FIELD OF THE INVENTION

The present invention relates to a liquid formulation for parenteral administration comprising a somatostatin analogue buffered to a pH of about 3 to about 7.5.

The present invention relates to a liquid formulation for parenteral administration comprising a somatostatin analogue or a pharmaceutically acceptable salt thereof and a buffer selected from citrate and/or phosphate, wherein the formulation has a pH of about 4 to about 4.5.

The present invention relates to a liquid formulation for parenteral administration comprising Pasireotide Diaspartate and a buffer, wherein the buffer does not comprise tartaric acid, and wherein the formulation has a pH of about 4 to about 4.5.

The present invention relates to a process of preparing a liquid formulation for parenteral administration comprising a somatostatin analogue or a pharmaceutically acceptable salt thereof and a buffer selected from citrate and/or phosphate, wherein the formulation has a pH of about 4 to about 4.5.

The present invention relates to a method of treating Gushing's disease by administering a parenteral liquid formulation of a somatostatin analogue or a pharmaceutically acceptable salt thereof and a buffer selected from citrate and/or phosphate.

BACKGROUND OF THE INVENTION
Somatostatin is a tetradecapeptide having the structure:

Somatostatin inhibits the secretion of several hormone including growth hormone (GH), thyroid stimulating hormone (TSH), insulin, glucagon and gastrin. It also reduces intestinal absorption of glucose. It produces a decrease in blood glucose concentration.

The somatostatin class is a known class of small peptides comprising the naturally occurring somatostatin-14 and analogues having somatostatin related activity, e.g. as disclosed by A. S. Dutta in Small Peptides, Vol. 19, Elsevier (1993). By "somatostatin analog" as used herein is . meant any straight-chain or cyclic polypeptide having a structure based on that of the naturally occurring somatostatin-14 wherein one or more amino acid units have been omitted and/or replaced by one or more other amino radical(s) and/or wherein one or more functional groups have been replaced by one or more other functional groups and/or one or more groups have been replaced by one or several other isosteric groups.

Natural somatostatin binds and activates all 5 somatostatin receptors (SSTR1-5) with nmol efficacy and thus causes its multiple physiological effects. Synthetically available somatostatin analogs differ in their binding affinity to the different somatostatin receptor " subtypes and often bind selectively to one or few subtypes with significantly higher affinity.

A somatostatin analog of particular interest according to the present invention has a high binding affinity to human and have been described e.g. inThe
preferred example of such a somatostatin (SRIF) peptidomimetic (also referred to as Somatostatin- or SRIF-analog) is pasireotide.

Pasireotide, also called cyclo
Phg meaning and Bzl meaning benzyl, is for instance
disclosed in and is represented by the following formula:

In WO02/10192 also disclosed a synthesis for and uses of pasireotide.

Pasireotide has been shown to have an inhibitory effect on the secretion of several hormones (e.g. GH, GH dependent and GH independent IGF-1 secretion, ACTH, Cortisol resp. corticosterone) and can be used, for instance, in the treatment of disorders with an aetiology comprising or associated with excess GH-secretion and/or excess of IGF-1.

Cushing's syndrome is a hormone disorder caused by high levels of Cortisol in the blood. This can be caused by taking, glucocorticoid drugs, or by tumors that produce. Cortisol or adrenocorticotropic hormone (ACTH) or CRH. Cushing's disease refers to one specific cause of the syndrome: a tumor (adenoma) in the pituitary gland that produces large amounts of ACTH,. which elevates Cortisol. It is the most common cause of Cushing's syndrome, responsible for 70% of cases excluding glucocorticoid related cases. The significant decrease of Cortisol levels in Cushing's disease patients on pasireotide support its potential use as a targeted treatment for Cushing's disease (Colao et al N Engl J Med 2012; 366:32-42).

International Patent Application WO2005/00893 describes parenteral liquid pharmaceutical compositions comprising a somatostatin analogue and tartaric acid. Preferably, parenteral . liquid pharmaceutical compositions of a pasireotide diaspartate and tartaric acid are described in detail under WO2005/00893.

WO2005/00893 also describes parenteral liquid pharmaceutical compositions comprising a somatostatin analogue and replacement of tartaric acid/tartrate by another buffer such as acetate/acetic acid, lactate/lactic acid, and Glycin/HCl.

Since, proteolytic degradation of the somatostatin analogues is high, liquid parenteral pharmaceutical compositions of somatostatin analogues for systemic delivery is highly desirable.

Despite WO2005/00893 describes parenteral liquid pharmaceutical compositions of pasireotide diaspartate with tartaric acid, there is a need for an alternative liquid compositions of pasireotide diaspartate and a process of preparing thereof.
Surprisingly, the inventors of present application have developed novel parenteral liquid pharmaceutical compositions comprising pasireotide or pharmaceutically acceptable salt thereof and citrate -phosphate buffer or citrate buffer, with improved properties.

SUMMARY OF THE INVENTION
Aspects of the present invention relates to a to a liquid formulation for parenteral administration comprising pasireotide diaspartate and a buffer, wherein the buffer does not comprise tartaric acid, and wherein the formulation has a pH of about 3 to about 7.5.
Aspects of the present invention relates to a to a liquid formulation for parenteral administration comprising pasireotide diaspartate and a buffer, wherein the buffer does not comprise tartaric acid, and wherein the formulation has a pH of about 4 to about 4.5.
Aspects of the present invention relates to a liquid formulation for parenteral administration comprising a somatostatin analogue or a pharmaceutically acceptable salt thereof and a buffer selected from citrate and/or phosphate, wherein the formulation has a pH of about 3 to about 7.5.
Aspects of the present invention relates to a liquid formulation for parenteral administration comprising a somatostatin analogue or a pharmaceutically acceptable salt thereof and a buffer selected from citrate and/or phosphate, wherein the formulation has a pH of about 4 to about 4.5.
Aspects of the present invention relates to a liquid formulation for parenteral administration comprising a pasireotide or a pharmaceutically acceptable salt thereof and a buffer selected from citrate and/or phosphate, wherein the formulation has a pH of about 4 to about 4.5.
Specific aspects of the present invention relates to a liquid formulation for parenteral administration comprising a pasireotide diaspartate and a buffer selected from citrate and/or phosphate, wherein the formulation has a pH of about 4 to about 4.5.
Aspects of the present invention relates to a liquid formulation for parenteral administration comprising a pasireotide diaspartate, a buffer selected from citrate and/or phosphate, tonicity agent and a base.
Specific aspects of the present invention relates to a liquid formulation for parenteral
Administration comprising pasireotide diasparated and a buffer selected from citrate and/or
' phosphate, mannitol and sodium hydroxide, wherein the formulation has a pH of about 4 to about 4.5.
Aspects of the present invention relates to a process for preparing a parenteral liquid formulations of pasireotide diaspartate.
Aspects of the present invention relates to a method of treating Cushing's disease comprising administering a parenteral liquid formulation of pasireotide diaspartate.
DETALIED DESCRIPTION OF THE INVENTION
An embodiment of the present invention provides a liquid formulation for parenteral administration comprising a somatostatin analogue or a pharmaceutically acceptable salt thereof and a buffer selected from citrate and/or phosphate, wherein the formulation has a pH of about 3 to about 7.5 or about 4 to about 4.5.
Salts of somatostatin analogue include acid addition salts with e.g. inorganic acids, polymeric acids or organic acids, for example with hydrochloric acid, acetic acid, lactic acid, aspartic acid, benzoic acid, succinic acid or pamoic acid. Acid addition salts may exist as mono- or divalent salts, e.g. depending whether 1 or 2 acid equivalents are added. Preferred salts are the lactate, aspartate, benzoate, succinate and pamoate including mono- and di-salts, more preferably the aspartate di-salt and the pamoate monosalt. The somtatostain analogue may be octreotide, lanreotide or pasireotide and their salts.
The terms "composition" and "formulation" can be used interchangeably according to the present invention.
One of the embodiments of the present invention provides a liquid formulation for parenteral administration comprising pasireotide or a pharmaceutically acceptable salt thereof and a buffer selected from citrate and/or phosphate, wherein the formulation has a pH of about 4 to about 4.5.

One of the particular embodiments of the present invention provides a liquid formulation for parenteral administration comprising pasireotide diaspartate and a buffer selected from citrate and/or phosphate, wherein the formulation has a pH of about 4 to about 4.5.,
Another embodiment of the present invention provides a liquid formulation for parenteral administration comprising pasireotide diaspartate, a buffer selected from citrate and/or phosphate, tonicity agent and a base, wherein the formulation has a pH of about 4 to about 4.5.
Citrate buffer contains citric acid and sodium citrate. Phosphate and citrate buffer (phosphate-citrate buffer) contains citric acid and dibasic sodium phosphate.
Base for a liquid parenteral formulation of present invention are selected from sodium hydroxide or potassium hydroxide, or a basic salt e.g. sodium hydrogen carbonate, sodium carbonate, potassium hydrogen carbonate, or potassium carbonate. The basic component is added in such an amount that the resulting pharmaceutical composition has a pH of about 4 to about 4.5. In an aspect, the basic component is added in such an amount to get a resultant solution pH of about 4.2.
The pH of a solution is the negative logarithm of the hydrogen ion activity, which may be measured potentiometrically. The pH can be measured using glass electrode or hydrogen electrode or calomel electrodes. But glass electrode finds wide applicability as it shows an immediate response to rapid changes of hydrogen ion concentrations even in poorly buffered solutions. Preferably the pH of the formulation is measured according to USP32-NF27 (791).
The parenteral liquid formulations of the present invention are water or aqueous based. By "aqueous based" is meant a solution consisting of water and a water-miscible organic solvent or solvents. When an organic co-solvent is employed it is preferred that the it is used in amounts of up to 10% by weight, e.g. 0.5 to 10, more particularly 1 to 10% by weight. Suitable solvents are those water-miscible solvents commonly used in the art, for example propylene glycol, polyethylene glycol 300, polyethylene glycol 400 and ethanol. Preferably, organic co-solvents are only used in cases where the active agent is not sufficiently soluble in water for a therapeutically effective amount to be provided in a single dosage form. In a aspect the solvent consists solely of water

A tonicity agent for a liquid parenteral formulation of the present invention is selected from a group comprising mannitol, sodium chloride, glucose, dextrose, sucrose, glycerin, and combinations thereof. Preferably, the tonicity agent is mannitol. The tonicity agent has the effect of rendering the osmotic pressure of the formulation the same as that of body fluid.

The isotonic agents may be used in quantities which impart to the parenteral formulation the same osmotic pressure as body fluid: The precise amount necessary to achieve the desired effect may depend on factors such as the concentration of active agent in the parenteral formulation, and is a matter of routine experimentation which the skilled person may determine without exercising any inventive thought and using only common general knowledge. E.g. mannitol preferably may be from about 1% to about 5% by weight of the composition.

One of the embodiments of the present invention provides a process of preparing a parenteral
liquid formulation of somatostatin analogue or a pharmaceutically acceptable salt thereof
comprising:

Step-(a): dissolving citrate or phosphate-citrate buffer and mannitol to get a clear solution,

Step-(b): dissolving a somatostatin analogue or a pharmaceutically acceptable salt thereof,

Step-(c): adjusting the pH of the solution to about 4 to about 4.5 with a base,

Step-(d): filtering the solution of step (c) through a sterile filter,

Step-(e): filling the solution (d) into a suitable injectable pack, and

Step-(f): sterilizing the injectable pack.

One of the particular embodiments of the present invention provides a process of preparing a
parenteral liquid formulation of pasireotide diaspartate comprising:

Step-(a): dissolving citrate or phosphate-citrate buffer and mannitol to get a clear solution,

Step-(b): dissolving pasireotide diaspartate,

Step-(c): adjusting the pH of the solution to about 4 to about 4.5 with a base,

Step-(d): filtering the solution of step (c) through a sterile filter,

Step-(e): filling the solution (d) into a suitable injectable pack, and

Step-(f): sterilizing the injectable pack.

Citrate buffer of present invention is a simple addition of appropriate amounts of citric acid and sodium citrate. Phosphate-citrate buffer contains citric acid and dibasic sodium phosphate. The buffers are prepared according to methods known in the art.

Citrate or Phosphate-citrate buffer, and mannitol are dissolved in water for injection, while the solution is optionally purged with nitrogen to reduce the oxygen level of solution.

Dissolving a somatostatin analogue or a pharmaceutically acceptable salt thereof can be achieved by adding the drug and gentle mixing to get clear solution.

The pH of the solution can be adjusted to about 4 to about 4.5 with a base. A suitable base is selected from sodium hydroxide or potassium hydroxide, or a basic salt e.g. sodium hydrogen carbonate, sodium carbonate, potassium hydrogen carbonate, or potassium carbonate. It involves a simple addition and mixing to get a clear solution of desired pH of about 4 to about 4.5.

The filtration of solution can be done through a sterile filter, for Eg: MILLIPAK-200®.

The parenteral formulation prepared as hereinabove described may be filtered through a sterile filter with, for example a 0.22 micron pore size, and collected into containers.

The injectable solution is filled into a suitable injectable pack. The suitable pack or containers are ampoules, vials, or syringes.

The process of filling containers with the parenteral formulation should be carried out under sterile, aseptic conditions according to procedures well known in the art Preferably the process is carried out in a Grade C clean area (Class 10,000).

The injectable pack may be stoppered and sealed, and sterilized in an autoclave at a temperature above 100°C for about 75 minutes or about 121 °C for about 15 minutes.

Alternatively the solution may be freeze-dried by a conventional method under aseptic conditions to give a powder for injection which may be jised to reconstitute the desired

solution for parenteral administration shortly before administration by mixing the powder with the desired amount of solvent e.g. with water for injection.

Additional excipients may be employed in the case of multi-dose vials. These are needed to provide the required stability and therapeutic efficacy. The excipients may include e.g. an antioxidant or a preserving agent.

Antioxidants may be employed to protect the active agent from oxidative degradation particularly under the accelerated conditions of thermal sterilisation. Antioxidants may be selected from any of those compounds known in the art. Similarly, the amount of antioxidant employed can be determined using routine experimentation. The antioxidants are selected from ascorbic acid, butylated hydroxy toluene, butylated hydroxy anisole, sodium thiosulfate, sodium metabisulfite, tocopherols. As an alternative to the use of antioxidant compounds, the antioxidant effect can be achieved by displacing oxygen (air) from contact with the solution of active agent. This is usually carried out by purging with, e.g. nitrogen, a container holding the solution. Preferably, the compositions of the invention do not contain an antioxidant.

A preserving agent, e.g. phenol, may be added to the composition when it is formulated as multidose vials, cartridges or syringes. The preservatives are selected from benzalkonium chloride, benzethonium chloride, methylparaben, propylparaben, sodium benzoate, and thimerosal.

In one of the embodiments of the present invention, it provides a method of treating
Cushing's disease comprising administering a parenteral liquid formulation of a somatostatin
analogue such as pasireotide. .

The compositions of the invention are useful for one or more of the following:
i) for the prevention or treatment of disorders with an aetiology comprising or associated with
ii) excess GH-secretion and/or excess of IGF-1 e.g. in the treatment of acromegaly as well as in the treatment of type I or type II diabetes mellitus, especially complications thereof, e.g. angiopathy, diabetic proliferative retinopathy, diabetic macular edema, nephropathy, neuropathy and dawn phenomenon, and other metabolic disorders related to insulin or
glucagon release, e.g. obesity, e.g- morbid obesity.or hypothalamic or hyperinsulinemic obesity,
ii) in the treatment of enterocutaneous and pancreaticocutaneous fistula, irritable bowel syndrom, inflammatory diseases, e.g. Grave's Disease, inflammatory bowel disease, psoriasis or rheumatoid arthritis, polycystic kidney disease, dumping syndrom, watery diarrhea syndrom, AIDS-related diarrhea, chemotherapy-induced diarrhea, acute or chronic pancreatitis and gastrointestinal hormone secreting tumors (e.g. GEP tumors, for example vipomas, glucagonomas, insulinomas, carcinoids and the like), lymphocyte malignancies, e.g. lymphomas or leukemias, hepatocellular carcinoma as well as gastrointestinal bleeding, e.g. variceal oesophagial bleeding,
iii) for the prevention or treatment of angiogenesis, inflammatory disorders as indicated above including inflammatory eye diseases, macular edema, e.g. cystoid. macular edema, idiopathic cystoid macular edema, exudative age-related macular degeneration, choroidal neovascularization related disorders and proliferative retinopathy,
iv) for preventing or combating graft vessel diseases, e.g. alio- or xenotransplant vasculo-pathies, e.g. graft vessel atherosclerosis, e.g. in,a transplant of organ, e.g. heart, lung, combined heart-lung, liver, kidney or pancreatic transplants, or for preventing or treating vein graft stenosis, restenosis and/or vascular occlusion following vascular injury, e.g. caused by catherization procedures or vascular scraping procedures such as percutaneous transluminal angioplasty, laser treatment or other invasive procedures which disrupt the integrity of the vascular intima of endothelium,
v) for treating somatostatin receptor expressing or accumulating tumors such as pituitary tumors, e.g. Cushing's Disease, gastro-enteropancreatic, carcinoids, central nervous system, breast, prostatic (including advanced hormone-refractory prostate cancer), ovarian or colonic tumors, small cell lung cancer, malignant bowel obstruction, paragangliomas, kidney cancer, skin cancer, neuroblastomas, pheochromocytomas, medullary thyroid carcinomas, myelomas, lymphomas, Hodgkins and non^Hodgkins lymphomas, bone tumours and metastases thereof, as well as autoimmune or inflammatory disorders, e.g. rheumatoid arthritis, Graves disease or other inflammatory eye diseases.

Preferably, the compositions of the invention are useful in the treatment of acromegaly and
cancer, e.g. Cushing's disease.
■
The liquid formulations of the present invention are useful for treating cushing's disease by administering the said formulation in a subject in need thereof.
Appropriate dosage of the composition of the invention will of course vary, e.g. depending on the condition to be treated (for example the disease type or the nature of resistance), the drug used, the effect desired and the mode of administration.
When given continuously, an effective amount of drug may be given in two or three doses spread over time such as by parenteral administration, e.g. intravenous drip, intramuscular or subcutaneous injection(s), or subcutaneous infusion, e.g. continuous subcutaneous infusion, preferably subcutaneous injection or infusion, with the total daily dose being spread across the portion or the entire administration period. When given by subcutaneous injection, it is most preferably administered from 3 times per week up to 3 times a day, preferably twice a week up to once or twice daily. A compound of the invention may also be administered in the form of e.g. a subcutaneous bolus injection.
The composition of the invention preferably is suitable for subcutaneous administration.
After injection, the composition of the invention is locally well tolerated. Particularly, the parenteral administration of a composition of the invention, e.g. subcutaneous injection, leads to mild to no-burning sensation at the injection site.
The following examples serve to illustrate the embodiments of the present invention. However, they do not intend to limit the scope of the invention.


Manufacturing process: Add and dissolve citric acid, dibasic sodium phosphate and mannitol in water for injection maintained at 20°C - 25°C, while the solution is purged with nitrogen. Then diaspartate salt of pasireotide is added, the solution is adjusted with sodium hydroxide to pH 4.20 and made up to 100 % batch size with WFL Under aseptic conditions, the solution is filtered through a 0.2 |i sterile filter, filled into ampoules, sealed and sterilized by autoclaving.

Manufacturing process: Add and dissolve citric acid, sodium citrate and mannitol in water for injection maintained at 20°C - 25°C, while the solution is purged with nitrogen. Then diaspartate salt of pasireotide is added, the solution is adjusted with sodium hydroxide to. pH 4.20 and make up to 100 % batch size with WFL Under aseptic conditions, the solution is filtered through a 0.2^ sterile filter, filled into ampoules, sealed and sterilized by autoclaving.

We Claim:

1. A liquid formulation for parenteral administration comprising pasireotide or a
pharmaceutically acceptable salt thereof and a buffer, wherein the buffer does not comprise
tartaric acid, and wherein the formulation has a pH of about 3 to about 7.5.
2. The liquid formulation according to claim 1, wherein the pasireotide salt is diaspartate.
3. The liquid formulation according to claim 1, wherein the buffer is citrate and/or phosphate.
4. The liquid formulation according to claim 3, wherein the composition is buffered by citric . acid/sodium citrate or citric acid/dibasic sodium phosphate.

5. The liquid formulation according to claim 1, additionally, comprising isotonicity agent and abase. .
6. The liquid formulation according to claim 5, which comprises pasireotide diaspartate, mannitol, citric acid, sodium hydroxide and sodium citrate.
7. The liquid formulation according to claim 5, which comprises pasireotide diaspartate, mannitol, citric acid, sodium hydroxide and dibasic sodium phosphate.
8. The liquid formulation according to claims 6 and 7, having a pH of about 4 to about 4.5.
9. A process of preparing liquid formulation of pasireotide diaspartate for parenteral
administration according to claim 1 comprising the following steps:
(a) buffer and isotoncity agent are dissolved in water for injection,
(b) pasireotide diaspartate is dissolved in step (a) solution,
(c) pH of step (b) solution is adjusted with a base to about 4 to about 4.5,

(d) step (c) solution is filtered through a sterile filter,
(e) step (d) solution is filled into suitable injectable packs, and
(f) packs of step (e) are sterilized.

10. The liquid formulation according to claim 1, which is useful for treating cushing's disease by administering the said formulation in a subject in need thereof.