NZ226816A - Parenteral formulation comprising somatotropin, m-cresol and glycerin - Google Patents

Description

New Zealand Paient Spedficaiion for Paient Number £26816 226818 NO DRAWINGS Priority Date(s): ... .V?..) .1 J.' Complete Specification Filed:<^".ii.sv.vi Class- A^IK^/Sb, vloao, ill i t • « i • • t » itI • la ■■••••«• Publication Date: .2.5.APR. ,m..

P.O. Journal, No: . ....13.46.; No.: Date: NEW ZEALAND PATENTS ACT, 1953 COMPLETE SPECIFICATION PARENTERAL GROWTH HORMONE FORMULATIONS X}c/We, ELI LILLY AND COMPANY, a corporation of the State of Indiana, United States of America, having a principal place of business at Lilly Corporate Center, City of Indianapolis, State of Indiana 46285, United States of America hereby declare the invention for which we pray that a patent may be granted to ma/us, and the method by which it is to be performed, to be particularly described in and by the following statement:- - 1 - (followed by page la) 22 6 8 1 6 X-7308 -1«*- TITLE PAiiEirrDnAL growth hormone formulations 5 Background of the Invention The routes available for the delivery of pharmacologically active agents include oral, rectal or parenteral administration, among others. Oral adminis-10 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 desirable to avoid first.pass hepatic metabolism, rectal 15 administration may be an alternative. Similarly, 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 disadvan-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 25 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 thera-30 peutic agents are preferably administered parenterally. 22 6 8 X-7308 -2- 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 5 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. 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 N-terminus of the protein.

Human growth hormone is administered subcuta neous ly 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 20 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 30 disclosed and claimed is a method for reducing muscle 226816 X-7308 irritation 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, 5 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 j resulting from an intramuscular injection of human j growth hormone. As mentioned earlier, human growth | hormone is commercially available as the native material isolated from human pituitary glands or as two biosyn- j j thetically produced forms, one of which is identical to j the native material and the other having an additional v methionine residue at the N-terminus. For purposes of the present invention any one or a combination of the 20 three may be present in the parenteral formulation —v although the biosynthetically produced material which is identical to native human growth hormone is preferred. The human growth hormone is present in said formulation in an effective amount. By "effective 25 amount" is meant that quantity of human growth hormone necessary to stimulate growth when administered in Vv-—■/ 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., 30 whether intended for single or multiple use administra- ) ! tion. 22 6 8 1 6 X-7308 -4- 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 10 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 15 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 injection and the like. Nonaqueous vehicles include 20 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 25 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 30 treatises such as Remington's Pharmaceutical Sciences, 22 6 8 1 6 X-7308 -5- 17th Edition (1985), which is incorporated herein by reference.

Upon intramuscular injection, the formulations of the present invention reduce muscle irritation when 5 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 10 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 25 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. 30 with increased muscle irritation. These creatinine phosphokinase measurements were made prior to, and 24 22 6 8 1 6 X-7308 -6- hours after injection. Additionally, 72 hours after injection, 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 assessments are shown in Table I.

Table I Formulation Mean CPK Mean Muscle No. Components Values Irritation 1 0.3% meta-cresol 1895 0.83 0.2% phenol 1.7% glycerin 1A Same as 1 but 2449 1.86 with 0.2% human growth hormone added 2 0.3% meta-cresol 1628 0.30 1.7% glycerin 2A Same as 2 but 911 O1^ with 0.2% human growth hormone added a In percent by weight b Mean creatinine phosphokinase values 24 hours after injection expressed in International units per liter c Expressed as the volume of water displaced (in milliliters) by the irritated portion of the muscle tissue excised 40 ^ No irritated muscle tissue present for measurement 22 6 8 1 6 X-7308 -7- 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 5 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 1). Surprisingly, when human growth 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 15 the incidence in severity of myositis in rabbits injected intramuscularly with formulation number 2A was. less than in rabbits injected with formulation number 1A. 22681G

Claims (8)

WHAT WE CLAIM IS:

1. A parenteral pharmaceutical formulation comprising an effective amount of human growth hormone, from 0.15 to 0.4 percent by weight meta-cresol and from 0.5 to 10 percent by weight glycerin.

2. The formulation of claim 1 as lyophilized powder.

3. The formulation of claim 2 additionally containing a pharmaceutically acceptable vehicle.

4. The formulation of any one of claims 1 to 3 containing from 0.2 to 0.3 percent by weight meta-cresol and from 1 to 2 percent by weight glycerin.

5. A method for reducing muscle irritation resulting from an intramuscular injection of human growth hormone administered to a non-human patient in need thereof comprising injecting a parenteral dosage form comprising an effective amount of human growth hormone, from 0.15 to 0.4 percent by weight meta-cresol, from 0.5 to 10 percent by weight glycerin and a pharmaceutically acceptable vehicle therefor.

6. The method of claim 5 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.

7. A parenteral pharmaceutical formulation as claimed in claim 1 substantially as hereinbefore described. described.

8. A method as claimed in claim 5 substantially as hereinbefore . , >c?/Their authorised Agent . J. f-ARK & SON, Per: '