CA1326439C - Parenteral growth hormone formulations - Google Patents
Parenteral growth hormone formulationsInfo
- Publication number
- CA1326439C CA1326439C CA 566846 CA566846A CA1326439C CA 1326439 C CA1326439 C CA 1326439C CA 566846 CA566846 CA 566846 CA 566846 A CA566846 A CA 566846A CA 1326439 C CA1326439 C CA 1326439C
- Authority
- CA
- Canada
- Prior art keywords
- growth hormone
- percent
- formulation
- cresol
- human growth
- 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.)
- Expired - Fee Related
Links
- 239000000203 mixture Substances 0.000 title claims abstract description 32
- 238000009472 formulation Methods 0.000 title claims abstract description 31
- 102000018997 Growth Hormone Human genes 0.000 title description 3
- 108010051696 Growth Hormone Proteins 0.000 title description 2
- 239000000122 growth hormone Substances 0.000 title description 2
- PEDCQBHIVMGVHV-UHFFFAOYSA-N Glycerine Chemical compound OCC(O)CO PEDCQBHIVMGVHV-UHFFFAOYSA-N 0.000 claims abstract description 34
- 102000002265 Human Growth Hormone Human genes 0.000 claims abstract description 27
- 108010000521 Human Growth Hormone Proteins 0.000 claims abstract description 27
- 239000000854 Human Growth Hormone Substances 0.000 claims abstract description 27
- 235000011187 glycerol Nutrition 0.000 claims abstract description 17
- RLSSMJSEOOYNOY-UHFFFAOYSA-N m-cresol Chemical compound CC1=CC=CC(O)=C1 RLSSMJSEOOYNOY-UHFFFAOYSA-N 0.000 claims abstract description 16
- 229940100630 metacresol Drugs 0.000 claims abstract description 14
- 229960005150 glycerol Drugs 0.000 claims abstract description 5
- 210000003205 muscle Anatomy 0.000 claims description 17
- 230000007794 irritation Effects 0.000 claims description 16
- 238000010255 intramuscular injection Methods 0.000 claims description 6
- 239000007927 intramuscular injection Substances 0.000 claims description 6
- 239000008194 pharmaceutical composition Substances 0.000 claims description 3
- 239000006201 parenteral dosage form Substances 0.000 claims 3
- 238000000034 method Methods 0.000 abstract description 4
- DDRJAANPRJIHGJ-UHFFFAOYSA-N creatinine Chemical compound CN1CC(=O)NC1=N DDRJAANPRJIHGJ-UHFFFAOYSA-N 0.000 description 10
- 238000002347 injection Methods 0.000 description 10
- 239000007924 injection Substances 0.000 description 10
- 239000003085 diluting agent Substances 0.000 description 7
- 229940109239 creatinine Drugs 0.000 description 5
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Chemical compound O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 4
- 239000003814 drug Substances 0.000 description 3
- 239000005556 hormone Substances 0.000 description 3
- 229940088597 hormone Drugs 0.000 description 3
- 239000000463 material Substances 0.000 description 3
- 239000003981 vehicle Substances 0.000 description 3
- 241000283973 Oryctolagus cuniculus Species 0.000 description 2
- ISWSIDIOOBJBQZ-UHFFFAOYSA-N Phenol Chemical compound OC1=CC=CC=C1 ISWSIDIOOBJBQZ-UHFFFAOYSA-N 0.000 description 2
- 239000003795 chemical substances by application Substances 0.000 description 2
- 238000005259 measurement Methods 0.000 description 2
- 125000001360 methionine group Chemical group N[C@@H](CCSC)C(=O)* 0.000 description 2
- 239000002687 nonaqueous vehicle Substances 0.000 description 2
- 238000007911 parenteral administration Methods 0.000 description 2
- 238000002360 preparation method Methods 0.000 description 2
- 102000004169 proteins and genes Human genes 0.000 description 2
- 108090000623 proteins and genes Proteins 0.000 description 2
- 229940124597 therapeutic agent Drugs 0.000 description 2
- 210000001519 tissue Anatomy 0.000 description 2
- FGRBYDKOBBBPOI-UHFFFAOYSA-N 10,10-dioxo-2-[4-(N-phenylanilino)phenyl]thioxanthen-9-one Chemical compound O=C1c2ccccc2S(=O)(=O)c2ccc(cc12)-c1ccc(cc1)N(c1ccccc1)c1ccccc1 FGRBYDKOBBBPOI-UHFFFAOYSA-N 0.000 description 1
- 102000000827 Anterior Pituitary Hormones Human genes 0.000 description 1
- 108010001897 Anterior Pituitary Hormones Proteins 0.000 description 1
- 102000011022 Chorionic Gonadotropin Human genes 0.000 description 1
- 108010062540 Chorionic Gonadotropin Proteins 0.000 description 1
- LVGKNOAMLMIIKO-UHFFFAOYSA-N Elaidinsaeure-aethylester Natural products CCCCCCCCC=CCCCCCCCC(=O)OCC LVGKNOAMLMIIKO-UHFFFAOYSA-N 0.000 description 1
- 102000012673 Follicle Stimulating Hormone Human genes 0.000 description 1
- 108010079345 Follicle Stimulating Hormone Proteins 0.000 description 1
- 101000664737 Homo sapiens Somatotropin Proteins 0.000 description 1
- 206010062767 Hypophysitis Diseases 0.000 description 1
- 206010061218 Inflammation Diseases 0.000 description 1
- 102000009151 Luteinizing Hormone Human genes 0.000 description 1
- 108010073521 Luteinizing Hormone Proteins 0.000 description 1
- 241001465754 Metazoa Species 0.000 description 1
- 201000002481 Myositis Diseases 0.000 description 1
- 235000019483 Peanut oil Nutrition 0.000 description 1
- 208000003443 Unconsciousness Diseases 0.000 description 1
- 206010047700 Vomiting Diseases 0.000 description 1
- 239000013543 active substance Substances 0.000 description 1
- 239000003329 adenohypophysis hormone Substances 0.000 description 1
- 230000001919 adrenal effect Effects 0.000 description 1
- 150000001413 amino acids Chemical class 0.000 description 1
- 239000008135 aqueous vehicle Substances 0.000 description 1
- 238000004500 asepsis Methods 0.000 description 1
- 239000008228 bacteriostatic water for injection Substances 0.000 description 1
- 230000036765 blood level Effects 0.000 description 1
- 239000002285 corn oil Substances 0.000 description 1
- 235000005687 corn oil Nutrition 0.000 description 1
- 230000003131 corticotrophic effect Effects 0.000 description 1
- 235000012343 cottonseed oil Nutrition 0.000 description 1
- 239000002385 cottonseed oil Substances 0.000 description 1
- 229940079593 drug Drugs 0.000 description 1
- LVGKNOAMLMIIKO-QXMHVHEDSA-N ethyl oleate Chemical compound CCCCCCCC\C=C/CCCCCCCC(=O)OCC LVGKNOAMLMIIKO-QXMHVHEDSA-N 0.000 description 1
- 229940093471 ethyl oleate Drugs 0.000 description 1
- 238000011156 evaluation Methods 0.000 description 1
- 238000011049 filling Methods 0.000 description 1
- 229940028334 follicle stimulating hormone Drugs 0.000 description 1
- 238000010353 genetic engineering Methods 0.000 description 1
- 210000004907 gland Anatomy 0.000 description 1
- 230000010224 hepatic metabolism Effects 0.000 description 1
- 229940084986 human chorionic gonadotropin Drugs 0.000 description 1
- 208000015181 infectious disease Diseases 0.000 description 1
- 230000004054 inflammatory process Effects 0.000 description 1
- 238000007918 intramuscular administration Methods 0.000 description 1
- 230000009545 invasion Effects 0.000 description 1
- 229940040129 luteinizing hormone Drugs 0.000 description 1
- 238000011587 new zealand white rabbit Methods 0.000 description 1
- 239000000312 peanut oil Substances 0.000 description 1
- 210000003635 pituitary gland Anatomy 0.000 description 1
- 239000000843 powder Substances 0.000 description 1
- 230000002035 prolonged effect Effects 0.000 description 1
- 238000007789 sealing Methods 0.000 description 1
- 238000007391 self-medication Methods 0.000 description 1
- 239000008159 sesame oil Substances 0.000 description 1
- 235000011803 sesame oil Nutrition 0.000 description 1
- 239000008223 sterile water Substances 0.000 description 1
- 230000001954 sterilising effect Effects 0.000 description 1
- 238000004659 sterilization and disinfection Methods 0.000 description 1
- 238000007920 subcutaneous administration Methods 0.000 description 1
- 238000002560 therapeutic procedure Methods 0.000 description 1
- 238000011179 visual inspection Methods 0.000 description 1
- 230000008673 vomiting Effects 0.000 description 1
Landscapes
- Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
- Medicinal Preparation (AREA)
Abstract
Abstract Parenteral dosage formulations of human growth hormone containing an effective amount of human growth hormone, meta-cresol and glycerin, and a method of use thereof.
Description
3 ~
T I TLE
PARENTERAL GROWTH HORMONE FORMULATIONS
5Background of the Invention The routes available for the delivery of pharmacologically active agents include oral, rectal or parenteral administration, among others. Oral adminis-tration is clearly the most convenient to the patient,however, it is not always possible to administer drugs orally. For example, in instances where the patient is vomiting or unconscious or where it may otherwise be de-sirable to avoid first pass hepatic metabolism, rectal administration may be an alternative. Similarly, parenteral administration may be reguired for t-he medicinal agent to be absorbed in an active form or where it is important to achieve rapid and predictable blood levels of the agent. However, certain disadvan-tages are inherent in parenteral therapy. For example,it is imperative that asepsis be maintained so as to avoid the possibility of infection as a result of the procedure. Also, where self-medication is feasible, it may be difficult for the patient to administer the injection. Particularly where intramuscular administra-tion is required, the patient may experience discomfort or pain owing to the physical invasion of the tissue or the particular parenteral formulation administered. Not-withstanding this apparent disadvantage certain thera-peutic agents are preferably administered parenterally.
132~9 One such group of therapeutic agents is the anterior pituitary hormones including adrenal cortico-tropic hormone, human chorionic gonadotropin, follicle stimulating hormone, luteinizing hormone and human growth hormone. Human growth hormone or somatotropin is a protein of 191 amino acids and has a molecular weight of 22,000 daltons. It can be isolated from human pituitary glands or can be prepared biosyntheti-cally as a result of advances in genetic engineering.
At present there are two commercially available forms of the genetically engineered hormone, one o~ which is identical to native human growth hormone. The other form has an additional methionine residue at the N-terminus of the protein.
Human growth hormone is administered subcuta-neously or intramuscularly. However, upon injection pain and inflammation at the site of injection typically occur. The present invention alleviates this problem by providing a parenteral formulation of human growth hormone which, upon administration, reduces muscle irritation at the site of injection thus leading to increased patient comfort and compliance.
Summarv_of the Invention The present invention is directed to a parenteral pharmaceutical formulation of human growth hormone. Said formulation includes an effective amount of human ~rowth hormone, meta-cresol and glycerin. Also disclosed and claimed is a method for reducing muscle ~326~
X-7308 _3_ irritation resulting from an intramuscular injection of human growth hormone. Said method is effected by injec-ting a parenteral formulation containing an effective amount of said human growth hormone, meta-cresol, glycerin and a pharmaceutically acceptable vehicle therefor.
Detailed Description of the Invention The parenteral formulation of the present invention reduces the amount of muscle irritation resulting from an intramuscular injection of human growth hormone. As mentioned earlier, human growth hormone is commercially available as the native material isolated from human pituit,ary glands or as two biosyn-thetically produced forms, one of which is identical to the native material and the other having an additional methionine residue at the N-terminus. For purposes of the present invention any one or a combination of the three may be present in the parenteral formulation although the biosynthetically produced material which is identical to native human growth hormone is pre-ferred. The human growth hormone is present in said formulation in an effective amount. By "effective amount" is meant that quantity of human growth hormone necessary to stimulate growth when administered in single or divided doses. The specific amount of human growth hormone in the formulation will, of course, depend upon the commercial embodiment sold, i.e., whether intended for single or multiple use administra-tion.
13 2 ~ r~
In addition to the human growth hormone, the formulation of the present invention also contains meta-cresol and glycerin as a diluent, the combination of which serves to reduce muscle irritation upon injection.
The meta-cresol (i.e., 3-methylphenol) may be present in said formulation in an amount of from about 0.15 to 0.4 percent by weight, preferably about 0.2 to 0.3 percent by weight. The amount of glycerin present may range from about 0.5 to 10 percent by weight and is a preferably about 1 to 2 percent by weight.
The commercially available formulation will preferably, though not necessarily, be in the form of a lyophilized (i.e., freeze-dried) powder for reconstitu-tion. Reconstitution of the formulation may be effected by the addition of a pharmaceutically acceptable vehicle therefor which may be aqueous or nonaqueous in nature.
Examples of aqueous vehicles include water for injection, bacteriostatic water for injection, sterile water for iniection and the like. Nonaqueous vehicles include corn oil, cottonseed oil, ethyl oleate, peanut oil, sesame oil and the like. The selection of the pharma-ceutically acceptable vehicle will be merely a matter of choice for the skilled artisan, although the nonaqueous vehicles are more generally suited where prolonged duration of action is the goal. The actual product preparation is conventional in the art including, for example, container selection, sterilization, filling and sealing. Further information relating to parenteral product preparations may be obtained from standard treatises such as Remington's Pharmaceutical Sciences, ~326439 17th Edition (1985).
Upon intramuscular injection, the formulations of the present invention reduce muscle irritation when administered to a patient in need thereof. By reduced muscle irritation is meant that upon administration of the formulation of the present invention less irritation will be observed at the site of injection than if human growth hormone was administered in a diluent which did lo not contain meta-cresol and glycerin. By reducing muscle irritation upon injection the patient will experience less discomfort and pain when the formulation of the present invention is being administered. Further, although these formulations are preferably provided for intramuscular injection, the skilled artisan will readily appreciate that said formulations are also satisfactory for subcutaneous administration.
In order to further illustrate the present invention, the following evaluation of injection site Z0 irritation was conducted. Four different foxmulations containing various diluents with or without human growth hormone were prepared as shown in Table I. Four groups of ten New Zealand white rabbits (five of each sex) were administered one of the four formulations shown in Table I, respectively. Each animal received an intramuscular injection of 1 milliliter of the test formulation into an erector spinae muscle. The extent of muscle irrita-tion as a result of the injection was monitored by quan-tifying creatinine phosphokinase levels which increase.
with increased muscle irritation. These creatinine phosphokinase measurements were made prior to, and 24 ~-.
hours after injection. Additionally, 72 hours after in-jection, the muscle was excised and the irritated portion thereof (based on visual inspection) was segregated and measured as a function of the volume of water displaced thereby (i.e., mean muscle irritation). The results of these assess~ents are shown in Table I.
Table I
10 Formulation a Mean C~K Mean Musclc No. Components Values_ Irritation_ 1 0.3% meta-cresol1895 0.83 0.2% phenol 1.7% glycerin lA Same as 1 but2449 1.86 with 0.2% human growth hormone added 2 0.3% meta-cresol1628 0.30 1.7% glycerin 2A Same as 2 but 911 od with 0.2% human growth hormone added a In percent by weight b Mean creatinine phosphokinase values 24 hours after n~ectlon expressed in International units per c Expressed as the volume of water displaced (in milliliters) by the irritated portion of the muscle tissue excised 0 d No irritated muscle tissue present for measurement ~2~
These data clearly show that when human growth hormone is added to a diluent containing glycerin, phenol and meta-cresol there is an increase in creatinine phosphokinase levels and mean muscle irritation as compared to the diluent alone (formulation number 1 versus lA). However, when meta-cresol and glycerin is used as the diluent (in the absence of human growth hormone) less tissue irritation is observed as shown by a decrease in creatinine phosphokinase levels (formula-tion number 2 versus l). Surprisingly, when humangrowth hormone is added to the meta-cresol/glycerin diluent (formulation 2A) muscle irritation is reduced even farther (formulation 2A versus 2). These results were confirmed histopathologically by observation that the incidence in severity of myositis in rabbits injected intramuscularly with formulation number 2A was less than in rabbits injected with formulation number lA.
T I TLE
PARENTERAL GROWTH HORMONE FORMULATIONS
5Background of the Invention The routes available for the delivery of pharmacologically active agents include oral, rectal or parenteral administration, among others. Oral adminis-tration is clearly the most convenient to the patient,however, it is not always possible to administer drugs orally. For example, in instances where the patient is vomiting or unconscious or where it may otherwise be de-sirable to avoid first pass hepatic metabolism, rectal administration may be an alternative. Similarly, parenteral administration may be reguired for t-he medicinal agent to be absorbed in an active form or where it is important to achieve rapid and predictable blood levels of the agent. However, certain disadvan-tages are inherent in parenteral therapy. For example,it is imperative that asepsis be maintained so as to avoid the possibility of infection as a result of the procedure. Also, where self-medication is feasible, it may be difficult for the patient to administer the injection. Particularly where intramuscular administra-tion is required, the patient may experience discomfort or pain owing to the physical invasion of the tissue or the particular parenteral formulation administered. Not-withstanding this apparent disadvantage certain thera-peutic agents are preferably administered parenterally.
132~9 One such group of therapeutic agents is the anterior pituitary hormones including adrenal cortico-tropic hormone, human chorionic gonadotropin, follicle stimulating hormone, luteinizing hormone and human growth hormone. Human growth hormone or somatotropin is a protein of 191 amino acids and has a molecular weight of 22,000 daltons. It can be isolated from human pituitary glands or can be prepared biosyntheti-cally as a result of advances in genetic engineering.
At present there are two commercially available forms of the genetically engineered hormone, one o~ which is identical to native human growth hormone. The other form has an additional methionine residue at the N-terminus of the protein.
Human growth hormone is administered subcuta-neously or intramuscularly. However, upon injection pain and inflammation at the site of injection typically occur. The present invention alleviates this problem by providing a parenteral formulation of human growth hormone which, upon administration, reduces muscle irritation at the site of injection thus leading to increased patient comfort and compliance.
Summarv_of the Invention The present invention is directed to a parenteral pharmaceutical formulation of human growth hormone. Said formulation includes an effective amount of human ~rowth hormone, meta-cresol and glycerin. Also disclosed and claimed is a method for reducing muscle ~326~
X-7308 _3_ irritation resulting from an intramuscular injection of human growth hormone. Said method is effected by injec-ting a parenteral formulation containing an effective amount of said human growth hormone, meta-cresol, glycerin and a pharmaceutically acceptable vehicle therefor.
Detailed Description of the Invention The parenteral formulation of the present invention reduces the amount of muscle irritation resulting from an intramuscular injection of human growth hormone. As mentioned earlier, human growth hormone is commercially available as the native material isolated from human pituit,ary glands or as two biosyn-thetically produced forms, one of which is identical to the native material and the other having an additional methionine residue at the N-terminus. For purposes of the present invention any one or a combination of the three may be present in the parenteral formulation although the biosynthetically produced material which is identical to native human growth hormone is pre-ferred. The human growth hormone is present in said formulation in an effective amount. By "effective amount" is meant that quantity of human growth hormone necessary to stimulate growth when administered in single or divided doses. The specific amount of human growth hormone in the formulation will, of course, depend upon the commercial embodiment sold, i.e., whether intended for single or multiple use administra-tion.
13 2 ~ r~
In addition to the human growth hormone, the formulation of the present invention also contains meta-cresol and glycerin as a diluent, the combination of which serves to reduce muscle irritation upon injection.
The meta-cresol (i.e., 3-methylphenol) may be present in said formulation in an amount of from about 0.15 to 0.4 percent by weight, preferably about 0.2 to 0.3 percent by weight. The amount of glycerin present may range from about 0.5 to 10 percent by weight and is a preferably about 1 to 2 percent by weight.
The commercially available formulation will preferably, though not necessarily, be in the form of a lyophilized (i.e., freeze-dried) powder for reconstitu-tion. Reconstitution of the formulation may be effected by the addition of a pharmaceutically acceptable vehicle therefor which may be aqueous or nonaqueous in nature.
Examples of aqueous vehicles include water for injection, bacteriostatic water for injection, sterile water for iniection and the like. Nonaqueous vehicles include corn oil, cottonseed oil, ethyl oleate, peanut oil, sesame oil and the like. The selection of the pharma-ceutically acceptable vehicle will be merely a matter of choice for the skilled artisan, although the nonaqueous vehicles are more generally suited where prolonged duration of action is the goal. The actual product preparation is conventional in the art including, for example, container selection, sterilization, filling and sealing. Further information relating to parenteral product preparations may be obtained from standard treatises such as Remington's Pharmaceutical Sciences, ~326439 17th Edition (1985).
Upon intramuscular injection, the formulations of the present invention reduce muscle irritation when administered to a patient in need thereof. By reduced muscle irritation is meant that upon administration of the formulation of the present invention less irritation will be observed at the site of injection than if human growth hormone was administered in a diluent which did lo not contain meta-cresol and glycerin. By reducing muscle irritation upon injection the patient will experience less discomfort and pain when the formulation of the present invention is being administered. Further, although these formulations are preferably provided for intramuscular injection, the skilled artisan will readily appreciate that said formulations are also satisfactory for subcutaneous administration.
In order to further illustrate the present invention, the following evaluation of injection site Z0 irritation was conducted. Four different foxmulations containing various diluents with or without human growth hormone were prepared as shown in Table I. Four groups of ten New Zealand white rabbits (five of each sex) were administered one of the four formulations shown in Table I, respectively. Each animal received an intramuscular injection of 1 milliliter of the test formulation into an erector spinae muscle. The extent of muscle irrita-tion as a result of the injection was monitored by quan-tifying creatinine phosphokinase levels which increase.
with increased muscle irritation. These creatinine phosphokinase measurements were made prior to, and 24 ~-.
hours after injection. Additionally, 72 hours after in-jection, the muscle was excised and the irritated portion thereof (based on visual inspection) was segregated and measured as a function of the volume of water displaced thereby (i.e., mean muscle irritation). The results of these assess~ents are shown in Table I.
Table I
10 Formulation a Mean C~K Mean Musclc No. Components Values_ Irritation_ 1 0.3% meta-cresol1895 0.83 0.2% phenol 1.7% glycerin lA Same as 1 but2449 1.86 with 0.2% human growth hormone added 2 0.3% meta-cresol1628 0.30 1.7% glycerin 2A Same as 2 but 911 od with 0.2% human growth hormone added a In percent by weight b Mean creatinine phosphokinase values 24 hours after n~ectlon expressed in International units per c Expressed as the volume of water displaced (in milliliters) by the irritated portion of the muscle tissue excised 0 d No irritated muscle tissue present for measurement ~2~
These data clearly show that when human growth hormone is added to a diluent containing glycerin, phenol and meta-cresol there is an increase in creatinine phosphokinase levels and mean muscle irritation as compared to the diluent alone (formulation number 1 versus lA). However, when meta-cresol and glycerin is used as the diluent (in the absence of human growth hormone) less tissue irritation is observed as shown by a decrease in creatinine phosphokinase levels (formula-tion number 2 versus l). Surprisingly, when humangrowth hormone is added to the meta-cresol/glycerin diluent (formulation 2A) muscle irritation is reduced even farther (formulation 2A versus 2). These results were confirmed histopathologically by observation that the incidence in severity of myositis in rabbits injected intramuscularly with formulation number 2A was less than in rabbits injected with formulation number lA.
Claims (7)
1. A parenteral pharmaceutical formulation comprising an effective amount of human growth hormone, meta-cresol and glycerin.
2. The formulation of claim 1 additionally containing a pharmaceutically acceptable vehicle.
3. The formulation of claim 2, containing from 0.15 to 0.4 percent by weight meta-cresol and from 0.5 to 10 percent by weight glycerin.
4. The formulation of claim 3 containing from 0.2 to 0.3 percent by weight metal-cresol and from 1 to 2 percent by weight glycerin.
5. The use of a parenteral pharmaceutical formulation in parenteral dosage form which contains an effective amount of human growth hormone, meta-cresol, glycerin and a pharmaceutic-ally acceptable vehicle therefor, for reducing muscle irritation resulting from an intra-muscular injection of human growth hormone to a patient in need thereof.
6. Use as in claim 5 wherein said parenteral dosage form contains from 0.15 to 0.4 percent by weight meta-cresol and from 0.5 to 10 percent by weight glycerin.
7. Use as in claim 6 wherein said parenteral dosage form contains from 0.2 to 0.3 percent by weight meta-cresol and from 1 to 2 percent by weight glycerin.
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| US11698387A | 1987-11-05 | 1987-11-05 | |
| US07/116,983 | 1987-11-05 |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CA1326439C true CA1326439C (en) | 1994-01-25 |
Family
ID=22370405
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CA 566846 Expired - Fee Related CA1326439C (en) | 1987-11-05 | 1988-05-16 | Parenteral growth hormone formulations |
Country Status (3)
| Country | Link |
|---|---|
| AU (1) | AU614551B2 (en) |
| CA (1) | CA1326439C (en) |
| NZ (1) | NZ226816A (en) |
Families Citing this family (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| ZA9711731B (en) * | 1996-12-31 | 1998-07-01 | Monsanto Co | Aqueous glycerol formulations of somatotropin |
-
1988
- 1988-05-16 CA CA 566846 patent/CA1326439C/en not_active Expired - Fee Related
- 1988-11-02 NZ NZ22681688A patent/NZ226816A/en unknown
- 1988-11-02 AU AU24621/88A patent/AU614551B2/en not_active Ceased
Also Published As
| Publication number | Publication date |
|---|---|
| NZ226816A (en) | 1991-04-26 |
| AU614551B2 (en) | 1991-09-05 |
| AU2462188A (en) | 1989-05-11 |
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Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| MKLA | Lapsed |