LU86971A1 - PHARMACEUTICAL COMPOSITIONS FOR NASAL ADMINISTRATION - Google Patents

Description

i

j v 'Ö 0 Q ^ | GRAND DUCHY OF LUXEMBOURG

^ Patent Nc ',' Mister Minister of A h ... ù l, A D * 1 ............. of the Economy and the Middle Classes

Intellectual Property Service

Tllredtlivrf ...............................- -...... 1 fpp LUXEMBOURG

s $ 2 $

Patent Application

Of - -............................................... .................................................. .................................................. .................-.............-.................. .. ------------------------------------ ............ ............................. (1) I. Request

The so-called company: SANDOZ SA, ...... Lichtstrasse ..... 35, ...... CH-4002 Baie, ...... Switzerland, _______ (2) represented by Mr. Louis EMRINGER, lawyer, residing in Luxembourg, acting in his capacity as agent ...................................... ...................-.............................. .................................................. ................... — ...............-...... — ....... ..........-....................................... -.......................................- (3) remove (s) what atorzeao û t 1 9 QQ -.quatr e-υ ing ts ep t .................................. ....................... ... (4) to .................... ..................... hours, at the Ministry of the Economy and the Middle Classes, in Luxembourg: 1. this request for obtaining a patent of invention concerning:

Pharmaceutical compositions ..... for J 'admi. ni s trat i on by n as ale .......... „(5) 2. description in French .............. language ..... ......................................... of the invention in triplicate; 3. .................................. / .. / .......... ......... drawing boards, in triplicate; 4. the receipt of taxes paid to the Registration Office: in Luxembourg, ...... 1.4 ..... a o û t. 19.87 ..........—; 5. the delegation of power, dated from Basel ___________________________________________________ on ........... 1.0 ........ a Q Û t ... 19 8 7 .....; 6. the successor document (authorization); claims (s) for the above patent application the priority of urn (s) request (s) of (7) ........................ ................. liËYâÎ ................................ .................................................. ........ filed (s) ;. (8) ________ GrandacB.re.tagn.e ........................................ .....

on (9) .18 ..... August ...... 19.86 ...... (n ° ...... 8620035) ...... and ...... on . 1.0 ..... November..J.986 ..... (n ° ....... 8626821) ..................... .......................

under N ° (10) ........................................... .................................................. .................................................. .......... ........................................ ......__........................................... ..................................................

in the name of (11) .............. the applicant ............................ .................................................. .................................................. .................................................. .....................................

elect (elect) domicile for him / her and, if designated, for his / her agent, in Luxembourg ...... 1.41., .. rue ................. ..............

Al b er t ........ U nd e n., 2,652 ....... L uxembourg ..................... .................................................. .................................................. ........................... (12) requests (s) the issue of a patent for the invention for the object described and represented in the aforementioned appendices, with adjournment of this deliverer to ....................................... .................................................. .................................................. .......month. (13)

The depositor / agent: ....................................-........ .......................-.......................... ................................-________________________ (14) Π. Deposit Minutes

The above application for a patent for invention has been filed with the Ministry of Economy and Middle Classes, Intellectual Property Service £ ** # "~ in Luxembourg, dated: / ¾¾ / ^ r · Minister of the Economy ; ^ and Middle Classes, at ....................................... hours J g / -Â 1..

y \ 0J The head of the intellectual property department, M Wt EXPLANATIONS RELATING TO THE FORMUlSmEaEBérffr j / I 4 vjt λ U) if necessary Request for certificate of addition to the main patent to the main patent application No .. .......... if ............ (2) enter the oom. first name, protest.

r. t% ndrKSP of the dpmmdiiir. Ifmnue. cetni> a Kt un nartÎndier nn les denniniltation snanle. fnmÿ ήιηιΐνηιρ adrKu> du tïèoA uvJn Inrrmiplp lipm ^ n / lptir mi un a runnnn »mnnl«. _ f înci ^ îr »ί Μ„ * Λ CLAIMING THE PRIORITY of the patent application In Great Britain From August 18, 1986 and from November 10, 1986 DESCRIPTIVE MEMORY filed in support of a request for

PATENT

at

LUXEMBOURG

in the name of: SANDOZ S.A.

for: Pharmaceutical compositions for nasal administration.

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The present invention relates to a new mode of administration of a somatostatin analog, SMS 201-995, as well as to new pharmaceutical compositions comprising this analog.

Somatostatin is a naturally occurring cyclic tetradecapeptide which was first isolated from hypothalamic tissue from beef and pork and which has potent inhibitory activity on growth hormone (GH) secretion. It has also been found in other parts of the central nervous system as well as in specialized D cells of the pancreas, stomach and small intestine. From these sites, somatostatin acts on the pituitary gland by inhibiting the secretion of the hormone GH and the thyroid stimulating hormone (TSH), on the pancreas by inhibiting secretion exocrine and endocrine (including secretion 15 insulin and glucagon), and locally on the gastrointestinal (GI) tract by inhibiting the secretion of gastrin, CCK, VIP and possibly other hormones. Due to this latter inhibitory effect, somatostatin plays an important physiological role in modulating gastrointestinal function, for example by reducing gastric acid secretion, delaying stomach emptying, slowing intestinal motility, reducing bile flow , increasing mucus production and reducing splanchnic blood flow.

Somatostatin has been proposed in many therapeutic applications, for example in the treatment of acromegaly or gastrointestinal disorders such as gastrointestinal bleeding. However, although somatostatin is biologically very active, its half-life is very short (2 to 3 minutes), which, added to the need for intravenous administration and to the rebound phenomenon observed at the end of intravenous administration makes this substance unsuitable for long-term clinical use.

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Research has therefore concentrated its efforts on the development of new somatostatin derivatives and analogues and in particular "mini-somatostatin", which are oli-peptide compounds containing substantially less amino acids than somatostatin itself but whose molecules contain one or more partial peptide sequences present in the somatostatin molecule. Hitherto, all of these analogs have been administered by injection, for example intravenously or subcutaneously, in order to obtain a therapeutic effect at non-toxic doses.

A particularly representative and promising compound of the class of mini-somatostatin is the compound SMS 201-995 (hereinafter referred to as SMS) corresponding to formula 15, ----- H- (D) Phe-Cys-Phe- ( D) Trp-Lys-Thr-Cys-Thr-ol

The common name of this compound is octreotide.

This compound, which is described in European Patent No. 0029579, is an octapeptide exhibiting a large number of pharmacological properties similar to those of somatostatin, although being apparently somewhat more selective in the inhibition of GH and glucagon than in the release of insulin. This compound has been proposed in particular for the treatment of acromegaly, complications of diabetes and various disorders of the gastrointestinal tract, including tumors secreting hormones in the GI.

For its therapeutic use, SMS, like most other peptide drugs, can of course be administered as it is, i.e. in free form, in the form of a salt and / or in the form of a pharmaceutically acceptable complex. The SMS can also be in the form of a solvated product, for example in the form of a hydrate. The form commonly chosen for the therapeutic application of SMS is acetate hydrate, hereinafter referred to as SMSac, which has a free peptide content of about 80 to 88%, for example. from 83 to 87%. Unless otherwise indicated, the designation "SMS" or "octreotide" used in the present patent application and in the claims must be understood as designating both the free peptide and its pharmaceutically acceptable salts, in particular its salts. addition of acids, and more especially acetate, as well as the complexes and / or the pharmaceutically acceptable solvates of this compound.

10 Although SMS is of considerable therapeutic potential, there are many practical difficulties in terms of its administration. Administration by intravenous or subcutaneous route has so far been the only route of administration allowing an effective dosage in clinic. In general, SMS is administered by injection or infusion. Such modes of administration are always inconvenient and can cause considerable pain and inconvenience to the patient when long-term therapy involving the administration of SMS at regular intervals is necessary. The discovery of new methods of administering SMS, in particular allowing self-administration by the patient, for example for outpatient treatment, therefore remains an essential objective.

The Applicant has now found, quite surprisingly, that an effective treatment with SMS 25 can be obtained by administering it nasally, that is to say by applying it to the nasal mucosa. In particular, it has been found that when SMS is administered nasally at doses within the tolerance limits, bioavailability rates are obtained which are quite suitable for long-term treatment when required. of the SMS, for example for the indications mentioned above.

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Since the administration by the nasal route constitutes a simple and painless mode of administration which can be repeated regularly without great inconvenience for the patient, the present invention therefore makes it possible to meet the needs stated previously. The compositions of the invention for nasal administration are, surprisingly, very well tolerated and have only a minimal effect on ciliary function.

In accordance with the above, the subject of the present invention is: a) the use of SMS for nasal administration, for example for the treatment of disorders with an etiology comprising or associated with an excessive secretion of GH or for the treatment of gastrointestinal disorders, for example as specified above, and b) a pharmaceutical composition for administration by the nasal route, said composition comprising SMS.

The pharmaceutical compositions can be formulated in a conventional manner using excipients compatible with the nasal mucosa, for example as described below. They can be formulated for local administration on the nasal mucosa and capable of producing a systemic action of SMS. The formulation can be for example a liquid, an endonasal application system or a powder.

The compositions as defined under b) are, for example, liquid compositions containing SMS in association with a diluent or liquid vehicle suitable for application to the nasal mucosa. Such compositions are preferably suitable for administration in the form of a nasal spray or drops.

The suitable liquid compositions b) are in particular aqueous solutions. For nasal administration, such solutions preferably having a weakly acidic pH, for example between about 4 and 5, preferably about 4.2. The required degree of acidity is conveniently achieved, for example, by the addition of HCl or other suitable mineral or organic acid. For nasal administration, such compositions will preferably be isotonic or substantially isotonic. Preferred additives to achieve the desired level of isotonicity include sugars acceptable for nasal administration, such as glucose, mannitol or sorbitol, or mineral salts acceptable for administration by nasal route, in particular NaCl. According to the present invention, the preferred additives making it possible to obtain the desired degree of isotonicity are glucose, ribose, mannose, arabi-nose, xylose or another aldose, or alternatively glucosamine.

The compositions of the invention may also contain other ingredients or excipients known in the art, such as stabilizers and / or preservatives. A preferred preservative for use in the compositions of the invention is sodium methylmercurithiosalicylate (Thiomersal) and benzalkonium chloride. Such preservatives are advantageously present in an amount of between about 0.05 and 0.2 mg / ml, for example about 0.1 mg / ml.

According to another aspect, the subject of the present invention is a solid and porous endonasal application system containing SMS dispersed inside this system. According to another aspect, the invention relates to a solid endonasal application system comprising a porous gelatin and / or hydroxypropyl-methylcellulose matrix containing SMS.

The endonasal application system can be prepared according to the usual methods, for example a) by distribution of the SMS in a porous matrix comprising gelatin and / or hydroxypropylmethylcellulose, for example by lyophilization of a liquid containing the SMS and a polymer capable of forming a matrix, or else b) by distribution of the SMS in an endonasal application system, for example by soaking a sponge in an aqueous solution of SMS, for example at temperature room, and evaporating the solvent.

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By "endonasal application system" is meant, for example, a device which is shaped, sized and adapted to be placed and held in one nostril, which is intended to be introduced into one nostril, or which is formed, shaped or adapted to be in-produced and / or maintained in one nostril, or which is shaped to adapt to the internal wall of the nostril, or which is equipped with means intended to facilitate insertion and / or maintenance in the nostril , or which is equipped with a dispensing means to facilitate insertion into the nostril, or which is accompanied by a manual for carrying out the insertion into the nostril. The endonasal application system can be maintained in the nostril but expelled by the nasal mucus and can be designed to release the active ingredient in the same place in the nostril. As a suitable type of endonasal application system, there may be mentioned na-15 wicks, tampons and the like. Advantageously, the volume and the porosity of this system are chosen so that the latter is maintained in the nostril without interfering with breathing.

Suitable dimensions are for example between about 0.05 and about 1 cm3, for example between about 0.5 and about 0.8 cm3. The endonasal application system can for example have more or less the shape of a cylinder, a cone, a cube or a sphere.

The SMS can be applied to said system for example by adsorption on the surface of the latter, or incorporated inside said system, for example by absorption, or by any other suitable means, for example by covering the surface of said system coating system, for example a solid or semi-solid coating, consisting of SMS in combination with one or more diluents or vehicles compatible with the nasal mucosa.

When the endonasal application system itself comprises a soluble or semi-soluble material, for example water-soluble polymers, or a material degradable in the nose, for example an aqueous proteinaceous material compatible with the nasal mucosa such as gelatin, SMS can also be presented in solid form, for example in the form of a lyophilisate dispersed inside said system, for example distributed in the matrix.

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The SMS is preferably applied, for example retained by absorption, in the system and distributed appropriately throughout the system.

The endonasal application system according to the invention is capable of releasing the peptide which it contains on the surface of the nasal mucosa. To this end, the system will preferably be designed or shaped so as to adapt to the internal surface of the nostril, for example so as to allow maximum contact between the surface of the system and the nasal mucosa. In addition, when the SMS 10 is retained in the system, for example by absorption, the characteristics of the system, in particular the absorption characteristics of the material of which it is made, will advantageously be such as to allow easy diffusion of the peptide to the surface of the system from which it is gradually absorbed by the nasal mucosa. When the SMS is retained in the system, for example by absorption, the latter can comprise any suitable material, for example a material compatible with the nasal mucosa, which forms a porous matrix or a reticular structure in the interstices of which the peptide can be retained, for example absorbed. Said material is advantageously elastic, so that it can be held in the nostrils without causing discomfort. It may for example be a fibrous material such as cotton wool or a spongy material such as natural sponge or synthetic sponges.

25 If desired, the material may swell slightly, for example increase in volume by about 50¾ after application.

The material from which the endonasal application system is prepared may for example be a water-soluble polymer. It is preferably a polymer which can be easily moistened by the nasal mucosa. It can be biodegradable in the nostril and can even dissolve slowly, for example over a period of one to several days. It must be possible to withdraw it once the dose of active ingredient has been administered. The polymer can be, for example, a lyophilized and absorbable gelatin sponge. If desired, the matrix may dissolve during or shortly after administration of the dose of active ingredient. Examples of suitable polymers that may be mentioned include water-soluble polyacrylates and cellulose derivatives such as cellulose, for example hydroxypropylcellulose and in particular hydroxypropylmethylcellulose. Water-insoluble crystalline cellulose can also be used.

The characteristics of the matrix used, for example viscosity or molecular weight, should be chosen so that the resulting application system is easy to use and maintain. Typical molecular weights for hydroxypropyl methylcellulose are between about 9000 and 15000 and the viscosity is for example between about 4 and about 15 cp, for a 2% solution.

Another suitable material is gelatin sponge. The United States Pharmacopoeia has established standards for absorbable gelatin sponges, for example for hemostasis in surgical procedures, and such sponges are preferred. They can be prepared, for example, by vigorously whipping an aqueous solution of pure gelatin to form a foam which is dried under controlled conditions to obtain a sponge which is cut and sterilized. The pieces obtained advantageously have dimensions of between approximately 5 × 5 × 5 and approximately 10 × 10 × 10 mm. The sponge is compressed by hand before use and is absorbed within a few hours. A spongy material particularly suitable for the preparation of an endonasal application system according to the invention is the product SPONGOSTAN® sold by the company A / S Ferrosan, 5 Sydmarken, DK-2860 Soeborg, Denmark.

Other polymers can be used such as hydroxypropyl-cellulose or polyvinylpyrrolidone.

As indicated above, the application system preferably has a porous structure. It is advantageous that the nasal mucosa can moisten the application system and that the active ingredient can diffuse through the pores of the system to the nasal mucosa.

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The pores of the application system can for example have a diameter of between a few microns and about 100 microns. The pores of a lyophilized absorbable gelatin sponge can be, for example, from about 5 to about 100 microns. The pore size can vary for example between about 5 and about 10 microns.

The pores of the spongy material may be sinuous. When the application system is prepared by lyophilization, the pores can be approximately linear.

The application system preferably contains a water-soluble sugar or similar excipient which gives the system a stable structure. Examples of suitable sugars include lactose, sucrose and mannitol. The weight ratio of sugar to the other substance is preferably between about 0.1 to 1 and about 10 to 1.

A preferred endonasal delivery system includes a water-soluble polymer such as hydroxypropyl methylcellulose and lactose. Examined under the electron microscope, a lyophilized sample appears to consist of laminar layers containing each of the pores. These pores extend substantially through the entire sample.

When the SMS is retained in the application system, for example by absorption, it will advantageously be applied in a diluted form, for example in the form of a composition containing the active principle in association with a fluid compatible with the nasal mucosa, for example a suitable liquid, diluent or vehicle. Such a composition will advantageously comprise the active principle in the form of a solution, suspension, dispersion or the like. Such compositions preferably contain the active ingredient in the form of an aqueous solution.

Preferably, the application system is prepared under essentially aseptic or sterile conditions.

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According to a preferred variant, the solution of active principle is lyophilized. The application system can be preformed or shaped during the lyophilization process, for example from a solution of the material constituting the system.

The lyophilization can be carried out under the usual conditions, preferably at low temperature, for example at a temperature of between approximately -100 ° C. and approximately -10 ° C. One can operate under the usual pressures, for example between about 0.01 mm and about 0.2 mm of mercury.

Lyophilization can lead to the formation of an outer layer of very fine pores which may have the appearance of a sponge. This outer layer can be between about 10 and 100 microns thick. If desired, its formation can be avoided by performing lyophilization at very low temperatures. This layer can also be removed by friction.

The compositions to be administered by the nasal route can also be in the form of a powder, for example based on lactose or water-absorbing polymers, insoluble in water or soluble in water.

As water-absorbent and water-soluble polymers, mention may be made of polyacrylates such as sodium, potassium and ammonium polyacrylate, lower alkyl ethers of cellulose such as methylcellulose, hydroxyethylcellulose, 1 hydroxypropylcellulose and sodium carboxymethylcellulose, polyvinylpyrrolidone, amylose and preferably a polyethylene glycol having a molecular weight between 1000 and 8000, and hydroxypropylmethylcellulose.

Examples of water-absorbent and water-insoluble polymers include water-absorbent and water-insoluble celluloses such as microcrystalline cellulose, cellulose, α-cellulose and carboxymethylcellulose crosslinked sodium, water-absorbing and water-insoluble starches such as hydroxypropyl friend don, carboxymethylami don, water-insoluble and water-absorbing proteins such as gelatin and casein, 35 gums absorbing water and water insoluble such as arabic gum, tragacanth and glucomannan, and crosslinked vinyl polymers such as crosslinked polyvinylpyrrolidone, crosslinked carboxy-vinyl polymers and their salts, crosslinked polyvinyl alcohol and polyhydroxyethylmethylacrylates. Among these compounds, water-absorbent and water-insoluble celluloses and crosslinked vinyl polymers are preferred, in particular water-absorbent and water-insoluble celluloses and more particularly microcrystalline cellulose.

Preferred polymers have the characteristics mentioned previously for the endonasal application system or are usually used for the administration of powders by the nasal route.

The preferred hydroxypropyl methylcelluloses have a content of 28 to 30% of methoxy groups and from 7 to 12% by weight of hydroxypropoxy groups. A preferred product is that sold under the brand Methocel E5. The viscosities are preferably between 1 and 50 cp (2¾ aqueous solution at 20 ° C).

Preferably, the average degree of polymerization of the preferred polymers, microcrystalline cellulose, is from approximately 200 to 20,000, preferably from 200 to 300. The preferred average molecular weights are between approximately 20,000 and approximately 100,000, for example between 30,000 and 50,000. The average particle size is preferably from about 5 to about 80 microns, for example from 20 to 70 microns, more preferably from 50 microns. Advantageously, the bulk density is for example around 260 to 300 g / l. Microcrystalline cellulose is advantageously obtained by mechanical treatment of polysaccharides consisting of glucose, for example natural cellulose, optionally with acid treatment. Its preparation is described, for example, in American patent 302978446.

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The preferred products are those sold under the Avicel® brand by the company FMC Corporation, Marcus Hook,

United States, in particular Avicel PH 101. These products meet the specifications indicated for microcrystalline cellulose in 5 USP / National Formulary XXI.

These powders can be prepared according to known methods, by mixing the SMS with the particles, for example the base polymer. The particle size and / or their density are preferably those indicated above for microcrystalline cellulose.

If desired, the particles can be coated. The polypeptide may be in solution, for example in aqueous or alcoholic solution when mixed with the particles, and the solvent is evaporated for example by drying and freezing or drying and spraying. Such drying can be carried out under the usual conditions, for example as described above for the application systems. In this way, particles coated with an SMS layer are obtained. The mixture can also be compressed or granulated and then be made into a powder and / or sieved. If desired, the mixture can be made into an application system, for example as described above, then powdered.

It is generally desirable to use the particles constituting the base powder in an amount greater than 5 times the weight of SMS, especially in a weight ratio of SMS to particles of between 1 and 10 to 100, for example between 1 and 10 to 30. For 20 mg of powder, the SMS load will be, for example, 0.2, 0.4, 0.8 and 1.6 mg. Preferably, the powder has a particle size between 10 and 250 microns.

The pharmaceutical compositions in powder form can be used directly as such for unit doses. If desired, this powder can be used to fill capsules, such as hard gelatin capsules. The contents of the capsule can be administered using, for example, an insufflator.

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The compositions of the invention may contain other excipients. Certain excipients have been described above for particular compositions but may also be present in other compositions of the invention. For example, sugars, such as lactose, stabilizers and isotonic agents may be present in powder form, if desired in the same preferred amounts.

If desired, the compositions of the invention may also contain an absorption promoting agent, particularly a nonionic agent, suitable for application to the nasal mucosa. Whereas, when nasal administration of peptides has been previously proposed in the art, for example in the case of insulin administered nasally, the use of a surfactant in general improves nasal resorption or may in fact be an essential condition for achieving bioavailability rates sufficient for therapeutic utility, according to the present invention it has surprisingly been found that in the particular case of SMS, the presence of a surfactant has little or no influence on re-sorption characteristics. Thus, it has been found in particular and even more surprisingly that SMS compositions can be prepared for nasal administration which do not contain any agent promoting absorption. This feature has the advantage of avoiding the drawbacks encountered in the preparation of effective formulations by the nasal route, resulting from the irritant side effects of the surfactants necessarily used.

However, when it is desired to use an absorption promoting agent which is compatible with the nasal mucosa, one may for example add a substance capable of promoting absorption through the nasal mucosa. Such absorption promoting agents include surfactants compatible with the nasal mucosa, and in particular: 1) bile acids and their salts such as sodium taurochlorate, sodium deoxycholate and glycocholate, s- sodium glycodeoxycholate, s-cholate and s-taurodeoxycholate; 2) cationic surfactants such as the condensation products of long chain amines with ethylene oxide and quaternary ammonium compounds, for example trimethylketylammonium bromide and dodecyldi-methylammonium bromide; 3) anionic surfactants such as alkylbenzene sulfonates, N-acyl-n-alkyltaurates, olefin α-sulfonates, sulfated linear primary alcohols and sulfated polyoxyethylene straight chain alcohols; 4) nonionic surfactants such as polyoxyethylenated alkylphenols, polyoxyethylenated straight chain alcohols, long chain carboxylic acid esters including glyceryl esters of natural fatty acids, propylene glycol esters, sorbitol and polyoxyethylene sorbitol, for example Polysorbate 80; 5) amphoteric surfactants such as imidazoline carboxylates, sulfonates, etc; and 6) phospholipids such as phosphatidylcholine, etc.

When it is desired to use a surfactant, it is preferable to use polyoxyalkylene higher alcohol ethers compatible with the nasal mucosa, for example those corresponding to formula I

R0-C- (CH2) n-0 -] - xH I

In which RO represents the residue of a higher alcohol, in particular a higher alkanol or an alkylphenol such as lauric or cetyl alcohol, or a sterolic residue, in particular a residue of lanosterol, dihydrocholesterol or cholesterol, as well as mixtures of two or more of these ethers. The preferred poly-oxyalkylene ethers for use according to the invention are polyoxyethylene and polyoxypropylene ethers (i.e. in which n in the above formula means 2 or 3), in particular the polyoxyethylenic and polyoxypropylene ethers of lauric and cetyl alcohol and cholesterol, as well as mixtures of two or more of these ethers.

The terminal hydroxy group of these ethers can be partially or entirely acylated, for example by acyl residues of aliphatic carboxylic acids such as acetic acid.

The ethers preferred for use according to the invention 10 have an HLB index (hydrophilic / lipophilic balance) of between approximately 10 and approximately 20, in particular between approximately 12 and approximately 16.

The ethers which are particularly suitable for use according to the invention are those in which the average number of repeating units in the polyoxyalkylene residue (x in the formula indicated above) is between 4 and 75, advantageously between 8 and 30, more especially between 16 and 26. These ethers can be obtained according to known techniques. A large number of these products are available on the market and marketed for example by the company Amerchol under the brand Solulan®, by the companies KAO Soap, ICI and Atlas under the brands Emalex®, Brij® and Laureth® and by the company Croda under the Cetomacrogol® brand.

Examples of suitable polyoxyalkylene ethers that may be mentioned include: (POE = polyoxyethylene ether; POP = polyoxypropylene ether; x = average number of sequences in the rest POE / POP).

1. Cholesterol ethers: 3Q 1.1 So lui an® C-24 - POE, x = 24.

f - 16 - 2. Ethers of lanolinic alcohols: 2.1 So lui an® 16 - POE, x = 16.

2.2 So lui an® 25 - POE, x - 25.

5 2.3 So lui an® 16 - POE, x = 75.

2.4 Solulan® PB-10 - PPE, x = 10.

2.5 Solulan® 98 - POE, x * 10 - partially acetylated.

2.6 Solulan® 97 - POE, x - 9 - fully acetylated.

10 3. Ethers of lauric alcohol: 3.1 Emalex® 709 / Laureth®9 - POE, x * 9.

3.2 Lauret h® 4 / Brij®30 - POE, x * 4.

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

15 4. Ethers of cetyl alcohol: 4.1 Cetomacrogol®- POE, x a 20 to 24.

Lanolin alcohols are also known as wool fatty alcohols and are a mixture of cholesterol, dihydrocholesterol and lanosterol.

The ethers which are preferred to use in the compositions of the invention are the polyoxyethylene ethers of cholesterol, that is to say those corresponding to the formula I indicated above, in which n signifies 2 and RO represents a residue of cholesterol, in particular ethers in which the number of sequences in the polyoxyethylenic residue is between 16 and 26, more preferably around 24.

Preferably, these ethers do not contain any impurities, in particular from other polyoxyalkylene ethers. They preferably contain at least 75¾. more preferably at least 85%, and very particularly at least 90% by weight of polyoxyethylene ether of cholesterol in the pure state.

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The desired viscosity of the compositions of the invention will vary depending on the mode of administration chosen, for example in the form of nasal drops, or, which is preferred, in the form of nasal spray.

5 For nasal drops, an appropriate viscosity will be between approximately 2 and 400 x 10 ~ 3 Pa.s. For the nasal spray, the viscosity will preferably be less than 2 x 10 ~ 3 Pa.s.

When a surfactant is used, for example a polyoxyalkylene ether, its amount in the compositions of the invention will vary depending on the particular surfactant chosen, the mode of administration chosen, for example drops or spray, and the desired effect. In general, the amount of surfactant is between about 0.01 and 100 mg / ml, more preferably between about 1 and 75 mg / ml, more especially between about 1 and 60 mg / ml.

The compositions according to the invention can be administered in any suitable form. The preferred forms have been described previously; however, other formulations can be prepared analogously, or as described, for example, in the literature. For administration, the formulations can be packaged according to the usual methods, preferably in a device for administration by the nasal route. For administration in the form of drops, such compositions will advantageously be packaged in a container 25 equipped for example with a conventional closure device with a dropper, comprising for example a pipette or the like, preferably delivering a substantially fixed volume of the composition per drop. For administration as a nasal spray, such compositions will be put into a suitable spray device, for example, a pump sprayer, an aerosol can or the like. The spray device comprises appropriate means allowing the application of the composition to the nasal mucosa. It will preferably be provided with means making it possible to deliver a substantially exact quantity of the composition on each spraying, that is to say per spraying unit. If desired, the composition can be packaged under pressure in an aerosol container. Advantageously, such a device makes it possible to deliver a determined quantity of composition. The propellant can be a gas or a liquid, for example a fluorinated and / or chlorinated hydrocarbon. The composition can be suspended in a liquid propellant. Stabilizers and / or agents allowing suspension can be added. If desired, soft gelatin or hard gelatin capsules can be filled with the composition in powder or liquid form. The device for the application may include means for opening the capsule.

The amount of active principle, that is to say SMS, in the compositions of the invention will obviously vary depending on various factors, such as the particular form of drug chosen (for example SMS in free base form , salt, solvate, or complex), the disease to be treated, the desired frequency of administration and the desired effect. The bioavailability of the compositions of the invention can be determined according to the usual methods, for example as described in the examples below. The doses can be chosen so as to have an activity identical to administration by injection, for example in one of the therapeutic indications mentioned above. The amount of active ingredient to be administered will generally be chosen so as to obtain an effective treatment, for example from 1 to 5 drops or spray units once or from 2 to 4 times per day. To this end, the active principle is advantageously present in an amount making it possible to obtain a free SMS concentration of between approximately 0.1 and approximately 3 mg, preferably between 5 and approximately 0.1 and approximately 1 mg, more preferably between approximately 0.6 and 1 mg per spray. Doses of SMS are for example 0.2 mg, 0.4 mg, 0.8 mg and 1.6 mg. The individual drops or powders preferably have a volume of from about 0.05 ml to about 0.2 ml, for example about 0.1 ml. The liquid compositions 10 of the invention therefore advantageously contain between approximately 2.0 and 20 mg / ml, preferably approximately 15, more preferably approximately 10 mg / ml of free SMS, for example approximately 6.0 mg / ml of free SMS. . When using SMS in salt, solvate or complex form, the amount of drug present will correspondingly be greater. When using SMSac, the liquid compositions of the invention will contain, for example, approximately 7.4 mg / ml of SMSac (ie approximately 6.0 mg of free SMS).

The following examples illustrate the present invention without in any way limiting its scope. Further details on the characteristics of the excipients can be found in the documents provided by the manufacturer and / or in the book by H.P.

Fiedler, Lexikon der Hilfsstoffe, Cantor Edition, Aulendorf, 1981.

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Example 1 INGREDIENTS QUANTITY / ml of final composition

A B

5 1. SMSac 7.796 mg * 3.19 mg + 5¾ excess 0.390 mg 0.16 mg 8.186 mg 3.35 mg 10 2. Glucose 50.0 mg 50.0 mg 3. 0.1N HCl for a pH of 4.20 for a pH of 4.20 4. Benzalkonium chloride 0.11 mg 0.11 mg 5. H2O (for injection) ... qs 1.0 ml qs 1.0 ml 15 * = 6.315 mg SMS free

Ingredients 1, 2 and 4 are mixed according to the usual methods with ingredient 5, a 5% excess of SMSac is added to compensate for the loss of filtration, then ingredient 3 is added to adjust the pH to 4, 20 and then water (5) to obtain the desired final volume. The mixture is stirred for 5 minutes, filtered (0.2 micron mesh) and filled with Rexo containers under CO 2 atmosphere. The solution thus obtained is clear and colorless, has a final pH of 4.2 + 0.5 and is suitable for nasal administration as a nasal spray using a spray device delivering approximately 0.095 ml / per spray unit (i.e. approximately 0.6 mg free SMS per spray unit for Example IA and 0.25 mg of free SMS per spray unit for Example IB).

Example 2

The procedure is analogous to that described in Example IA but by adding 3.0 mg (per ml of final composition) of SOLULAN C24® powder [poly (24) oxyethylene ether of choles-35 terol] to ingredients 1, 2 and 4 at the first stage.

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Bioavailability study The study is carried out on 12 healthy volunteers (4 women, 8 men, average age 31.5 years, average weight 68 kg, average height 183 cm) according to the guidelines of Tokyo amendment 5 ( 1975) of the Declaration of Helsinki (Federal Register 40, p. 16056, April 9, 1975).

Excluded from the study are patients suffering from liver or kidney function disorders, cardiac disorders or disorders in biological media, as well as pregnant women and people who have already had allergies. Chronic signs of constipation, diarrhea, acute pathological signs in the gastrointestinal tract or chronic or acute sinusitis as well as serious respiratory tract infections at the time of the study are also reasons for exclusion.

An EEG (12 electrodes) is performed before the start of the study. Laboratory tests (in the blood: number of red blood cells, hemoglobin, number of white blood cells, erythrocyte sedimentation rate, platelet count, postprandial glucose; in serum: total proteins and electrophoresis, sodium, potassium, creatinine , uric acid, SGOT, SGPT, y-GT, LDH, alkaline phosphatase, cholesterol, bilirubin, a-amylase; in the urine: pH, proteins, glucose, sediment) are carried out before and at the end of the study.

Each patient receives two doses comprising: 1. 0.6 mg of free SMS administered by nasal route in the form of a spray corresponding to the composition given in Example IA; and 2. 0.6 mg of free SMS administered by the nasal route in the form of a spray corresponding to the composition of Example 2.

Administration is carried out randomly in cross-over. The intervals between each administration represent at least 3 days. The drug is administered in the morning after a light breakfast taken with drinks that do not contain caffeine. Each patient is shown how to administer the nasal spray into the right nostril while maintaining the head in a vertical position. The patient should thoroughly blow their nose before proceeding with nasal administration. During and after administration, patients should hold their breath for 10 seconds. Patients should drink at least 100 ml of water or 5 fruit teas every hour to ensure satisfactory urinary excretion.

Blood samples are taken immediately before SMS administration, and 5, 10, 15, 20, 30, 40, 50, 60, 75, 90 minutes and 2 hrs., 2.5 hrs., 3 hrs., 4 a.m., 5 a.m., 6 a.m. and 8 a.m. after administration of the drug. These samples are collected by means of a catheter introduced into the ulnar vein at the start of the study and are placed in empty tubes cooled with ice, centrifuged about 15 to 30 minutes later at 4 ° C, and the serum is frozen at -20 ° C until analyzed.

15 Urine samples are collected before administration of the drug and between midnight. and 2 a.m., 2 a.m. and 4 a.m., 4 a.m. and 6 a.m., 6 a.m. and 8 a.m. after administration. The total volume of each urine sample is measured and about 5 ml of it is frozen at -20 ° C until analysis is carried out.

20 Blood pressure and heart rate are recorded immediately before and 1 hr, 2 hrs., 3 hrs., 4 hrs., 5 hrs., 6 hrs. and 8 a.m. after administration of the drug.

The concentrations of SMS 201-995 in serum and urine are analyzed according to the radioimmunological assay method with a detection limit of 0.2 ng / ml.

Results

The compositions administered were well tolerated, side effects (hypermotility in the abdomen / steatorrheic stools) having been observed in only 4 patients. In each of the 30 cases, the side effects were mild and lasting no more than 2 hours.

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The bioavailability rates calculated based on the concentration of serum levels and cumulative urinary excretion indicate that the therapeutic levels of SMS in serum are achieved by the use of the two compositions and that the treatment carried out by the nasal route with each of the two compositions is suitable for long-term clinical application.

Example 3: Solution for nasal spra.y containing SMS

This solution is prepared by proceeding in a similar manner to that described in Example 1 with the following components: 10 mg / ml 1. SMSac 11.55 * + 5% excess 0.55 2. Glucose 50.00 15 3 0.1N HCl for a pH of 4.2 4. Benzalkonium chloride 0.111 5. H2O (for injection) qs 1 ml * = 11 mg of free SMS 20 Under CO2 "2.5 ml of the solution are poured into a 3.5 ml glass container with a nasal spray device. This gives 1 mg of free SMS per spray.

Example 4: Endonasal application system containing lyophilized SMS 25 A lyophilized application system (wick) is prepared from the following ingredients: mg (4A) mg (4B) SMSac 0.316 1) 0.315 1) 30 Lactose 2, 0 1.0 HPMC (Pharmacoat 606) 3.0 HPMC (Methocel E5) 1.5 PEG (molecular weight: 4000) 1.5 35 1) Equivalent to 0.25 mg of free peptide.

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Preparation of an endonasal application system from hydroxypropyl methylcelluiose

30 g of pure water are heated to 70 ° C. and 1.5 g of HPMC are added thereto (in the case of Example 4A, and 0.75 g of HPMC + 0.75 g of 5 PE6 4000 in the example 4B). The suspension is cooled to room temperature and 1 g of lactose (200 mesh) is added thereto (in the case of Example 4A, and 0.5 g of lactose in the case of Example 4B). The SMS is dissolved in 15 g of pure water. The liquids are mixed and water is added until a total volume of 50 ml is obtained. The solution is filtered through 0.2 micron mesh and poured using a pipette in 0.1 ml portions into the recesses (5 mm) of an aluminum plate.

The plate is cooled to -35 ° C for 4 hours, then lyophilized at -10 ° C for 40 hours, then at + 15 ° C for 24 hours (in the case of Example 4A, and in the case of Example 4B at -10 ° C for 66 hours and at + 10 ° C for 24 hours).

After having brought the temperature of the lyophilizer back to room temperature, the lyophilized blocks thus obtained are carefully withdrawn and they are introduced into a 1 ml syringe 20 (equipped with a plunger) the end of which intended for the needle has been cut about 3 mm from the end. Each lyophilized block weighs approximately 5 mg.

The endonasal application system thus obtained is stable and easily soluble in water. It is a lyophilizer with a diameter of about 5 mm and a length of about 6 to 7 mm. When examined under the electron microscope, it appears as a system of laminar layers comprising long channels of parallel pores with a diameter between about 5 and 10 microns. The lyophilisate is coated with a layer about 50 microns thick having a fine, porous structure, of spongy appearance.

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Example 5: Powder to be Administered Nasally Containing SMS A powder (particle size 38-68 pm (sieved)) is prepared containing 20 mg 0.3 mg of SMSac (ie 0.25 mg of free SMS) and 19.7 mg of microcrystalline cellulose (AVICEL PH 101) 5 (= example 5A) or lactose (= example 5B). This powder is then poured into capsules which can be administered nasally by means of an insufflator.

Bioavailability: tests carried out on monkeys

The compositions of the invention were administered nasally to groups of 4 rhesus monkeys at a dose of 0.5 mg of SMS. The pharmacokinetic parameters obtained are as follows:

Cpmax t max. AUC (0 - 6 hrs.) 15 (ng / ml) in hours ng / ml-1 per hour

Example 4A 23.60 0.25 37.25

Example IB 2.60 0.25 13.16

Example 4B 9.54 0.25 24.80

Example 5A 55.75 0.25 77.83 20 Example 5B 19.96 0.25 32.14

EXAMPLE 6 Lyophilized Endonasal Application System

Lyophilized application systems A and B were prepared in a similar manner to that described in Example 25 4 and contain the following ingredients: mg (6A) mg (6B) SMSac 1.20 1.20 + 5¾ d 'excess 0.06 0.06 30 Lactose 1.0 2.0 HPMC (Methocel E5) 1.5 3.0 PEG 4000 1.5 H2O (for injection) qs 1 ml.

AT

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The lyophilized application systems (length 5 mm, diameter 5 mm) were well tolerated locally and generally. EXAMPLE 7 Nasal Powders

Nasal powders A and B were prepared containing the following in-5 ingredients: mg (7A) mg (7B) SMSac 1.32 1.32 + 5¾ excess 0.07 0.07 10 Microcrystalline cellulose (Avicel PH 101 - particle size 38-68 microns) 18.61 HPMC (Methocel E5) - 18.61 15 particle size 38-68 microns _ _

Total 20 20

These powders were prepared from a charge representing approximately 300 unit doses by mixing the SMS with approximately a quarter of the polymer. The mixture was sieved, the rest of the polymer added and the whole mixed thoroughly.

If desired, the SMS can be dissolved in an aqueous alcoholic solution and mixed with the polymer. The suspension or solution thus obtained is frozen or spray-dried to obtain a powder.

In its final form, the powder has particles having a size of about 20 to about 250 microns.

These powders are put into capsules which can be administered nasally by means of an insufflator. 4 sprays make it possible to administer 1 mg of SMS in 18 mg of powder.

The powders for nasal administration have been well tolerated locally and generally.

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Bioavailability studies referring to examples 6 and 7

These studies were carried out on 12 healthy volunteers, [3 (eg 6) or 4 (eg 7) women and 9 resp. 8 men, average age 26 and 27, average weight 69 kg, average height 175 and 5,178 cm] according to the guidelines of the Tokyo amendment (1975) of the Declaration of Helsinki (Federal Register 40, p. 16056, April 9, 1975).

Patients with the disorders indicated above are excluded from the study for the studies carried out with the com-positions of Examples 1 and 2.

An EEG (12 electrodes) is performed before the start of studies. Laboratory tests identical to those indicated above for the studies carried out with the compositions of Examples 1 and 2 are carried out before and at the end of the studies.

Each patient receives two doses comprising: 1. 1 mg of free SMS administered by the nasal route in the form of an endonasal application system or a nasal powder corresponding to the composition given in Example 6A or 7A respectively, and 2. 1 mg of free SMS administered by the nasal route in the form of an endonasal application system or a nasal powder corresponding to the composition of Example 6B or 7B respectively.

The endonasal delivery system was administered into the right nostril using an applicator. Gelatin capsules (powders) are administered by the nasal route using an in-sufflator similar to those used for medicines intended for the treatment of asthma (Intal® Insufflator, Fisons). Four sprays are carried out, changing each nostril each time and starting with the right nostril. After each breath, the patient should inhale the administered powder. Before administration, one of the persons carrying out the study cleans the nostrils of the patient placed in a sitting position.

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Blood samples are taken immediately before SMS administration, and 5, 10, 15, 20, 30, 40, 50, 60, 75, 90 minutes and 2 hrs., 2.5 hrs., 3 hrs., 4 a.m., 5 a.m., 6 a.m., 8 a.m., 10 a.m. and 11 a.m. after administration of the drug. These samples are collected by means of a catheter introduced into the ulnar vein at the start of the study and are placed in empty ice-cold tubes, centrifuged approximately 15 to 30 minutes later at 4 ° C, and the serum is frozen at -20 ° C until analyzed. Blood pressure and heart rate are recorded very immediately before and 1 a.m., 2 a.m., 3 a.m., 4 a.m., 5 a.m., 6 a.m. after administration of the drug.

The concentrations of SMS 201-995 in the serum (powders) and in the plasma (endonasal application system) are analyzed with the radioimmunological assay method with a detection limit of 0.2 to 0.1 ng / ml.

The bioavailability rates calculated on the basis of the concentration of serum and plasma levels and of cumulative urinary excretion indicate that the therapeutic levels of SMS in serum are achieved by the use of the two compositions and that the treatment carried out by the nasal with each of the two compositions is suitable for long-term clinical application.

Pharmacokinetic parameters 25 SMS nasally administered (dose = 1.0 mg)

Average values

Example 6A 6B 7A 7B

30 Tmax (min.) 35.0 20.0 15.0 30.0

Cp (Tmax) (ng / ml) 1.4 2.5 26.1 * 3.2 AUC (0‘-7201) (ng * min./ml) 227.0 334.0 2066.0 560.0

Claims (12)

2. A pharmaceutical composition for administration by nasal route, characterized in that it comprises octreotide. 3. A composition according to claim 2, characterized in that it is adapted to contain between 0.1 and 3 mg of octreotide per dose. 4. A composition according to claim 2 or 3, characterized in that it is in the form of a liquid. 5. A composition according to claim 4, characterized in that it is in the form of an aqueous solution. 6. A composition according to claim 2 or 3, characterized in that it is in the form of an endonasal application system. 7. A composition according to claim 2 or 3, characterized in that it is in the form of a powder. 8. A composition according to claim 7, characterized in that the particles are coated with an octreotide layer. 9. A composition according to claim 7 or 8, characterized in that the powder comprises particles of hydroxypropylmethylcellulose. 10. A composition according to claim 7 or 8, characterized in that the powder comprises particles of lactose. II. - A composition according to claim 7 or 8, charac-terized in that the powder comprises particles of microcrystalline cellulose. 12. A composition according to any one of claims 7 to 11, characterized in that it comprises between 0.2 and 1.6 mg of octreotide per 20 mg of powder. w - 30 - "! * * * the 13. A composition according to any one of claims 7 to 12, characterized in that the weight ratio of octreotide to particles is between 1 and 10 to 100. 14. A composition according to any one of claims 5 tions 2 to 13, characterized in that it is in the form of unit doses. 15. A composition according to claim 14, characterized in that it is packaged in a capsule. 16. A composition according to any of claims 10 to 2 from 13 to 13, characterized in that it is packaged in a nasal application device. 17. A composition according to claim 16, characterized in that it is in an aerosol can. 18. The use of octreotide for the preparation of pharmaceutical compositions for administration by the nasal route.