GB2417202A

GB2417202A - Pharmaceutical preparation comprising calcitonin

Info

Publication number: GB2417202A
Application number: GB0418270A
Authority: GB
Inventors: Amar Lulla; Geena Malhotra
Original assignee: Cipla Ltd
Current assignee: Cipla Ltd
Priority date: 2004-08-16
Filing date: 2004-08-16
Publication date: 2006-02-22
Also published as: GB0418270D0

Abstract

A pharmaceutical formulation for nasal administration comprising (i) calcitonin, or a pharmaceutically acceptable salt or derivative (ii) a pharmaceutically acceptable liquid carrier and (iii) at least one preservative selected from sorbic acid, benzoic acid or pharmaceutically acceptable salts of sorbic or benzoic acid. Preferably the preservative is potassium sorbate, sodium benzoate or potassium benzoate. The calcitonin may be human, salmon, eel or porcine and is preferably present as a hydrochloride or acetate salt. The pharmaceutical may be used to treat osteoporosis. Methods of manufacturing the pharmaceutical are also described.

Description

241 7202

PHARMACEUTICAL FORMULATION

The present invention is concerned with a novel formulation comprising calcitonin, a process for preparing such a formulation, therapeutic uses thereof and methods of treatment employing the same.

Calcitonin comprises pharmaceutically active, long-chain polypeptides. Calcitonin is a hormone known to participate in calcium and phosphorus metabolism. In mammals, the major source of calcitonin is from the parafollicular or C cells in the thyroid gland, but it is also synthesized in a wide variety of other tissues, including the lung and intestinal tract. In birds, fish and amphibians, calcitonin is secreted from the ultimobrachial glands.

Calcitonin is a 32 amino acid peptide cleaved from a larger prohormone. It contains a single disulfide bond, which causes the amino terminus to assume the shape of a ring. Alternative splicing of the calcitonin premRNA can yield an mRNA encoding calcitonin gene-related peptide, which appears to function in the nervous and vascular systems. Calcitonin can be extracted from a number of sources including salmon, porcine, eel and human. Calcitonins with amino acid sequences identical to natural forms have been produced by chemical synthesis as well as by recombinant technology.

A large and diverse set of effects has been attributed to calcitonin. It seems clear, however, that calcitonin plays a role in calcium and phosphorus metabolism as referred to above. In particular, calcitonin has the ability to decrease blood calcium levels at least in part by its effects on bone and kidney. In this respect, calcitonin suppresses resorption of bone by inhibiting the activity of osteoclasts, a cell type that "digests" bone matrix, releasing calcium and phosphorus into blood. In kidney, calcium and phosphorus are prevented from being lost in urine by reabsorption in the kidney tubules, with calcitonin inhibiting tubular reabsorption of these two ions.

There are several therapeutic uses for calcitonin. It is used to treat hypercalcemia resulting from a number of causes, and has been a valuable therapy for Paget disease, which is a disorder in bone remodeling. Calcitonin also appears to be a valuable aid in the management of certain types of osteoporosis. Despite their size and chemical composition, various formulations of calcitonin are available on the market, for example injections, nasal preparations and the like.

US 5759565 describes the nasal formulation of calcitonin in a multi-dose container that was stable for an extended period of time and resisted bacterial contamination. The preservative in the formulation, benzalkonium chloride, was found to enhance the absorption of salmon calcitonin.

EP 0277462B describes pharmaceutical compositions in the form of aqueous solutions for the nasal administration of human calcitonin, a process for the production of these pharmaceutical compositions and their use. The pharmaceutical composition contains: a) a therapeutically effective amount of human calcitonin or a derivative thereof; b) viscosity- increasing swelling agents, and c) an aqueous vehicle optionally containing isotonic additives and / or additional auxiliaries.

WO 01/56594 describes a liquid pharmaceutical composition comprising calcitonin or an acid addition salt thereof, and citric acid or salt thereof, in a form suitable for nasal administration.

US 6197328 describes a nasal composition containing insulin, calcitonin, prostaglandin (PG) derivatives, monoclonal antibodies or interleukin derivatives (IL), and enhances the in viva adsorbability of the drug when administered nasally.

EP 0471618B describes emulsion preparations for nasal administration containing calcitonin.

The emulsions are prepared by using a calcitonin as the active ingredient, an azacycloalkane derivative, such as 1-[2-(decylthio)ethyl] azacyclopentan-2-one, as an absorption promoter, and glycyrrhizic acid or a salt thereof.

A problem that has been experienced with prior art nasal formulations of calcitonin as discussed above is the avoidance of contamination e.g. by micro-organisms. Provision of an appropriate, compatible and effective preserving agent to protect against contamination is especially critical for a nasal pharmaceutical composition, where the risk of contamination is particularly high. The preserving agent must suffice to provide not only for initial contamination avoidance, e.g. during formulation and filling of the composition into its container, but continued contamination avoidance during use, particularly where multiple dosing from a single container is required.

Hence, it is an object of the present invention to provide a pharmaceutical formulation of calcitonin, or salts or derivatives thereof, for nasal administration comprising a suitable preservative, along with other excipients in the formulation.

Another object of the present invention is to provide a method of improving the stability of a liquid pharmaceutical formulation comprising calcitonin or salts or derivatives thereof, with a suitable preservative and other excipients in the formulation Yet another object of the present invention is also to provide a method of administering calcitonin to a subject requiring calcitonin treatment, which method comprises administering via the nasal route to said subject a liquid pharmaceutical formulation comprising calcitonin or salts or derivatives thereof, with a suitable preservative and other excipients in the formulation.

Yet another object is to provide a process for manufacturing a pharmaceutical formulation comprising calcitonin or salts or derivatives thereof, for nasal administration comprising a suitable preservative agent along with other excipients in the formulation.

According to the present invention, therefore, there is provided a pharmaceutical formulation for nasal administration, which formulation comprises (i) calcitonin, or a pharmaceutically acceptable salt or derivative thereof, (ii) a pharmaceutically acceptable liquid carrier, and (iii) at least one preservative selected from the group consisting of sorbic acid, pharmaceutically acceptable salts of sorbic acid, benzoic acid and pharmaceutically acceptable salts of benzoic acid.

It is preferred that a formulation according to the present invention may be applied to the nasal mucosa in the form of a nasal solution or nasal spray form, more preferably in the form of nasal spray, i.e. in the form of finely divided droplets. Accordingly, in a further aspect of the present invention there is provided a nasal spray comprising (i) calcitonin, or a pharmaceutically acceptable salt or derivative thereof, (ii) a pharmaceutically acceptable liquid carrier, and (iii) at least one preservative selected from the group consisting of sorbic acid, pharmaceutically acceptable salts of sorbic acid, benzoic acid and pharmaceutically acceptable salts of benzoic acid.

It is preferred that the preservative is selected from the group consisting of pharmaceutically acceptable salts of sorbic acid, and pharmaceutically acceptable salts of benzoic acid. It certain embodiments one or more pharmaceutically acceptable salts of sorbic acid are preferred for use as a preservative in a formulation as provided by the present invention.

Alternatively it may be preferred that the preservative is selected from one or more pharmaceutically acceptable salts of benzoic acid. A preferred salt of sorbic acid for use in accordance with the present invention is potassium sorbate. Preferred salts of benzoic acid for use in accordance with the present invention are sodium benzoate and potassium benzoate, especially sodium benzoate.

In the case where the preservative comprises one or more pharmaceutically acceptable salts of sorbic acid, such as potassium sorbate, a preferred concentration thereof is in the range of about 0.1% - 0.2%, typically about 0.12%, of the formulation. In the case where the preservative comprises one or more pharmaceutically acceptable salts of benzoic acid, such as sodium benzoate, a preferred concentration thereof is in the range of about 0.02% - 0.5%, typically about 0.1% of the formulation.

The term "calcitonin" as used herein in the entire specification and claims is employed in a broad sense to include not only naturally occurring calcitonins, but also its pharmaceutically available derivatives and analogues, e.g. in which one or more of the peptide residues present in the naturally occurring product is replaced or in which the N- or Cterminal is modified.

More specifically, the present invention covers the use of"variants", "analogs", "derivatives" and "fragments" of naturally occurring calcitonins, and the terms "variants", "analogs", "derivatives" and "fragments" as used herein can be characterised as polypeptides which retain essentially the same biological function or activity as naturally occurring calcitonins.

Thus, for example, an analog might include a proprotein, such as a larger prohormone from which calcitonin can be derived, which can be activated by cleavage of the proprotein portion s to produce active mature calcitonins. Suitably, variants, analogs, derivatives and fragments, and variants, analogs and derivatives of the fragments as described herein have a primary structural conformation of amino acids in which several or a few (such as 5 to 10, I to 5 or I to 3) amino acid residues are substituted, deleted or added, in any combination when compared to the sequence of naturally occurring calcitonins. Especially preferred among these are silent substitutions, additions and deletions which do not alter or substantially alter the biological activity or function associated with naturally occurring calcitonins.

Conservative substitutions can be preferred as hereinafter described in greater detail.

More particularly, variants, analogs or derivatives may be: (i) ones in which one or more of the amino acid residues are substituted with a conserved or non-conserved amino acid residue (preferably a conserved amino acid residue); or (ii) ones in which one or more of the amino acid residues includes a substituent group; or (iii) ones in which additional amino acids are fused to the mature calcitonins, such as a proprotein or prohormone sequence as referred to above.

Such variants, derivatives and analogs are deemed to be within the scope of those skilled in the art from the teachings herein.

Most typically, variants, analogs or derivatives are those that vary from a reference calcitonin by conservative amino acid substitutions. Such substitutions are those that substitute a given amino acid by another amino acid of like characteristics. Typically seen as conservative substitutions are the replacements, one for another, among the aliphatic amino acids A, V, L and I; among the hydroxyl residues S and T; among the acidic residues D and E; among the amide residues N and Q; among the basic residues K and R; and among the aromatic residues F and Y. More particularly, the term "fragment" as used herein denotes a calcitonin having an amino acid sequence that entirely is the same as part but not all of the amino acid sequence of a naturally occurring calcitonin and such fragments may be "free standing", i.e. not part of or fused to other amino acids or polypepbdes, or they may be comprised within a larger polypepbde of which they form a part or region.

Naturally occurring calcitonin can be extracted from a number of sources including salmon, porcine, eel and human and have been extensively described in the literature along with their uses. The preferred source of calcitonin for use in accordance with the present invention is salmon and as such it is preferred that calcitonin as present in a formulation in accordance with the present invention is characterised as being salmon calcitonin.

Calcitonins with amino acid sequences identical to natural forms, as well as one or more variants, analogs, derivatives and fragments thereof, suitable for use in the present invention, can be produced by chemical synthesis as well as by recombinant technology.

Calcitonin used in formulations according to the present invention may be in the free form, or may be employed as a pharmaceutically acceptable salt or complex form. Such salts and complexes are well known in the art and are equivalent in degree of activity and tolerability to the free forms. Suitable acid addition salt forms include e.g. hydrochlorides and acetates.

An acceptable liquid carrier for the purpose of nasal administration in a formulation in accordance with the present invention comprises water, and more preferably saline water.

The formulations of the present invention are such that they are administered via the nasal route as hereinbefore described and hence may include certain minimum amounts of additional ingredients or excipients, as required.

For the purpose of nasal administration a mildly acidic pH is generally preferred. Preferably the formulations of the present invention have a pH in the range of 3 to 6, more preferably in the range of 3.5 to 4.5. The pH can be adjusted by addition of an appropriate acid, such as hydrochloric acid.

The formulations of the present invention also possess appropriate isotonicity and viscosity.

Preferably formulations according to the present invention have an osmotic pressure of 270 to 350 mOsm/liter.

For nasal administration the desired dose of calcitonin is about 200 IU per day, with the administration involving alternating nostrils daily.

For the purpose of nasal application a formulation according to the present invention is included in a suitable container provided with means enabling the application of the contained formulation to the nasal mucosa. Suitable applicators are known in the art and include those aiding the administration of liquid nasal formulations in the solution or spray form. Since the dosing of calcitonins should be done as accurately as possible, spray form is a more suitable medium. Spray form administrators suitable for use include atomizers, pump-atomizers, aerosols and the like.

It will be appreciated, therefore, that the present invention further provides a pharmaceutical product comprising (i) a housing containing a formulation comprising calcitonin, or a pharmaceutically acceptable salt or derivative thereof, a pharmaceutically acceptable liquid carrier and at least one preservative selected from the group consisting of sorbic acid, pharmaceutically acceptable salts of sorbic acid, benzoic acid and pharmaceutically acceptable salts of benzoic acid; and (ii) means enabling the application of the contained formulation to the nasal mucosa.

The stability of the formulations in accordance with the present invention may be defined by standard methods. For example, the content of calcitonin in a formulation as provided by the present invention under an inert atmosphere of nitrogen degrades less than about 10% in 24 months.

Also according to the present invention there is provided a process for preparing a pharmaceutical formulation substantially as hereinbefore described, in which process a pharmaceutically acceptable liquid carrier, at least one preservative selected from the group consisting of sorbic acid, pharmaceutically acceptable salts of sorbic acid, benzoic acid and pharmaceutically acceptable salts of benzoic acid, and calcitonin, or a pharmaceutically acceptable salt or derivative thereof substantially as hereinbefore described, are combined to provide a formulation according to the present invention.

Also according to the present invention there is provided a method of administering calcitonin to a subject requiring calcitonin treatment, which method comprises administering via the nasal route to said subject a pharmaceutical formulation as described herein. In particular, the treatment is of postmenopausal osteoporosis in humans.

There is also provided by the present invention for use in the manufacture of a medicament for the treatment of a disease state requiring calcitonin treatment, especially postmenopausal osteoporosis, (i) calcitonin, or a pharmaceutically acceptable salt or derivative thereof substantially as hereinbefore described, (ii) a pharmaceutically acceptable liquid carrier, and (iii) at least one preservative selected from the group consisting of sorbic acid, pharmaceutically acceptable salts of sorbic acid, benzoic acid and pharmaceutically acceptable salts of benzoic acid.

Also according to the present invention there is further provided a method of improving the stability of a liquid pharmaceutical formulation comprising calcitonin, or a pharmaceutically acceptable salt or derivative thereof substantially as hereinbefore described, and a pharmaceutically acceptable liquid carrier therefor, which method comprises including in the formulation at least one preservative selected from the group consisting of sorbic acid, pharmaceutically acceptable salts of sorbic acid, benzoic acid and pharmaceutically acceptable salts of benzoic acid.

There is also provided by the present invention use of one or more of the following: sorbic acid, pharmaceutically acceptable salts of sorbic acid, benzoic acid and pharmaceutically acceptable salts of benzoic acid; as a preservative to substantially inhibit contamination of a pharmaceutical formulation comprising calcitonin, or a pharmaceutically acceptable salt or derivative thereof, together with a pharrnaccutically acceptable liquid carrier therefor.

Preferably the above use employs pharmaceutically acceptable salts of sorbic acid and / or pharmaceutically acceptable salts of benzoic acid, especially potassium sorbate and / or sodium benzoate.

There is also provided a method of inhibiting contamination of a pharmaceutical formulation which comprises calcitonin, or a pharmaceutically acceptable salt or derivative thereof, together with a pharmaceutically acceptable liquid carrier therefor, which method further comprises including in the formulation one or more of the following in an inhibitory amount: sorbic acid, pharmaceutically acceptable salts of sorbic acid, benzoic acid and pharmaceutically acceptable salts of benzoic acid.

The present invention is now illustrated by the following Examples, which do not limit the scope of the invention in any way.

Examples

Example I

Nasal spray or nasal solution of calcitonin: Sr.no Ingredients Quantity (mg/ml) 1. Calcitonin (Salmon) 0.367 2. Sodium Chloride 8.50 3. Potassium Sorbate 0.0012 4. Hydrochloric Acid (as 0.1 N solution) q.s. to pH 3.5-4.5 Purified water q.s. to lml Components I to 3 were dissolved in purified water under an inert atmosphere. Component 4 was then added to bring the pH to 3.5-4.5 and purified water was added to make the volume.

The formulation was then filtered. The composition was filled in appropriate containers fitted with nasal spray assembly. The resulting composition comprises 2200 IU/ml of calcitonin and the nasal spray assembly delivers 200 IU per spray.

Example 2:

Nasal spray or nasal solution of calcitonin: Sr.no Ingredients Quantity (mg/ml) 1. Calcitonin (Salmon) 0.367 2. Sodium Chloride 8.50 3. Sodium Benzoate 0.001 4. Hydrochloric Acid (as 0.1 N solution) q.s. to pH 4.2 5. Purified water q.s. to lml Process: same as Example 1.

Example 3

Nasal spray or nasal solution of calcitonin: Sr.no Ingredients Quantity (mg/ml) Calcitonin 0.367 2. Sodium Chloride 8.50 3. Potassium Sorbate 0.0012 4. Hydrochloric Acid (as 0.1 N solution) q.s. to pH 3.5-4.5 5. Purified water q.s. to lml Process: same as Example 1

Claims

CLAIMS: I A pharmaceutical formulation for nasal administration, which

formulation comprises (i) calcitonin, or a pharmaceutically acceptable salt or derivative thereof, (ii) a pharmaceutically acceptable liquid carrier, and (iii) at least one preservative selected from the group consisting of sorbic acid, pharmaceutically acceptable salts of sorbic acid, benzoic acid and pharmaceutically acceptable salts of benzoic acid.
2 A nasal spray formulation comprising (i) calcitonin, or a pharmaceutically acceptable salt or derivative thereof, (ii) a pharmaceutically acceptable liquid carrier, and (iii) at least one preservative selected from the group consisting of sorbic acid, pharmaceutically acceptable salts of sorbic acid, benzoic acid and pharmaceutically acceptable salts of benzoic acid.
3 A formulation according to claim 1 or 2, wherein the preservative is selected from the group consisting of pharmaceutically acceptable salts of sorbic acid, and pharmaceutically acceptable salts of benzoic acid.
4 A formulation according to claim 3, wherein the preservative is selected from one or more pharmaceutically acceptable salts of sorbic acid.
A formulation according to claim 4, wherein said preservative is potassium sorbate.
6 A formulation according to claim 4 or 5, wherein said preservative is present at a concentration in the range of about 0.1% - 0.2% of the formulation.
7 A formulation according to claim 6, wherein said preservative is present at a concentration in the range of about 0.12% of the formulation.
8 A formulation according to claim 3, wherein the preservative is selected from one or more pharmaceutically acceptable salts of benzoic acid.
9 A formulation according to claim 8, wherein the preservative comprises sodium benzoate and / or potassium benzoate.
A formulation according to claim 9, wherein the preservative is sodium benzoate.
11 A formulation according to any of claims 8 to 10, wherein the preservative is present at a range of about 0.02% - 0.5% of the formulation.
12 A formulation according to claim 11, wherein the preservative is present at a range of about 0.1% of the formulation.
13 A formulation according to any of claims I to 12, wherein said calcitonin comprises, or is derived from, salmon, porcine, eel or human calcitonin.
14 A formulation according to claim 13, wherein said calcitonin comprises, or is derived from, salmon calcitonin.
A formulation according to any of claims I to 14, wherein said calcitonin is present as either a hydrochloride or acetate salt.
16 A formulation according to any of claims I to 15, wherein said liquid carrier comprises water.
17 A formulation according to claim 16, wherein said liquid carrier comprises saline water.
18 A formulation according to any of claims 1 to 17, which has a pH in the range of 3 to 6.
19 A formulation according to claim 18, which has a pH in the range of 3. 5 to 4.5.
A formulation according to claim 18 or 19, wherein the pH of the formulation is adjusted by addition of hydrochloric acid.
21 A formulation according to any of claims 1 to 20, which has an osmotic pressure of 270 to 350 mOsm/liter.
22 A pharmaceutical product comprising (i) a housing containing a formulation according to any of claims 1 to 21; and (ii) application means for administering the contained formulation to the nasal mucosa of a patient.
23 A process for preparing a pharmaceutical formulation according to any of claims I to 21, in which process a pharmaceutically acceptable liquid carrier, at least one preservative selected from the group consisting of sorbic acid, pharmaceutically acceptable salts of sorbic acid, benzoic acid and pharmaceutically acceptable salts of benzoic acid, and calcitonin, or a pharmaceutically acceptable salt or derivative thereof, are combined to provide a formulation according to any of claims I to 21.
24 A process according to claim 23, wherein the calcitonin or salt or derivative thereof is dissolved in the carrier liquid.
A process according to claim 24, wherein the carrier liquid comprises water.
26 A process according to claim 23, 24 or 25, wherein the pH of the solution is adjusted to be in the range 3 to 6.
27 A method of administering calcitonin to a subject requiring calcitonin treatment, which method comprises administering via the nasal route to said subject a pharmaceutical formulation according to any of claims I to 21.
28 A method according to claim 27, for the treatment of osteoporosis in humans.
29 A method according to claim 28, for the treatment of postmenopausal osteoporosis in humans. 1 /
Use in the manufacture of a medicament for the treatment of a disease state requiring calcitonin treatment (i) calcitonin, or a pharmaceutically acceptable salt or derivative thereof, (ii) a pharmaceutically acceptable liquid carrier, and (iii) at least one preservative selected from the group consisting of sorbic acid, pharmaceutically acceptable salts of sorbic acid, benzoic acid and pharmaceutically acceptable salts of benzoic acid.
31 Use according to claim 30, wherein said medicament is for the treatment of postmenopausal osteoporosis in humans.
32 A method of improving the stability of a liquid pharmaceutical formulation comprising calcitonin, or a pharmaceutically acceptable salt or derivative thereof, and a pharmaceutically acceptable liquid carrier therefor, which method comprises including in the formulation at least one preservative selected from the group consisting of sorbic acid, one or more pharmaceutically acceptable salts of sorbic acid, benzoic acid and one or more pharmaceutically acceptable salts of benzeic acid.
33 Use of one or more of the following: sorbic acid, pharmaceutically acceptable salts of sorbic acid, benzoic acid and pharmaceutically acceptable salts of benzoic acid; as a preservative to substantially inhibit contamination of a pharmaceutical formulation comprising calcitonin, or a pharmaceutically acceptable salt or derivative thereof, together with a pharmaceutically acceptable liquid carrier therefor.
34 Use according to claim 33, wherein said preservative is potassium sorbate.
Use according to claim 33, wherein said preservative is sodium benzoate.
36 A method of inhibiting contamination of a pharmaceutical formulation which comprises calcitonin, or a pharmaceutically acceptable salt or derivative thereof, together with a pharmaceutically acceptable liquid carrier therefor, which method further comprises including in the formulation one or more of the following in an inhibitory amount: sorbic acid, pharmaceutically acceptable salts of sorbic acid, benzoic acid and pharmaceutically acceptable salts of benzoic acid.