phe-Asn-Lys-Phe-His-Thr-Phe-Pro-Gln-lhr-Ala-Ile-Gly-Val-Gly-Ala-Pro-N~32.
22. Glycine8-D-Arginine24 Calcitonins having the following stuctures:
(a) H-Cys-Ser-Asn-Leu-Ser-Thr-Cys-Gly-Leu-Gly-Lys-Leu-Ser-Gln-Glu-Leu-His-Lys-Leu-Gln-Thr-Tyr-Pro-D-Arg-Thr-Asn-Thr-Gly-Ser-Gly-Thr-Pro-NH2 (Salmon): and-(b) H-Cys-Ser-Asn-Leu-Ser-Thr-Cys-Gly-Leu-Gly-Lys-Leu-Ser-Gln-Glu-Leu-~is-Lys-Leu-Gln-Thr-Tyr-Pro-D-Arg-Thr-Asp-Val-Gly-Ala-Gly-Thr-Pro-NH2 (Eel).
, : ~
:
W O 91/13601 PCT/US90/0137 ~
~73:L3~
` 16 23. L-Tyrosine21 Calcitonins having the following structures:
(a) H-Cys-Ser-Asn-Leu-Ser-Thr-Cys-Val-Leu-Gly-Lys-Leu-Ser-Gln-Glu-Leu-His-Lys-Leu-Gln-Tyr-Tyr-Pro-Arg-Thr-Asn-Thr-Gly-Ser-Gly-Thr-Pro-NH2 (Salmon); and (b) H-Cys-Ser-Asn-Leu-Ser-Thr-Cys-Val-Leu-'~ Gly-Lys-Leu-Ser-Gln-Glu-Leu-His-Lys-Leu-Gln-Tyr-Tyr-Pro-Arg-Thr-Asp-Val-Gly-Ala-Gly-Thr-Pro-NH2 (Eel).
24. D-Arginine24 Calcitonins having the following structures:
(a) H-Cys-Ser-Asn-Leu-Ser-Thr-cys-Val-Leu-Gly-Lys-Leu-Ser-Gln-Glu-Leu-His-Lys-Leu-Gln-Thr-Tyr-Pro-D-Arg-Thr-Asn-Thr-Gly-Ser-Gly-Thr-Pro-NH2 (Salmon); and ! ~ ' , , .
(b) H-Cys-Ser-Asn-Leu-Ser-Thr-Cys-Val-Leu-Gly-Lys-L~u-Ser-Gln-Glu-Leu-His-Lys-, Leu-Gln-Thr-Tyr-Pro-D-Arg-~hr-Asp-Val-Gly-Ala-Gly-Thr-Pro-NH2 (Eel).
25. Amides Analogues of Calcitonin having the following structures:
(a) Y-Cys-Ser-Asn-Leu-Ser-Thr-Cys-Val-Leu-Gly-1 2 3 4 5 6 7 8 9 lO
Lys-Leu-Ser-Gln-Glu-Leu-His-Lys-Leu-Gln-Thr-Tyr-Pro-Arg-Thr-Asn-Thr-Gly-ser-Gly-Thr-Pro-NH2 wherein Y is N(a) decanoyl and X is N(e) decanoyl.
W O 91/13601 2 ~ 7 ~ 1 3 ~ PC~r/US90/01373 : 17 26. [N-aipha, 1,7-Di-Alanine, Des-19-LeUcine] Calcitonins having the following structures:
i ~ (a) [N-alpha-X, 1, 7 Di-Alanine (8-Y) Des-l9-Leucine]
calcitonins, wherein X is H, free amino or acyl-amino wherein acyl is derived from a carboxylic acid having l-lo caroon atoms, _-lactic acid or half amide of ~ malonic, succinic, glutaric, or adipic acids; Y is . L-valine, glycine, L-methionine, _-alanine, L-leucine or L-isoleucine; and (b) [N-alpha-X, 1, 7-Di-Alanine, Des-l9-Leucine]
calcitonins, wherein X is an acyl derived fro~
. carboxylic acid having 1-5 carbon atoms.
. . .
; 27. 1,7-Di-Alanine, B-Glycine, Des-l9-Leucine Calcitonin having the following structure:
.: H2N-Ala-Ser-Asn-Leu-Ser-Thr-Ala-Gly-Leu-Gly-Lys-Leu-Ser-Gln-Glu-Leu-His-Lys-Gln-Thr-Tyr-Pro-Arg-~, 15 20 Thr-Asn-Thr-Gly-Ser-Gly-Thr-Pro-(C=O)-NH2.
28. N~-Propionyl, 1,7-Di-Alanine, Des-l9-Leucine Calcitonin having the following structure:
CH3-cH2-(c=o)-Hn-Ala-Ser-Asn-Leu-Ser-Thr-Ala-Val-Leu-Gly-Lys-Leu-Ser-Gln-Glu-Leu-His-Lys-Gln-Thr-Tyr-Pro-lS 20 Arg Thr-Asn-Thr-Gly-Ser-Gly-Thr-Pro-(C=0)-NH2 .: - ' -.
: ~ : . .
..
.. ..
.~; .
. . , ~ . ,, . :
wo 9l,l360l 2 ~ 7 ~ ~ 3 ~ PCT/US90/0137 ~
.
CaPrvlic Acid MonoalyCeride Absorption of calcitonin through the rectal mucosa is enhanced by the presence-of caprylic acid monoglyceride in the formulations of the present invention. Caprylic acid monoglyceride or glyceryl caprylate may be obtained by using a state-of-the-art method of preparation, or it may be obtained from commercial suppliers, such as Dynamit Nobel under the tradename Imwitor 308, which contains a mixture of mono-, di- and triglycerides of caprylic acid with a typical ratio of 60:30:10.
As used in co~nection with the specification and claims o-f the -present invention, the term caprylic acid monoglyceride will be used to denote the commercially supplied mixture of mono-, di-and triglycerides of caprylic acid.
The Sup~ositorv Vehicle The biologically/pharmacologically active calcitonin, as hereinbefore defined, and caprylic acid monoglyceride are formulated with a suppository vehicle adapted for rectal administration.
~ he suppository vehicle comprises a suppository base and certain adjuvenants and additives suitable for making such formulations. The suppository base may be an aqueous or a fatty base material, the latter being preferred mainly for ease of formulation and administration. The fatty base material for use in the present invention includes: fatty oils and fats, such as cocoa butter, palm oil, coconut oil, lard; waxes, such as lanolin and vasoline; fatty acids, such as, oleic-, stearic-, and lauric acids. We prefer to use a suppository base consisting essentially of polyethylene qlycols or mixtures of mono-, di-, and triglycerides of fatty acids of Clo to C20 chain length.
These are obtainable as polyethylene glycol l,ooo-a,ooo (PEG
, - ~ r. . , , , ; ; ' ~ :, ' :
'. , . , ~
. ~ ' ' ' ' ~ .
'.: ' '.
.' ' .
WO 91/13601 2 0 7 ~ 1 3 ~ PCT/US90/01373 ' 19 :
,' polymer of ethylene oxide, mol. wt. 1,000-8,000); cocoa butter, NF (fat obtained from the roasted seed of TheobrOma cacao);
Suppocire AIX (semi-synthetic glycerides with ethoxylated fatty acid esters containing 95% mono-, di- and triglycerides and 5%
polysorbate 65~; Witepsoi S 55 (semi-synthetic glycerides with ethoxylated fatty acid esters containing 98~ mono-, di- and triglycerides and z% PEG25 - cetyl stearyl alcohol) and Witepsol E75, supplied by Dynamit Nobel, which is glyceryl esters of saturated fatty acids of chain length Cl0-Cl8 .
The preparations of the present invention may also contain other additives, such as antioxidants, stabilizers, viscosity builders, preservatives, and the like. The concentration of these additives may vary according to the particular additive used and the desired result sought. The use of the kind and concentration of additives are well within the ability of the skilled artisan.
We contemplate three methods by which calcitonin can be incorporated into the s~ppository system, namely, by the use of:
l) a buffer system, 2) a gelatin stabilizer and 3) a bulking agent.
l) According to this method, a buffer system is used as a carrier for the calcitonin which provides stability for the sàme and facilitates its admixture with the suppOsitory vehicle.
l'he buffer system of the present invention preferably contains a sodium or potassium phosphate/phosphoric acid bufSer or a sodium or potassium acetate/acetic acid buffer or a sodium or potassium citrate/citric acid buffer in the range of 0.0l M to 0.5M and preferably in the range of 0.05 M to 0.2 M. The p~
range of these buffers are between 2.0 to 8Ø This ..... . . ~
~ :. . '' , .
- ~ :
. .: ~ , .. ~, - ~ " ";, ' :~ ' .
.:
- , .
W O 91~13601 2 ~ 7 313 ~ PCT/US90/0137 .''.' ' concentration was found effective to provide stability of the dissolved calcitonin in the vehicle.
2) According to this method, the stabilizer system contains from about l to about 32% w/w of a gelatin hydrolized in a o.s% w/w sodium chloride solution or in purified water. The pH
range of the stabilizer system is between 2.0 to ~Ø This stabilizer system has been found very effective in providing ~stability to the dissolved calcitonin.
..
; 3) Accordi~g to this method, a lyophilized or dry mixed bul~ing agent is used as a carrier for calcitonin. The ratio of calcitonin to the bulking powder is about lO to 60,000 IU per mg.
Examples of bulking agents include, but are not limited to gelati~, methionine, dextrose, sucrose, mannitol, sorbitol, lactose, methyl cellulose, povidone, sodium chloride and sodium acetate.
Prepa~atio~ o~ the Formulations : -:
In general the preparation of the formulations of the present inventior. is as follows: the absorption promoter is melted with the suppository base: antioxidants, such as aHA
~butylated hydroxyanisole, USP) and ~HT (butylated - hydroxytoluene, USP) are added thereto and dissolved thereby forming the suppository vehicle: calcitonin is dissolved in a buffer solution or a stabilizer system or homogenously distributed in a bulk powder mix and is blended with the suppository vehicle: and the formulation is then poured into suitable suppository molds and allowed to solidify.
Ingredients and amounts contemplated by the present invention are shown in the general Formulas A, B and C.
, :, :..., - :
~ .
, - -. . . ' :' , `' 2Q7~133 General Formula A
Ingredient Ouantity in mq : Calcitonin 25 - 6,000 I.U. 0.006 - 1.0 0.005 - 1.0 M Acetate buffer, l-lOO~l Imwitor 308 37.5 - 750 B~A
0.015 - 1.5 BHT 0.015 - 1.5 Witepsol S 55 or Suppocire AIX or PEG l,ooo - 8,000 Qs Ad 1,500*
General Formula B
Ingredient Ouantity in ma Calcitonin 25 - 6,000 I.U. 0.006 - 3.0 l-100 ~l per gram of suppository base of:
1 to 32% w/w gelatin solution hydrolized : in 0.9% w/w sodium chloride or purified water; pH adjusted to 2.0 to 8.0 with HCl or NaOH.
Imwitor 308 37.5 _ 750 BHA
0.015 - 1.5 BHT
0.015 - 1.5 Witepsol S 55 or Suppocire AIX or PEG l,OOO - 8,000 Qs Ad 1,500*
* While 1,500 mg quantity suppository units are illustrated in General Formula A, B and C, the quantity per unit may be in the : , 2~7 ~ 3 ~
WO 91/13601 PCT/US90/0137?
'~
; General For~yl~ C
.
. .
, In~redient Ouantity in mq ,;
Calcitonin 25 - 6,000 I.U. 0.006 - 3.0 Mannitol, USP 37 5 750 Imwitor 308 37 5 ~ 750 BHA
O.OlS - l.5 ~HT
0.015 - l.5 Witepsol S 55 or suppocire AIX or l,OOO - 8,000 Qs Ad l,500*
. .
-~ Preparative examples and typical formulations are set forth below. However, it is to be understood that these examples are given by way of illustration only and are not to be construed as limiting the invention either in spirit or in scope as many modifications will be appàrent to those skilled in the art.
.'' . .
:
Imwitor 308 (promoter) is melted with Witepsol S 55 bas~ at approximately 45C. ~he antioxidants, BHA and BHT, are addad and dis~olved. The melted mixture is then allowed to cool to a slightly thicker mass. Calcitonin (powder) is dissolved in O.l M
acetate buffer (pH 4.0? to contain 25 to 6,000 I.U. of salmon calcitonin in 37.5 ~l of the solution. The calcitonin solution is added to ~he blended base and mixed. The mixture is poured into suppository molds and allowed to solidify.
lt While 1,500 mg quantity suppository units are illustrated in General Formula A, ~ and C, the quantity per unit may be in the range of 500 mg to 5,000 mg.
.~
"' ' .' ' ', ' . ': , " . ~
, ~
,: , ' ' ' ' ` " ' ` , ' ' ' ' ' ' ' . " , ' ' ' '', ` . ,`' . , ' ~' `" ' '',' "'. ' `~'`', ;; `' ,'' ' .' '''~ ' ''' " '"' ' ` ' ' ` ` . . ' ' ~ '` . ' '. : , ', . , ` . ' ' ' ' ~ W O 91/13601 2 ~ 7 ~ 1 3 ~ pC~r~US90/01373 Imwitor 308 (promoter) is melted with Suppocire AIX ~ase at approximately 45C. The antioxidants, BHA and BHT, are added and dissolved. ~he melted mixture is then allowed to cool to a slightly thic~er mass. calcitonin powder is dissolved in 0.1 M
acetate buffer (pH 4.0) to contain the desired calcitonin potency in 37.5 ~1 of the solution. The calcitonin solution is added to the blended base and mixed. The mixture is poured into suppository molds and allowed to solidify.
':.
Imwitor 308 (promoter) is melted with PEG 1450 base at approximately 50C. The antioxidants, ~HA and BHT, are added and dissolved. The melted mixture is then allowed to cool to a slightly thicker mass. Calcitonin powder is dissolved in 1-32%
gelatin/0.9~ sodium chloride solution (pH 3.2) to contain the desired I.U. of calcitonin in 37.S ~1 of the solution. ~he calcitonin solution is added to the blended base and mixed. The mixture is poured into suppository molds and allowed to solidify.
EXAM~E 4 Imwitor 308 (promoterJ is melted with Witepsol E 75 or Suppocire AIX base at approximately 50C. The antioxidants, BHA
and BHT, are added and dissolved. Ihe melted mixture is then allowed to cool to a slightly thicXer mass. Calcitonin, as a calcitonin-mannitol lyophilized powder mixture, is added to the suppository vehicle above and suspended uniformly. The suspension is poured into suppository molds and allowed to solidlfy.
2 0 7 .~
W O 91/1360t PCT/US90/0137 ; 24 E~X~1PLE 5 Inqt~edient 0uantity SCT 45 I.U. in 37.5 ~1 of a o.1 M
acetate buffer (pH 4.0) 0.025 mg Imwitor 308 BHA mg ~ .
~HT 0.15 mg Witepsol S 55 QS 0.15 mg 1500 mg :`~
In~redient Ouantitv SCT 500 I.U. in 37.5 ~1 of a 0 acetate buffer (pH 4.0) .1 M 0.1 mg Imwitor 308 100 mg SHT 0.15 mg Suppocire AIX QS 0.15 mg 1500 mg In~edient Ouantity SCT 5,000 I.U. in 37.5 ~1 o~ 0 acetate buffer (pH 4.0) a .1 M 0.050 mg Imwitor 308 700 mg ~HT 0.15 mg Witepsol S 55 QS 0.15 m~
ISoo =g , .
W O 91/13601 2 0 7 ~ ~ 3 ~ PCT/US90/01373 Inq~edient Ouantity SCT 2,000 I.U. 0.075 mg Mannitol, USP 75 r,g Imwitor 308 75 r,g B~A
0.15 ~.g BHT
0.15 r.,g Suppocire AIX QS Ad 1500 r~g `::
Inqredient Q~antlt~
SCT 400 I.U. 0.045 mg Mannitol, USP 225 rug Imwitor 308 750 ~g BHA
. 0.15 ~g ~ BHT
0.15 ~g Witepsol E 75 QS Ad 1500 rg . EXAMPLE l0 In~redient Oua~tity SCT l00 I.U. 0.l r~g Mannitoi, USP 250 mg Imwitor 308 500 mg B~A 0.15 rg : 8HT 0.lS rg Suppocire AIX QS Ad 1500 mg ~. ~
wo 9l~l360- 2 ~ 7 313 ~ PCT/US90/0137 -~
EXA~PLE Il . ' ~ .
Inqredient Quantity : Calcitonin* in a 20% solution of gelatin 0.1 m hydrolized in 0.9% sodium chloride vehicle, : pH adjusted to 3.2 with HCl, 25 ~l/g suppository base Imwitor 308 600 mg BHA
0.15 mg BHT
0.15 mg Suppocire AIX QS Ad 1500 mg * 1,7-Di-Alanine, 8-glycinë, Des-l9-Leucine Calcitonin . .
EXA~ 2 I~gredient Ouantity vine Calcitonin 400 I.U. in a 32% solution O.1 . of gelatin hydrolized in purified water 5uephpocliet pH adjusted to 3.2 with HCl, 25 ~l/g , Imwitor 308 75 mg BHA
0.15 mg BHT
0.15 mg Suppocire AIX QS Ad 1500 mg - , , - : . .. , ,~ , .,, .
- . - . . : . . - ,-, .
,, ' : ' ~ ' ' ' :~
~XAMPLE 13 In~redient Quantitv ., Calcitonin* in a 10% solution of gelatino.l mg hydrolized in 0.9% sodium chloride vehicle, p~ adjusted to 3.2 with ~Cl, 25 ~l/g suppository base Imwitor 308 750 mg Bl~ 0.15 mg BH~ 0.15 mg Witepsol S 55 1500 mg :, ;~ * N~-Propionyl, 1,7-Di-Alanine, Des-l9-Leucine Calcitonin "~ ~
Suppository formulations of the present invention were tested for hypocalcemic effect according to the following procedure:
' Non-promoter and promoter containing salmon calcitonin suppositories were administered rectally into rats and the rectums were sealed to avoid expulsion of the suppositories.
Blood samples were analyzed for serum calcium leveis at base line, 1, 2, 3 and 4 hours and percent serum calcium level depressions from base line values were calculated and expressed as hypocalcemic response. Reduction of serum calcium levels from base line is a measure of salmon calcitonin activity.
~ .
Results obtained are illustrated in ~able I. The formulation used is that described in Example 5 with varying amounts of Imwitor 308.
.
W O 91/13601 2a73i3~ PCT/US90/0137^~
TA8L~ I
Effect of promoter (Imwitor 308) in Rectally,,Administered SCT,Suppository to R~ats .
Imwitor % % Hypocalcemic Effect in Suppository (Post Administration) l Hour 2 Hour 3 Hour 4 Hour O l9 18 ll 9 2.5 23 I6 3 2 .0 28 25 15 8 lO.0 26 34 38 32 25.0 26 34 35 34 ', 50.0 28 35 37 35 While only certain embodiments of our invention have been : ' described in specific detail, it will be apparent to those skilled in the art that many other specific embodiments may be . practiced and many chan~es may be made all within the spirit of the invention and the,scope of the appended claims.
.. , . . ~. . . .
.: . . - ~. . . .
Claims (39)
1. A suppository composition for rectal or vaginal administration comprising: from about 0.0004% w/w to about 0.200% w/w of a polypeptide having calcitonin activity (as hereinbefore defined); from about 2.5% w/w to about 50.0%
w/w of caprylic acid monoglyceride; and a pharmaceutically acceptable suppository vehicle in a quantity to make weight.
w/w of caprylic acid monoglyceride; and a pharmaceutically acceptable suppository vehicle in a quantity to make weight.
2. The suppository composition of claim 1 wherein said polypeptide is salmon calcitonin.
3. The suppository composition of claim 1 wherein said polypeptide is an analog of salmon calcitonin.
4. The suppository composition of claim 1 wherein said polypeptide is selected from the group consisting of eel, bovin, porcine, ovine, rat, chicken, and human calcitonins.
5. The suppository composition of claim 1 wherein said polypeptide is obtained from natural sources.
6. The suppository composition of claim 1 wherein said polypeptide is obtained by a synthetic route.
7. The suppository composition of claim 1 wherein said polypeptide has a potency of from about 25 to about 10,000 international units per mg of polypeptide.
8. A method for enhancing absorption, through the rectal or vaginal mucosal membranes, of a polypeptide having calcitonin activity comprising: adding from about 2.5% w/w to about 50.0% w/w of caprylic acid monoglyceride to a composition comprising 0.0004% w/w to 0.200% w/w of a WO 91/13601 PCT/US90/0137?
polypeptide having calcitonin activity and a pharmaceutically acceptable suppository vehicle in a quantity sufficient to make weight.
polypeptide having calcitonin activity and a pharmaceutically acceptable suppository vehicle in a quantity sufficient to make weight.
9. A method for the treatment of a patient suffering from diseases of hyperparathyroidism, idiopathic hypercalcemia of infancy, Paget's disease, vitamin D intoxication, or osteolytic bone metastases, said diseases characterized by hypercalcemia and high phosphate concentrations in the blood of said patient comprising: administering to said patient in need of such treatment to effect control of at least one of said diseases an effective amount of the composition of claim 1.
10. A suppository composition for rectal or vaginal administration comprising: from about 0.005% w/w to about 0.05% w/w of a polypeptide having calcitonin activity; from about 10% w/w to about 40% w/w of a caprylic acid monoglyceride; and a pharmaceutically acceptable suppository vehicle in a quantity to make weight.
11. The suppository composition of claim 10 wherein said polypeptide is [N-alpha-X, 1,7 Di-Alanine (8-Y) Des-19-Leucine] calcitonin, wherein X is H, free amino or acyl-amino wherein acyl is derived from a carboxylic acid having 1-10 carbon atoms, L-lactic acid or half amide of malonic, succinic, glutaric, or adipic acids; and Y is L-valine, glycine, L-methionine, L-alanine, L-leucine or L-isoleucine.
12. The suppository composition of claim 10 wherein said polypeptide is: [N-alpha-X, 1,7-Di-Alanine, Des-19-Leucine]
calcitonin, wherein X is an acyl derived from carboxylic acid having 1-5 carbon atoms.
calcitonin, wherein X is an acyl derived from carboxylic acid having 1-5 carbon atoms.
13. The suppository composition of claim 10 wherein said polypeptide is:
.
.
14. The suppository composition of claim 10 wherein said polypeptide is:
.
.
15. The suppository composition of claim 10 wherein said polypeptide is:
.
.
16. The suppository composition of claim 10 wherein said polypeptide is:
.
WO 91/13601 PCT/US90/0137?
.
WO 91/13601 PCT/US90/0137?
17. The suppository composition of claim 10 wherein said polypeptide is:
.
.
18. The suppository composition of claim 10 wherein said polypeptide is:
.
.
19. The suppository composition of claim 10 wherein said polypeptide is:
.
.
20. The suppository composition of claim 10 wherein said polypeptide is:
.
.
21. The suppository composition of claim 10 wherein said polypeptide is:
.
.
22. The suppository composition of claim 10 wherein said polypeptide is:
.
.
23. The suppository composition of claim 10 wherein said polypeptide is:
.
.
24. The suppository composition of claim 10 wherein said polypeptide is:
.
.
25. The suppository composition of claim 10 wherein said polypeptide is:
; where R1 is S-n-alkyl, Cys or H and R2 is S-n-alkyl or H, R1 being S-n-alkyl, Cys or H
when R2 is H and R2 being S-n-alkyl or H when R1 is H.
; where R1 is S-n-alkyl, Cys or H and R2 is S-n-alkyl or H, R1 being S-n-alkyl, Cys or H
when R2 is H and R2 being S-n-alkyl or H when R1 is H.
26. The suppository composition of claim 10 wherein said polypeptide is:
.
.
27. The suppository composition of claim 10 wherein said polypeptide is:
.
.
28. The suppository composition of claim 10 wherein said polypeptide is:
.
.
29. The suppository composition of claim 10 wherein said polypeptide is:
.
.
30. The suppository composition of claim 10 wherein said polypeptide is:
.
.
31. The suppository composition of claim 13 wherein said polypeptide is:
.
.
32. The suppository composition of claim 10 wherein said polypeptide is:
.
WO 91/13601 PCT/US90/0137?
.
WO 91/13601 PCT/US90/0137?
33. The suppository composition of claim 10 wherein said polypeptide is:
.
.
34. The suppository composition of claim 10 wherein said polypeptide is:
.
.
35. The suppository composition of claim 10 wherein said polypeptide is:
.
.
36. The suppository composition of claim 10 wherein said polypeptide is:
.
.
37. The suppository composition of claim 10 wherein said polypeptide is:
wherein Y is N(a) decanoyl and X is N(e) decanoyl.
wherein Y is N(a) decanoyl and X is N(e) decanoyl.
38. The suppository composition of claim 10 wherein said polypeptide is:
.
.
39. The suppository composition of claim 10 wherein said polypeptide is:
.
.
Priority Applications (3)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| PCT/US1990/001373 WO1991013601A1 (en) | 1990-03-15 | 1990-03-15 | Calcitonin suppository formulations |
| EP19900905311 EP0520983A4 (en) | 1990-03-15 | 1990-03-15 | Calcitonin suppository formulations |
| CA002078133A CA2078133A1 (en) | 1990-03-15 | 1990-03-15 | Calcitonin suppository formulations |
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| PCT/US1990/001373 WO1991013601A1 (en) | 1990-03-15 | 1990-03-15 | Calcitonin suppository formulations |
| CA002078133A CA2078133A1 (en) | 1990-03-15 | 1990-03-15 | Calcitonin suppository formulations |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CA2078133A1 true CA2078133A1 (en) | 1991-09-16 |
Family
ID=4150402
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CA002078133A Abandoned CA2078133A1 (en) | 1990-03-15 | 1990-03-15 | Calcitonin suppository formulations |
Country Status (1)
| Country | Link |
|---|---|
| CA (1) | CA2078133A1 (en) |
-
1990
- 1990-03-15 CA CA002078133A patent/CA2078133A1/en not_active Abandoned
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| Date | Code | Title | Description |
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| FZDE | Discontinued |