AU614551B2 - Parenteral growth hormone formulations - Google Patents

Description

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4551 S F Ref: 74103 FORM COMMONWEALTH OF AUSTRALIA PATENTS ACT 1952 COMPLETE SPECIFICATION

(ORIGINAL)

FOR OFFICE USE: Class Int Class Complete Specification Lodged: Accepted: o Published: o Priority: Related Art: 0o o Name and Address of Applicant: Eli Lilly and Company i Lilly Corporate Center Indianapolis Indiana 46285 UNITED STATES OF AMERICA Address for Service: Spruson Ferguson, Patent Attorneys Level 33 St Martins Tower, 31 Market Street Sydney, New South Hales, 2000, Australia Complete Specification for the invention entitled: Parenteral Growth Hormone Formulations The following statement is a full description of this invention, including the best method of performing it known to me/us 5845/3

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TITLE

PARENTERAL GROWTH HORMONE FORMULATIONS Background of the Invention The routes available for the delivery of pharmacologically active agents include oral, rectal or parenteral administration, among others. Oral administration is clearly the most convenient to the patient, however, it is not always possible to administer drugs o orally. For example, in instances where the patient is o o vomiting or unconscious or where it may otherwise be desirable to avoid first.pass hepatic metabolism, rectal S00 15 administration may be an alternative. Similarly, s parenteral administration may be required for the 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 d'isadvan- S 20 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 administration is required, the patient may experience discomfort or pain owing to the physical invasion of the tissue or the particular parenteral formulation administered. Notwithstanding this apparent disadvantage certain therapeutic agents are preferably administered parenterally.

i ~1 LYI-*IIY X-7308 -2f cr t tf t $i t t~ SCLef ft t C O C f t C: C I cc L C cc CC C C C One such group of therapeutic agents is the anterior pituitary hormones including adrenal corticotropic hormone, human chorionic gonadotropin, follicle stimulating hormoie, 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 biosynthetically as a result of advances in genetic engineering.

10 At present there are two commercially available forms of the genetically engineered hormone, one of which is identical to native human growth hormone. The other form has an additional methionine residue at the Nterminus of the protein.

15 Human growth hormone is administered subcutaneously 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.

Summary 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 growth hormone, meta-cresol and glycerin. Also disclosed and claimed is a method for reducing muscle

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4Ii -3irritation resulting from an intramuscular injection of human growth hormone. Said method is effected by injecting a parenteral formulation containing an effective amount of said human growth hormone, meta-cresol, glycerin and a pharmaceutically acceptable vehicle therefor.

According to a first embodiment of this invention, there is provided a parenteral pharmaceutical formulation comprising an effective amount of human growth hormone, meta-cresol and glycerin.

According to a second embodiment of this invention, there is provided a method for reducing muscle irritation resulting from an intramuscular injection of human growth hormone administered to a patient in need thereof comprising injecting a parenteral dosage form which contains an effective amount of human growth hormone, meta-cresol, glycerin and a pharmaceutically acceptable vehicle therefor.

Detailed Descrintion of the Invention I 0 fI b 0000 i 000 o0, a 15 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 pituitary glands or as two biosynthetically produced forms, one of which .o0 20 is identical to the native material and the other having an additional methionine residue at the N-terminus. For purposes of the present o° 0 invention any one or a combination of the three may be present in the 0000 parenteral formulation although the biosynthetically produced material which is identical to native human growth hormone is preferred. The Oo°o 25 human growth hormone is present in said formulation in an effective 0 0 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, whether intended for single or multiple use administration.

-i X-7308 -4- In addition to the human growth hormone, the formulation of the present invention also contains metacresol and glycerin as a diluent, the combination of which serves to reduce muscle irritation upon injection.

The meta-cresol 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 preferably about 1 to 2 percent by weight.

The commercially available formulation will t preferably, though not necessarily, be in the form of a lyophilized freeze-dried) powder for reconstituition. Reconstitution of the formulation may be effected 2? 15 by the addition of a pharmaceutically acceptable vehicle therefor which may be aqueous or nonaqueous innature.

Examples of aqueous vehicles include water for injection, bacteriostatic water for injection, sterile water for injection and the like. Nonaqueous vehicles include corn oil, cottonseed oil, ethyl oleate, peanut oil, sesame oil and the like. The selection of the pharmaceutically 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, 2 X-7308 1 r 7th Edition (1985), which is incorporated herein by eference.

i- 0 4* 4 0 40*0 4140 10 0 4 4 00 4t 0 4 4 1 4 C 00 C 0 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 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 15 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 20 irritation was conducted. Four different formulations 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 irritation as a result of the injection was monitored by quantifying creatinine phosphokinase levels which increase.

with increased muscle irritation. These creatinine phosphokinase measurements were made prior to, and 24 r -1 X-7308 -6hours after injection. Additionally, 72 hours after in- Ki 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 mean muscle irritation). The results of these assessments are shown in Table I.

Table I

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r! 0 -r t 00 0 0 0 S 0 rr t f t 0 00e 00 00 0 t 0 0000 S 10 Formulation No.

1 15 Componentsa 0.3% meta-cresol 0.2% phenol 1.7% glycerin Same as 1 but with 0.2% human growth hormone added 0.3% meta-cresol 1.7% glycerin Same as 2 but with 0.2% human growth hormone added Mean CEK Values 1895 2449 Mean Muscl Irritation 0.83 1.86 t t C 0r 0 00 0 0 00 0r 0 0 0 0 1628 911 0.30

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d In percent by weight Mean creatinine phosphokinase values 24 hours after injection expressed in International units per liter Expressed as the volume of water displaced (in milliliters) by the irritated portion of the muscle tissue excised No irritated muscle tissue present for measurement d 7 m.Lly~-~ll~ I X-7308 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 7 phosphokinase levels and mean muscle irritation as compared to the diluent alone (formulation number 1 versus 1A). 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- 10 tion number 2 versus Surprisingly, when human growth hormone is added to the meta-cresol/glycerin diluent (formulation 2A) muscle irritation is reduced even farther (formulation 2A versus 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.

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Claims (8)

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 1 or 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 meta-cresol and from 1 to 2 percent by weight glycerin.

A method for reducing muscle irritation resulting from an intramuscular injection of human growth hormone administered to a patient S in need thereof comprising injecting a parenteral dosage form which contains an effective amount of human growth hormone, meta-cresol, glycerin and a pharmaceutically acceptable vehicle therefor.

6. The method of claim 5 wherein said parenteral dosage form contains from 0.15 to 0.4 percent by weight meta-cresol and from 0.5 to percent by weight glycerin.

7. The method of claim 6 wherein said parenteral dosage form I 20 contains from 0.2 to 0.3 percent by weight meta-cresol and from 1 to 2 percent by weight glycerin.

8. A parenteral pharmaceutical formulation, substantially as hereinbefore described with reference to Formulation 2A of Table I. DATED this ELEVENTH day of JUNE 1991 Eli Lilly and Company Patent Attorneys for the Applicant SPRUSON FERGUSON N, O /LMM/547Z