FORM 2
THE PATENTS ACT, 1970
(39 of 1970)
&
The Patents Rules, 2003
PROVISIONAL / COMPLETE SPECIFICATION
(See section 10 and rule 13)
1. TITLE OF THE INVENTION :
'PHARMACEUTICAL FORMULATION'
2. APPLICANT (S)
(a) NAME : CIPLA LIMITED
(b) NATIONALITY : INDIAN

(c) ADDRESS

289 Bellasis Road, Mumbai Central, Mumbai 400 008, India.

3. PREAMBLE TO THE DESCRIPTION

PROVISIONAL
The following specification describes the invention

• COMPLETE
The following specification particularly describes the invention and the manner in which it is to be performed.

4. DESCRIPTION (Description shall start from next page)
5. CLAIMS (not applicable for provisional specification. Claims should start with the preamble "I/we claim" on separate page)
6. DATE AND SIGNATURE (to be given at the end of last page of specification)
7. ABSTRACT OF THE INVENTION (to be given along with complete specification on separate page)
Note:-
* Repeat boxes in case of more than one entry.
*To be signed by the applicant(s) or by authorized registered patent agent.
*Name of the applicant should be given in full, family name in the beginning.
*Complete address of the applicant should be given stating the postal index no./code, state and country
*Strike out the column which is/are not applicable.

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PHARMACEUTICAL FORMULATION
I he 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 ceils 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 pre-m RNA can yield an in RNA 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 valunble therapy for Paget disease, which is a disorder in bone remodeling. Calcitonin also appears to be a valuable aid in the management

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of certain t\oe.s of osteoporosis. Despue their size and chemical competition, various ionmilations of calcitonin are available on the market, for example inactions, nasai prepa/auons nnd 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.
HP 0277462 B 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 (PGj derivatives, monoclonal antibodies or interleukin derivatives (IL), and enhances the in vivo absorbability of the drug when administered nasally.
EP 047161 SB 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 l-[2-(decylthio)ethyl] azacyclopentan-2-one, as an absorption promotor, 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 pharmaceurical composition, where the risk of contamination is particularly high. The'preserving agent must suffice to provide not only for initial

contamination awudance. e.g. during formulation and tilling of the- composition into its container, bui continued contamination avoidance during use, particularlv 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, u; 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 (ij calcitonin, or a pharmaceutical^-acceptable salt or derivative thereof, (it) a pharmaceutically acceptable liquid carrier, and (iii) at least one preservative selected from the group consisting of sorbic acid, pharmaccurically 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 (ij calcitonin, or a pharmaceutically acceptable salt or derivative thereof, (ii; a pharmaceutically acceptable

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liquid earner., and i m / at least one preservative selected from the group cor,..;:^:;:y of sorbic acid, phamidCeuti^aiK acceptable salts of sorbic acid, benzoic acid and phdrmaceuticallv acceptable sails u! ncr./oic acid.
ft is preferred that the preservative is selected from the group consisting of phdniaccuucally acceptable salts of sorbic acid, and pharmaceutical!}- acceptable sails of benzoic acid. It. certain embodiments one or more pharmaceutical!}' 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 pharmaceutical Iv acceptable salts of benzoic acid. A preferred salt of sorbic acid for use in accordance with the present invention is potassium sorbate. Preferred salts ol 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 phamiaceutically 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 pharmaceutical ly available denvatives 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 C- terminal 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 proprotcin, such as a larger prohormone from which calcitonin can be derived, which can be activated by cleavage of the proprotcin pomon

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to produce active mature calcitonins Suitably, variants, analogs, dorr, ative-- a J fraumenis. and variants, analogs ^nd derivatives of the fragments.as described herein ,:iav c a primary structural conformation of ammo acids in which several or a few (such as .5 to i'..». ! to 5 or I to 3) ammo acid residues are subsntuted. 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 ammo acid residue (preferably a conserved amino acid residue); or
(ii) ones in 'which one or more of the amino acid residues includes a subsntuent group; or
(iii) ones in which additional amino acids arc 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 an 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 ammo acid by another amino acid of like characteristics. Typically seen as conservative substitutions are the replacements, one for another, among the aliphatic ammo acids A, V\ L and I; among the hydroxyl residues S and T; among the acidic residues D and F; among the amide residues K 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

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"^
fused to other amino acids or polypeptides, or they may be comprised within a larger polypeptide of which tliey form a pari 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 m 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 pharmaceutical^ acceptable salt or complex form. Such sails 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 puiposc of nasal administration a mildly acidic pH is generally preferred. Preferably the fonnalarions 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 10 350 mOsm/liter.

For nasal administration the desired dose of calcitonin is about 200 IU per J;n ■,\i;h the administration involvmg 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 an and include those aiding the administration of liquid nasal formulations in the solution or spra\ form. Since the dosing of calcitonins should be done as accurately as possible, sprav 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 (1) a housing containing a formulation comprising calcitonin, or a pharmaceuticaliy acceptable salt or derivative thereof, a pharmaceutical!}' acceptable liquid carrier*and at least one preservative selected from the group consisting of sorbic acid, pharmaceuticaliy acceptable salts of sorbic acid, benzoic acid and pharmaceutical!}-' 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 pharmaceutical!}- acceptable liquid earner, at least one preservative selected from the group consisting of sorbic acid, pharmaceuticaliy acceptable salts of sorbic acid, benzoic acid and pharmaceuticaliy acceptable salts of benzoic acid, and calcitonin, or a pharmaceuticaliy acceptable salt or derivative thereof substantially as hereinbefore described, are combined to provide a formulation according to the present invention.

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Also according to the present invention there is provided a method of administering calcitonin lo 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 phamiaceutically acceptable salt or derivative thereof substantially as hereinbefore described, (Ti) a pharmaceutically acceptable liquid carrier, and (111;. at least one preservative selected from the group consisting of sorbic acid: phanrtaceutically acceptable salts of sorbic acid, benzoic acid and phamiaceutically 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 phannaceutically acceptable salt or derivative thereof substantially as hereinbefore described, and a pharmaceuticaliy acceptable liquid carrier there for, 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 phamiaceutically acceptable salts of benzoic acid.
There is also provided by the present invention use of one or more of the following; sorbic acid, phannaceutically acceptable salts of sorbic acid, benzoic acid and pharmaceutically acceptable salts of benzoic acid; as a preservative to substantially inhibit contamination of a phamiaceutical formulation comprising calcitonin, or a phamiaceutically acceptable salt or derivative thereof, together with a pharmaceutically acceptable liquid carrier there for 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.

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"there is also provided a method of inhibiting contamination of a pharmaceutical formulatior. v, which comprises calcitonin, or a pharmaceutical^-' acceptable salt or derivative thereof, together with a pharmaceutical!) acceptable liquid carrier therefor, which method further comprises including in the formulation one or more of the following m 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. any way
Examples Example 1
Nasal spray or nasal solution of calcitonin:

; Sr.no , Ingredients

Quantity (nig/ml)

1.

Calcitonin (Salmon)

0.367

,2. , Sodium Chloride

8.50

• 3. ! Potassium Sorbate
1 i
: 4.
Hydrochloric Acid (as 0.1 N solution)

0.0012
q.s. to pH 3.5-4.5

. 5

Purified water

q.s. to lml

Components 1 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 lU'ml of calcitonin and the nasal spray assembly delivers 200 IU per spray.
Example2:
Nasal spray or nasal solution of calcitonin:

Sr no .' Ingredients
Calcitonin ('Salmon) Sodium Chloride
Sodium Benzoate
Hydrochloric Acid (as 0 1 N solution)
Purified water

Quantity ('mg-ml i 70J67 '
78.50
0.001
j q.s to pi I 4.2 | q.s. to 1ml

Process, same as Example 1
Example 3
Nasal spray or nasal solution of calcitonin:

Sr.no Ingredients 1 i Calcitonin

i

Quantity (mg/ml)
0.367

Sodium Chloride

8.50

I Potassium Sorbate

0.0012

Hydrochloric Acid (as 0.1 N solution)

q.s. to pH 3.5-4.5

Purified water

j q.s. to I ml

Process: same as Example 1
Pharmaceutical formulation comprising (i) calcilonin, or pharmaceutically acceptable salt or derivative thereof , (ii) a pharmaceutically acceptable liquid carrier, and )iii) at least one preservative selected from the group concisiting of sorbic acid, pharmaceutically acceptable salts of sorbic acid, benzoic acid and pharmaceutically acceptable salts of benzoic acid is a synergestic formulation.

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CLAIMS:
i A pharmaceutical formulation' for nasal administration, which formulation comprises
(i) calcitonin, or a pharmaceutical!)/ acceptable salt or derivative thereof (in a pharmaccuticallv acceptable liquid carrier, and (iii) ai least one 'preservative selected from the group consisting of sorbic acid, phamiaceuticaliy acceptable salts of sorbic acid, benzoic acid and pharmaccuticallv acceptable salts of benzoic acid.
2 A nasal spray formulation comprising d") calcitonin, or a phannaceuticallv acceptable
salt or derivative thereof, (n) a phannaceuticallv acceptable liquid carrier, and (uij at least
one preservative selected from the group consisting of sorbic acid, phannaceuticallv
acceptable salts of sorbic acid, benzoic acid and phamiaceuticaliy acceptable sails of benzoic
acid.
3 A formulation according to claim I or 2, wherein the preservative is selected from the group consisting of pharmaceutically acceptable salts of sorbic acid, and phannaceuticallv acceptable salts of benzoic acid.
4 A fonnulation according to claim 3, wherein the preservative is selected from one or more phamiaceuticaliy acceptable salts of sorbic acid.
5 A fonnulation according to claim 4, wherein said preservative is potassium sorbate
6 A fonnulation 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 fonnulation.
7 A fonnulation according to claim 6, wherein said preservative is present at a concentration in the range of about 0.12% of the fonnulation.
8 A formulation according to claim 3, wherein the preservative is selected from one or more phamiaceuticaliy acceptable salts of benzoic acid.

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9 A formulation according to claim 8. therein the preservative comprises sodium
benzoate and or potassium benzoate
10 A formulation according to claim 9, wherein the preservative is sodium benzoate.
11 A formulation according to any of claims 8 to !0. wherein the preservative is present
ai a range of about 0.02% - 0.5% of the formulation.
12 A formulation according to claim 1 L wherein the preservative is present at a range of
about 0.1% of the formulation.
13 A formulation according to any of claims 1 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.
15 A formulation according to any of claims 1 to 14, wherein said calcitonin is present as either a hydrochloride or acetate salt.
16 A formulation according to any of claims 1 to 15, wherein said liquid carrier comprises water
17 A formulation according to claim 16, wherein said liquid earner 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.

20 A formulation according to claim JS 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 1 to 21, in which process a phannaceutically acceptable liquid earner, at least one preservative selected from the group consisting of sorbic acid, phannaceutically acceptable salts of sorbic -acid, benzoic acid and phannaceutically acceptable salts of benzoic acid, and calcitonin, or a phannaceutically acceptable salt or derivative thereof, arc combined to provide a formulation according to any of claims 1 to 21.
24 A process according to claim 23, wherein the calcitonin or salt or derivative thereof is dissolved in the carrier liquid.
25 A process according to claim 24, wherein the carrier liquid comprises water
26 " A process according to claim 23, 24 or 25, wherein the phi of the solution ^ 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 lo claim 27, for the treatment of osteoporosis in humans
29 . A method according to claim 28, for the treatment of postmenopausal osteoporosis in humans

30 Use :n the manufacture of a medicament for the treatment of a disease state requiring" caiciionih treatment (lj calcitonin, or a pharmaceutical!}- acceptable salt or derivative thereof (iij a phannaceutically acceptable liquid carrier, and (iii) at least one preservative selected from the group consisting of sorbic acid, phannaceutically 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 earner 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 sails of benzoic acid.
33 Use of one or more of the following: sorbic acid, pharmaceutically acceptable salts of sorbic acid, benzoic acid and phannaceutically acceptable salts of benzoic acid, as a preservative to substantially inhibit contamination of a phannaceutical 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.
35 Use according to claim 33, wherein said preservative is sodium benzoate.
36 A method of inhibiting contamination of a phannaceutical 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 fonnulation one or more of the following in an inhibitory amount, sorbic

16
1-5 ~
acid, pharmaceutical))' acceptable salts of sorbic acid, benzoic acid and pharmaceutically acceptable salts of benzoic acid.
37. A pharmaceutical formulation for nasal administration and nasal spray formulation substantially as herein described with reference to the foregoing examples.
38. A process of preparing a pharmaceutical formulation, and product substantially as herein described with reference to the foregoing examples.

Dated this 8th day of August, 2005.


VIBHA SHUKLA
OF K & S PARTNERS
AGENT FOR THE APPLICANTS

17
ABSTRACT
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 More particularly, there is provided a pharmaceutical formulation for nasal administration, which formulation comprises (1) calcitonin, or a pharmaceutically acceptable salt or derivative thereof, (ii) a pharmaceutically acceptable liquid earner, and (iii) at least one preservative selected from the group consisting of sorbic acid, pharmaceuucally acceptable salts of sorbic acid, benzoic acid and pharmaceutically acceptable salts of benzoic acid.