DK174540B1 - Compsn. for nasal admin. contg. calcitonin - for treatment of paget's disease, hypercalcaemia and osteoporosis - Google Patents

Abstract

Pharmaceutical compsns. for admin. intranasally, such as a liquid nasal spray, contain a calcitonin (I), a benzalkonium chloride and a suitable liquid diluent or carrier. (I) is derived from fish, esp. salmon or eels, humans, or pigs. That derived from salmon is preferred. The preferred concentration of the benzalkonium chloride is 0.003-0.03% w/v. Other materials that may be present include surfactants, preservatives, oiliary stimulants and pH regulators. The unit dose of (I) is 50-400 MRC units, given at a rate between once per day and 3 times per week. The total volume given per admin. is pref. between 0.05 and 0.15 ml. (I) is known for the treatment of Paget's disease, hypercalcaemia, and osteoporosis. Previously, (I) needed to be administered by injection, usually intramuscularly. This was painful and inconvenient since regular administration is necessary. The present compositions allow self-medication to take place.

Description

DK 174540 B1

The present invention relates to a process for the preparation of a liquid pharmaceutical composition containing calcitonin and a container containing such a composition.

5 The calcitonins constitute a known class of pharmaceutically active.

long-chain polypeptides with varying, well-documented c pharmaceutical utility. Various calciconins, including, for example, salmon and eel ciciconin, are commercially available and are commonly used in the treatment of, for example, Paget's disease, hypercalcaemia and osteoporosis.

10

However, as is usually the case with polypeptides, the provision of convenient and effective agents for the administration of calciconins has posed many problems. Because they are polypeptides. For example, the calcitonins are sensitive to degradation by administration and only pass readily into the body fluids. For this reason, parenteral administration has so far been the only widely available route. allowing effective treatment. Administration is usually done by injection. Such modes of administration are always unpleasant, and when administered at 20 regular intervals may cause considerable pain to the patient. For many years, it was an important goal to develop usable, alternative modes of administration that caused less discomfort to the patient and, foreroxes, enabled simple self-administration, and at the same time achieved levels of biofilm accessibility that were insufficient for effective treatment at clinics.

Applicants have now discovered that it is possible to provide effective clinical treatment with calciconins by nasal administration, ie by application to the nasal mucosa. In particular, in accordance with the particular features of the present invention, applicants have found that ac biosilence levels of calcitonin equivalent to those achieved by standard intramuscular doses can be achieved by nasal administration at dose levels that are fully for the limits of the tolerable and practical muii ^ 35 It has also been found that the ac fish calcitonins and their derivatives. for example iaxecalcitonin and eelcalcitonin derivatec 1 7-Asu-eelecai ciconin, hereinafter called Elcatonin. and especially Iaxecalcitonin. DK 174540 B1 2 is particularly suitable for use via the nasal route in accordance with the present invention.

It has been found, in accordance with the present invention, that the use of a nonionic surfactant in relation to nasal application of calcitonins, especially salmon calcitonin, can enhance resorption via the nasal mucosa and thus improve the bioavailability obtained.

Thus, the present invention relates to a process for the preparation of a liquid pharmaceutical composition adapted for administration in the form of a liquid nasal spray, the process being characterized in that 1) a calcitonin, 2) a nonionic surfactant, suitable for application to the nasal mucosa, and 3) a diluent or carrier suitable for application to the nasal mucosa is combined.

The nasal route provides a simple and painless method of administration that can be easily performed by the patient himself, for example, by administering a nasal spray or drop solution from a nasal applicator. It is clear that this pathway has a major advantage over parenteral administration, which should generally be given under medical supervision.

The term "calcitonin" is used in the present specification and claims in a broad sense and does not include only the naturally occurring calcitonins. but also their pharmaceutically active derivatives and analogs in which f: <one or more of the peptide residues present in the naturally occurring product are replaced, or in which the N or C terminus is modified.

3 DK 174540 B1

Preferred calcitonins for use in the present invention are salmon, chicken and porcine calcitonins as well as Elcaconin. All of these compounds are commercially available and have been extensively described in the literature together with their pharmaceutical properties.

As previously stated, it has been found that exceptionally good results are obtained, for example in terms of bioavailability levels and duration of blood plasma presence, by nasal administration of salmon calcitonin. Accordingly, salmon calcitonin is the most preferred calcitonin for use in the present invention.

It will be appreciated that the calcitonins used in the invention may be in free form or in the form of a pharmaceutically acceptable salt or complex, e.g., a pharmaceutically acceptable acid addition salt.

Such salts and complexes are known and have efficacy and tolerability equivalent to the free forms. Suitable acid addition salt forms for use in the present invention, for example, redefine the hydrochlorides and acetates.

20

The above-defined compositions may be applied to the nasal mucosa, for example either in drop or spray form. However, as dec described in dec following, they are applied especially in spray form. i.e. in the form of finely divided droplets.

25

The liquid diluent or carrier 3) for use in the process of the invention will comprise water (pharmaceutical purity). The liquid diluent or carrier in particular comprises aqueous saline solution. In the method of the invention, the compositions are formulated in such a way that they allow administration by the nasal route. For this purpose, the compositions may also contain, for example, smaller amounts of any desired additional ingredient or excipient, e.g., preservatives or, for example, ciliary stimulants such as caffeine. For nasal administration, a slightly acidic pH is usually preferred. Preferably, the composition prepared by the method of the invention has a pH of from ca. 3 to 5, especially from ca. 3.5 to approx. 4.5. Adjustment of pH is carried out by the addition of a suitable acid such as hydrochloric acid.

The compositions of the invention should also have appropriate isotonic properties and viscosity. It is preferred that they have an osmotic pressure of about 5 260 to approx. 380 mOsm / liter. A desired viscosity of the compositions prepared by the process of the invention will depend on the specific mode of administration, i.e. whether to administer by nasal or nasal spray. For nasal drops, an appropriate viscosity of approx. 2 to approx. UO x LO'3 Pa x s. For 10 nasal sprays, the viscosity will conveniently be less than 2 x LO'3 Pa x s, for example from 1 to 2 x 10'3 pa x s.

Particularly preferred nonionic surfactants are polyoxyalkylene-higher alcohol ethers, e.g., of general formula I

RO (CH2) n-0 XH I

wherein RO is a residue of a higher alcohol, especially a higher alkanol or alkylphenyl such as lauryl or cetyl alcohol, βiter a sterol residue. especially a lanosterol, dihydrocholesterol or c'nolesterol residue, as well as mixtures of two or more of such ethers. Preferred polyoxyalkyls there for use in the process of the invention are polyoxyethylene and polyoxypropylene ethers (i.e. where n in the formula shown above is 2 or 3). especially polyoxyechylene and polyoxypropylene lauryl, cecyl and cholesteryl ethers, as well as mixtures of two or more of such ethers.

The hydroxy group at the end of the alkylene unit of such aforementioned 30 ethers may be fully or partially acylated, for example, with acyl residues of aliphatic carboxylic acids such as acetic acid.

Preferred ethers for use in the process of the invention have a hydrophilic-lipophilic balance (HLB number) of from about. 10 to about 35, especially from about 12 to approx. 16th

Particularly suitable echoes for use in the process of the invention are those in which the average average number of recycled units in the polyoxyalkylene portion (x in the above formula) is from 4 to 75, especially 8-30, special 16-26. The echoes can be obtained according to known techniques.

5 Ec-wide spectrum of such products are commercially available, for example from firm Amerchol under the trade name Solulan, KAO Soap, ICI and Atlas under the trade names Emalex, Brij and Laureth and from Croda under the trade name Cetomacrogol®, 10 Examples of polyoxyalkylene ethers suitable for used in the process of the invention are the following: (POE - polyoxyechylene ether; POP - polyoxypropylene ether; x - average number of repeating units in the POPO / POE portion).

15 1. CholesCerylechere: 1.1 Solulan C-24 - POE, x - 24 2. Ethers of Ianolina Iconols: 2.1 Solulan 16 - POE, x - 16.

2.2 Solulan 25 - POE, x = 25.

2.3 Solulan 75 - POE, x - 75.

2.4 Solulan PB-10 - PPE, x - 10.

2.5 Solulan 98 - POE, x - LO - Partially the acetyl ethyl.

2.6 Solulan 97 - pog, χ - 9 - completely acecylated.

25 3. Laurylechere: 3.1 Exalex 709 / Laurech 9 - POE. x = 9.

3.2 Laurech 4 / Brij 30 - POE, x - h.

3.3 Laureth 23 / Brij 35 - POE, x - 23.

30 4. Cerylechere: 4.L Cetomacrogol® - POE. x - 20-24.

Lanolin alcohols are also called wool fat alcohols and are a mixture of 35 cholesterol, dihydrocholesterol and lanosterol.

6 DK 174540 B1

Preferred esters for use in the process of the invention are polyoxyechylene cholesteryl ethers, i.e. with the above general formula I, wherein n - 2 and RO are a cholesterol residue, especially such echoes in which the number of repeating units in the polyoxyethylene moiety 5 is from 16 to 26, especially about 2 * '.

It is especially preferred. ac such ethers are substantially free of contaminants, especially from other polyoxyalkylene ethers. They preferably comprise at least 75% by weight, especially at least 85% by weight, especially 10 at least 90% by weight, of pure polyoxyethylene cholesteryl ether.

The amount of surfactant, for example, a polyoxyalkylene ether present in the compositions of the process of the invention, will vary depending on the surfactant selected, the specific mode of administration (e.g., drops or spray), and the desired effect.

However, the amount present will generally be of the order of about 2.0 mg / ml to approx. 200 mg / ml (preferably to about 100 mg / ml, especially to about 20 mg / ml). appropriately from approx. 5 mg / ml to approx. 30 mg / ml (preferably to about 15 mg / ml). and especially approx. 10 mg / ml.

25 The amount of calcitonin to be administered. and, consequently, the amount of active ingredient in the composition prepared by the process of the invention will, of course, depend on the specifically selected calcitonin, the condition to be treated, the desired administration and the desired effect.

30

As indicated in Example 2 below, it has been found that the bioavailability of calcitonins. in particular salmon calcitonin, determined as blood plasma concentration after nasal administration was found to be surprisingly high, generally of the order of ca. 502 of the levels achieved by intramuscular injection. Accordingly, administration of the prepackaged racemaker method according to the invention will conveniently be carried out in such a manner that a dose of the order of two or more is given. eg from approx. 2 to approx. 4 times the dose required for inertial therapy, eg 5 ineramuscular administration.

Where treatment with calcitonin, e.g. salmon calciconin, so far taken by ineramuscular injection, is individual doses of approx.

50-100 MRC units have been added from approx. Once daily to approx. three 10 times weekly. Therefore, for nasal administration, the treatment will conveniently comprise administration of doses of from ca. 50 to approx.

400 MRC units, in particular from about 100 to approx. 200 MRC units, with a frequency of approx. once daily to about three times a week. Dosages, as mentioned above, will conveniently be administered in a single application, i.e. the treatment will comprise administration of single nasal doses comprising from ca. 50 to approx. 400 MRC units. preferably, approx.

100 to approx. 200 MRC units calcitonin. Alternatively, such dosages may be divided over a series of, for example, 2-4 applications taken at intervals throughout the day, with the dose at each application then comprising 20 from ca. 10 to approx. 200 MRC units, preferably from approx. 25 to approx.

100 MRC units.

Conveniently, the total amount of preparation administered with each nasal application comprises from ca. 0.05 µl O, L5 ml, typically approx.

0.1 ml. e.g., 0.09 ml. Accordingly, the compositions prepared by the process of the invention suitably comprise from ca. 150 to approx. 8000, preferably from ca. 500 to approx. 4000, especially from approx. 500 to approx. 2500. and especially from approx. 1000 to about 2000 MRC units calcitonin, eg salmon calcitonin. per. ml.

30

For the purpose of nasal administration, the compositions prepared by the method of the invention will preferably be placed in a container provided with parts. enabling application of dec containing nasal mucosa preparation, for example, arranged in a nasal applicator device. Suitable applicators are known in the art and include those adapted for administration of liquid preparations to the nasal mucosa in droplet or spray form. Since the dosage of calciconins boron is regulated as precisely as possible, in general use spray applicators are preferred. where the amount administered can be subject to precise regulation. Suitable administrators include, for example, atomizers, e.g., mechanical atomizers and aerosol containers. In the latter case, the applicator will contain a preparation made by the method of the invention together with a propellant suitable for use in a nasal applicator. The nebulizer will be provided with a suitable spray adapter which permits delivery of the contained preparation to the nasal mucosa. Such devices are well known in the art.

The view holder, for example, is. nasal applicator, may contain degrading preparation for a single nasal dosage or for delivery of several 15 consecutive doses, e.g., in the Isbet of a few days or weeks.

Preferably, the amounts of the single doses passed will be as defined above.

In accordance with the foregoing, the present invention 20 further relates to a container containing a composition prepared by the method of the invention and provided with portions which permit application of the contained composition to the nasal mucosa, preferably in spray form.

Conveniently, containers of the invention are nasal aerosol applicators. Preferably, they allow application of the contained composition in individually determined amounts of from ca. 0.05 ml to approx. 0.15 ml, e.g. 0.1 ml.

Suitable compositions as well as individual components 1), 3) or 4} for use with the container are as described above. Appropriate dose ranges are also as described above.

35 DK 174540 B1 9

The stability of the composition prepared by the method of the invention can be determined by conventional means. The calcitonir content of the preparations prepared by the process of the invention under an inert nicrogenic atmosphere will degrade less than 102 in 2 years at 1205C. as suggested by standard analysis tests.

For example, nasal spray preparation. is described in Example 1 below, stored for 2 months at 5 ° C, 20 ° C and 30 ° C under nitrate in a glass container. No measurable (less than 10 12) degradation of calcitonin was observed at 5 ° C and 20 ° C. At 30 ° C a £ 2 degradation was observed, which was no more than would be expected for a clean. aqueous solution. These results indicate sufficient stability, viz. less than 102 degradation over 2 years under nichrogen in a sealed container.

15

The compositions are well tolerated, as suggested by standard tests, for example, by observing less than 50% inhibition of the twilight stroke rate up to 20 minutes after administration according to the microphoto-oscillographic method described by L. Chevance et al., Acta Otolaryng. 70, p.

26-28 (1970).

Insignificant or no tingling sensation and good stability against contamination during use can also be demonstrated by standard clinical testing.

The invention is illustrated by the following examples: 30 35 10 DK 174540 B1 REFERENCE EXAMPLE (not according to the invention)

Composition containing salmon calciconin and suitable for nasal administration:

Ingredient Amount (per ml) 1) Salmon calcitonin (active ingredient) 0.1375 mg 10% excess 0.01375 mg 10 --- 0.15125 mg 2) NaCl 7.5 mg 3) Benralkonium chloride 0.1 mg 4) HCl (IN) added to pH 3.7 15 5) Distilled water to a final volume of 1.0 ml

Components l) -3) are combined under the protection of nitrogen gas (in a quantity giving a final volume of 2500 ml) in a conventional manner, adding L0% salmon calcium silicon for ac to offset losses by filtration. Component (a) was then added cil to bring pH cil 3.7 and distilled water was added to cil ec final volume of 2500 ml.

The obtained solution is filtered (e.g., using 0.2 μπιι filter) to give a praparac suitable for nasal application and 25 to fill in a nasal spray container with ec solution volume of 2 ml.

Preparacec ranges approx. 550 MRC units active scandal / ml and the applicator emits a quantity corresponding to 55 units per activation,

EXAMPLE

Preparations containing salmon calciconin together with ec nonionic surfactant suitable for nasal administration 35 The preparations are prepared in a manner analogous to the reference example, but without benralkonium chloride and with the addition of the following ingredients: 11 DK 174540 B1

Composition Component Amount of polyoxyethylene cholesteryl ether: x = 24 30 mg / ml b polyoxyethylene cholesteryl ether: x = 24 10 mg / ml c polyoxyethylene acetyl ether: x = 20-24 100 mg / ml.

5

The compositions are placed in a nasal applicator as described in the reference example.

Claims (6)

A method of preparing a liquid pharmaceutical composition adapted for administration in the form of a liquid nasal spray, characterized in that: 1. a calcitonin, 4. a nonionic surfactant suitable for application to the nasal mucosa, and 3 a liquid diluent or carrier suitable for application 10 to the nasal mucosa is combined. Process according to claim 1, characterized in that 1) is selected from the class consisting of salmon calcitonin, human calcitonin, porcine calcitonin and elcatonin. A process according to claim 1 or 2, characterized in that a composition is prepared in which 20 1) is present in an amount of from approx. 100 to approx. 8000 MRC units / ml. Process according to any one of claims 1-3, characterized in that l) is salmon calcitonin. The method according to claim 1, characterized in that a composition is prepared in which 4) is present in an amount of from approx. 2 to approx. 200 mg / ml. Container containing a composition prepared according to any one of claims 1-5 and provided with portions which allow application of the contained composition to the nasal mucosa.