FI93307C - A process for preparing a pharmaceutical composition containing octreotide - Google Patents

Description

93307 METHOD FOR THE PREPARATION OF A PHARMACEUTICAL COMPOSITION CONTAINING OCTREOTIDE - FÖRFARANDE FÖR FRAMSTÄLLNING AV EN OKTREOTID INNEHAlLANDE PHARMACEUTICAL SAMMANSÄTT-NING 5

The invention relates to a process for the preparation of a novel pharmaceutical composition comprising the somatostatin analog SMS 201-995 (octreotide).

Somatostatin or SRIF is a naturally occurring 10-cyclic tetradecapeptide first isolated from bovine and porcine hypothalamic tissues and has potent growth hormone (GH) inhibitory activity. It has since been found in other parts of the central nervous system, and pancreas, stomach and small intestine 15 D-differentiated cells. From these sites, SRIF acts on the pituitary gland by inhibiting the secretion of GH and thyroid stimulating hormone (TSH), inhibiting open and endocrine secretion of the pancreas (including insulin and glucagon secretion), and locally acting in the digestive tract (GI), where it inhibits the release of gastrin secretion, CCK (cholecystokinin), VIP (vasoactive intestinal polypeptide), and possibly other hormones. The latter, through the inhibition effects SRIF-licenses of its own role in important physiological digestive functions 25 in the modulation, for example by reducing gastric acid secretion, delaying gastric emptying, slowing down bowel movements, reducing the flow of bile, increasing mucus formation and lowering the internal blood flow.

Several suggestions have been made for the therapeutic applications of this compound in the treatment of, for example, acromegaly (giant tip) or gastrointestinal disorders such as bleeding. However, despite its high biological activity, SRIF is very 35 short-lived (half-life 2-3 minutes). Therefore, it must be administered intravenously (i.v.). Iv However, in view of the above, this substance is not suitable for long-term clinical use.

Recently, research has thus focused on the development of new analogs and derivatives of somatostatin. These are oligopeptide compounds that have substantially fewer amino acid residues than somatostatin itself, but have one or more partial peptide chains from the somatostatin molecule.

So far, all of these analogs have had to be administered by injection, for example, intravenously (i.v.) or subcutaneously (s.c.) in order to obtain a therapeutic effect at non-toxic doses.

One analog that is promising therapeutically and is now well advanced in clinical trials is the compound SMS 201-995 (hereinafter "SMS"), and has the formula i-1 H- (D) Phe-Cys-Phe- (D) Trp -Lys-Thr-Cys-Thr-was The chemical common name for SMS is octreotide.

This compound, described in detail in EP 0029579 (= US 4,395,403), is an octa-peptide with many of the same pharmacological properties as SRIF, although it is apparently slightly more selective in inhibiting the release of GH and glucagon rather than insulin. . In particular, the situations for which the use of this compound is indicated are e.g. acromegaly, complications of diabetes, and a number of GI disorders, including tumors secreting GI hormone (e.g., VIPoma and the like).

In therapeutic applications, SMS, like most other peptide drugs, can be administered as such, i.e., in free form or as a pharmaceutically acceptable salt and / or complex. The SMS may additionally or alternatively be in the form of a solvate, e.g. as a hydrate.

The current form used in clinical applications of SMS is acetate hydrate, 3,930,307 referred to herein as SMSac, with a free peptide content of about 80-88%, e.g., 83-87%. Unless otherwise stated, the terms "SMS" and "octreotide" as used throughout this application and claims are understood to mean both the free peptide and its pharmaceutically acceptable salts, especially acid addition salts and especially acetate, as well as pharmaceutically acceptable complexes and / or solvates thereof. .

5 Despite the very significant therapeutic potential, there are practical problems with the provision of SMS; iv this s.c. injection has so far been the only viable route that has allowed the use of clinically effective doses. Generally, injection or infusion has been used as the route of administration. Such routes of administration are always uncomfortable and when long-term treatment is required at regular intervals, it can cause undue pain and discomfort to the patient. Thus, the development of alternative modes of administration of SMS, in particular those that allow it to be performed by the patient himself, e.g. in outpatient settings, has remained the main goal.

The object of the invention is to provide a process for the preparation of a pharmaceutical composition containing octreotide.

For aspects of the invention, reference is made to the claims.

According to the present invention, it has now surprisingly been found that effective SMS treatment can be achieved by nasal administration, i.e. by performing administration to the nasal mucosa. In particular, it has been found that nasal administration of doses well within tolerability limits achieves levels of bioavailability that are fully sufficient to allow effective, long-term treatment in conditions where SMS therapy is used, e.g., as previously described herein.

Since nasal administration provides a simple and painless mode of administration that can be performed repeatedly and regularly without significant discomfort to the patient, the present invention accordingly meets existing needs as previously described.

The compositions for the nose of the invention are surprisingly well tolerated, for example they have a minimal effect on the function of the cilia.

In the process of the invention for preparing a pharmaceutical composition comprising octreotide (SMS), a nasal pharmaceutical composition is prepared in the form of nasal drops, nasal sprays, nasal powders or nasal inserts, wherein in a) a nasal powder form is prepared by doping oct-15 reotide , comprising lactose and water-absorbent and water-insoluble cellulose having an average particle size of 5 to 80 microns, and optionally blending 20 with other nasally acceptable excipients selected from the group consisting of hydroxypropylmethylcellulose and polyethylene glycol; or b) the nasal spray or nasal drop form is prepared by mixing octreotide in solution with at least one nasally acceptable excipient selected from the group consisting of glucose, benzalkonium chloride and water, and optionally mixing the polyoxyethylene cholesteryl ether with 4, and adjusting the pH to an aqueous solution. 5 with a suitable acid; or c) the nasal insert formulation is prepared by mixing octreotide in solution form with at least one nasally: * acceptable excipient selected from the group consisting of lactose, hydroxypropylmethylcellulose and water, and optionally doping with polyethylene glycol and, if necessary, removing the solvent present; and d) optionally formulating the composition into a unit dosage form or filling the nasal delivery device with the composition.

In view of the above, the invention also relates to: i) a method of administering octreotide (SMS) to a subject in need thereof, e.g. for the treatment of disorders caused by or associated with GH hypersecretion or for the treatment of gastrointestinal disorders as previously described , and comprising nasal administration of octreotide (SMS); and also ii) a nasal pharmaceutical composition containing octreotide (SMS).

According to the invention, the pharmaceutical composition may be prepared in a conventional manner using excipients compatible with the nasal mucosa, e.g. as described below.

Furthermore, the pharmaceutical composition may be formulated for nasal mucosa for topical administration and such that a systemic effect of SMS is possible. The preparation may be, for example, a liquid, an insert or a powder.

According to the invention, the compositions described in ii) above can be prepared, for example, in the form of liquid compositions containing SMS and a liquid diluent or carrier suitable for application to the nasal mucosa.

Such compositions are best suited for administration in the form of a nasal spray or drops.

Of the liquid compositions ii) according to the invention, aqueous solutions are particularly preferred. For nasal administration, such solutions are preferably slightly acidic, for example a pH of about 4 to 5, preferably about 4.2. The required degree of acidity is achieved, for example, by the addition of HCl or another appropriate mineral acid or organic acid. For nasal use, such compositions should also be isotonic or substantially isotonic. The best additives to achieve the desired isotonicity are e.g. nasally acceptable sugars such as glucose, mannitol or sorbitol or nasally acceptable salts, especially NaCl. According to the present invention, the most preferred additive for achieving the desired degree of isotonicity is glucose, ribose, mannose, arabinose, xylose or other aldose, or glucosamine.

In the method according to the invention, other ingredients or excipients, which are known, for example, as stabilizers and / or preservatives, can also be included in the compositions. The most preferred preservatives in the compositions of the invention are sodium methyl mercurothiosalicylate (= Thiomersal) and benzalkonium chloride. The concentration of preservatives preferably ranges from about 0.05 to 0.2 mg / ml, e.g. about 0.1 mg / ml.

Furthermore, according to the invention, the pharmaceutical composition can be prepared in the form of a porous, solid nasal-insert in which the SMS is distributed throughout. The present invention further provides a method of making a solid nasal insert that is porous to a meter consisting of gelatin and / or hydroxypropylmethylcellulose and SMS.

The method of making the nasal insert 25 of the invention can be implemented utilizing any conventional method, i. can be e.g.

a) distributing the SMS throughout into a porous matrix of gelatin and / or hydroxypropylmethylcellulose, e.g. by lyophilizing the polymer-containing liquid which may form the matrix, and the SMS; or b) distributing the SMS throughout the nasal insert, for example by immersing the sponge in an aqueous solution, e.g. at room temperature, and evaporating the solvent.

The term "nasal insert" refers to a Kap-35 piece that, in size and shape, is suitable for insertion into and remains in the nostril; is intended to be inserted into the nostril; or which has been manufactured, 7 93307 shaped and otherwise shaped for insertion and retention in the nostril; or shaped to conform exactly to the inner surface of the nostril; or provided with means for facilitating insertion and / or retention in the nostril; or provided with a delivery device to facilitate insertion into the nostril; or accompanied by instructions for performing the nostril. The insert may remain in the nostril but is in contact with the nasal mucosa and may be designed to release the active substance while in place in the nostril. Suitable nasal insert types include nasal plugs, tampons and the like. Most conveniently, the volume and porosity of the insert is selected to remain in the nostril, but respiration is not significantly impeded. Suitable external dimensions are, for example, about 0.05 to 1 cm 3, for example about 0.5 to 0.8 cm 3. The shape can be, for example, cylindrical, conical, cubic or spherical.

In one embodiment of the invention, the SMS is applied to the surface of the insert, e.g. by adsorption thereto, or absorbed into it, e.g. by absorption, or in some other useful manner, e.g. SMS together with one or more nasally acceptable solvents or other aids. as a semi-solid coating.

• Alternatively, when the insert itself is intended to contain a soluble or semi-soluble substance, e.g. a water-soluble polymer or an otherwise nasally degradable substance, such as a nasally acceptable protein such as gelatin, the insert may be prepared so that the SMS is dispersed. -: inserted into the insert, e.g. distributed throughout the matrix, in solid form, for example as a lyophilisate.

Preferably, the insert is made such that the SMS is retained, e.g., by absorption in the insert, and is suitably distributed throughout it.

8 93307

The inserts prepared in accordance with the present invention are capable of releasing the peptide they carry onto the nasal mucosa. To this end, they are preferably shaped or manufactured to conform to the inner surface of the nostril, for example so that maximum contact is made between the surface of the insert and the nasal mucosa. In addition, when the SMS is intended to be retained in the insert, e.g., by absorption, the properties of the insert, e.g., the absorption properties of its components, are suitably selected to allow unimpeded passage of the peptide to the insert surface and increased transport to the nasal mucosa.

When the active ingredient is intended to be retained in the insert, e.g. by absorption, the insert may be made of any suitable, e.g. nasally acceptable, material which produces a porous medium or reticulated structure from which the peptide can be absorbed. The material is suitably elastic, so it stays in the nostril with ease. It may be, for example, a fibrous material such as cotton wool or a fungal material such as a natural or synthetic fungus.

If desired, the material may swell slightly, e.g., increase in volume by about 50% upon administration.

The material from which the insert is made may be. . <for example a water-soluble polymer. Preferably, the polymer is readily hydrogenated by the nasal mucosa. In the nostril, it can biodegrade, it can even dissolve slowly, e.g. within one or more days. It may also need to be removed as long as the active ingredient is administered. An example is a lyophilized, absorbent gelatin sponge. If desired, the medium may be selected so that it dissolves immediately or slightly after administration of the active ingredient. Examples include water-soluble acrylate polymers and cellulose derivatives such as cellulose, e.g. hydroxypropylcellulose and especially hydroxypropylmethylcellulose. Alternatively, water-insoluble crystalline cellulose may be used.

The properties of the medium material used, e.g. viscosity and molecular weight, should be chosen so that the resulting insert is easy to handle and store. Typical molecular weights for hydroxypropylmethylcellulose are about 9,000 to 15,000 and the viscosity is e.g. 4 to 15 cp in a 2% solution.

Another useful material is gelatin sponge. The U.S. Pharmacopoeia provides definitions for absorbent gelatin fungi, for example in surgical procedures to stop bleeding, and such fungi are preferred. Such sponges can be prepared, for example, by vigorously mixing an aqueous solution containing pure gelatin and drying the resulting foam under controlled conditions to form a sponge, as well as cutting the resulting sponge into suitable pieces and sterilizing the pieces. Suitable sizes are about 5 x 5 x 5 to 10 x 10 x 10 mm. The sponge 20 is squeezed by hand before use and allowed to absorb for several hours. A particularly suitable fungal material for use in the manufacture of the nasal inserts of this invention is SPONGOSTAN *, available from A / S Ferrosan, address 5 Sydmarken, 25 DK-2860 Soeborg, Denmark.

: Alternative polymers are, for example, hydroxypropylcellulose or polyvinylpyrrolidone.

As indicated above, the insert made according to the invention preferably has a porous structure. The nasal mucosa can conveniently moisten the insert and the active agent can spread through the pores of the insert: to the surface of the nose.

»

The pores of the insert may be from a few microns to about 100 microns in diameter, for example.

The pores of the lyophilized absorbent gelatin sponge may be, for example, from about 5 to about 100 microns. The pore size can be, for example, about 5 to about 10 microns.

• · 10 93307

In the fungal material, the pores may be disordered. When the insert is prepared by lyophilization, the pores can be almost linear.

Preferably, a water-5 soluble sugar or similar excipient is included in the insert to make the structure of the insert stable. Examples of suitable sugars are e.g. lactose, sucrose and mannitol. Preferably, the sugar / other ingredients weight ratio is about 0.1: 1 to 10: 1.

In a preferred embodiment, an insert is prepared comprising a water-soluble polymer such as hydroxypropylmethylcellulose and lactose. In electron microscopy, the lyophilized sample appears to consist of thin films, each with 15 openings. Gaps appear throughout the sample.

When the SMS is intended to be retained in the insert, e.g. by absorption, the insert may be prepared in a form suitably diluted in the carrier, e.g. in the form of a composition containing the active ingredient and a nasally acceptable liquid, e.g. a solvent, diluent or carrier. Such compositions preferably contain the active ingredient in the form of a solution, suspension, dispersion or the like. The compositions preferably contain the active ingredient in aqueous solution.

The insert is preferably prepared under completely microorganism-free or sterile conditions.

In one embodiment, a solution containing 30 active ingredients is lyophilized. The insert can be formed in advance or during the lyophilization process, e.g. from a solution of the insert material.

Lyophilization can be performed under conventional conditions, preferably at low temperatures, e.g.

35 to about (-100) to (-10) ° C. Conventional pressures, e.g. about 0.01 to 0.2 mm Hg, can be used.

Lyophilization can produce very small openings in the outer layer «11 93307, which can be porous. This outer layer may be about 10 to 100 microns thick. If desired, its formation can be prevented by lyophilization at very low temperatures. Alternatively, it can be removed by rubbing.

Furthermore, according to the invention, the nasal compositions can be prepared in powder form, e.g. based on lactose or water-absorbent, water-insoluble or water-soluble polymers.

Among the water-absorbent and water-soluble polymers useful in the invention, mention may be made, for example, of polyacrylates such as sodium polyacrylate, potassium polyacrylate and ammonium polyacrylate; lower alkyl ethers of cellulose such as methylcellulose, hydroxyethylcellulose, hydroxypropylcellulose and sodium carboxymethylcellulose; polyvinylpyrrolidone, amylose and preferably polyethylene glycol, e.g. having a molecular weight (MW) of between 1000 and 8000, and hydroxypropylmethylcellulose.

Preferred examples of water-absorbent and water-insoluble base materials include:

For example, water-absorbent and water-insoluble celluloses such as microcrystalline cellulose, cellulose, α-cellulose and cross-linked sodium-r: carboxymethylcellulose; water-absorbing and water-insoluble starches such as hydroxypropyl starch, carboxymethyl starch; water-absorbing and water-insoluble proteins such as gelatin, casein; water-absorbent and water-insoluble gums such as gum arabic, gum tragacanth and glucomannan; And crosslinked vinyl polymers such as crosslinked polyvinylpyrrolidone, crosslinked carboxyvinyl polymer or a salt thereof, crosslinked polyvinyl alcohol 35 and polyhydroxyethyl methyl acrylate. Of the above, water-absorbent and water-insoluble celluloses and crosslinked vinyl polymers are preferred, and water-absorbent and water-insoluble celluloses are more preferable, with microcrystalline cellulose being particularly preferred.

Preferred polymers have the above-mentioned properties for nasal inserts or have been used conventionally for nasal powder delivery.

The hydroxypropyl methylcelluloses useful in the invention have a methoxyl content of 28-30% and a hydroxypropoxyl content of 7-12% by weight. One preferred product is Methocel E5. The viscosities are preferably 1 to 50 cP (2% aqueous solution at 20 ° C).

A preferred polymer, microcrystalline cellulose, has an average polymer number of about 200 to 2,000, most preferably 200 to 300. Preferred average molecular weights are from about 20,000 to about 100,000, e.g., 30,000 to 50,000.

Preferably, the average particle size is about 5 to 80 microns, e.g. 30 to 70 microns. The preferred average particle size is 50 microns. A suitable free specific gravity is e.g. about 260 to 300 g / l. The microcrystalline cellulose is preferably obtained by treating glucose-based polysaccharides, e.g. natural cellulose, mechanically optionally in combination with an acid treatment. Their preparation is described in e.g. U.S. Pat. No. 2,978,446.

. . Useful formats are AVICEL (registered trademark of the FMC Corporation). The material used was Avicel PH 101 (registered trademark), available from FMC Corporation, Marcus Hook, 30 USA. The product conforms to the specifications given for microcrystalline cellulose in USP / National Formulary XXI: - •. s sä.

• · These powders can be prepared by mixing SMS into particles, e.g., on a polymer base in a conventional manner. The particle size and / or specific gravity are preferably as given above for the microcrystalline cellulose.

* «13 93307

If desired, the particles can be coated. The polypeptide may be in solution, e.g. in aqueous or alcoholic solution, with stirring into particles, and the solvent is evaporated off, e.g. by freeze-drying or spray-drying. Such drying can be performed under conventional conditions, as described in connection with the insert. This produces an octreotide coating. Alternatively, the mixture may be compressed or granulated and then ground and / or screened. If desired, the powder 10 can be prepared in insert form, e.g., as described above, and then ground.

In general, it is desirable to use particles that weigh more than 5 times the weight of the SMS, especially 10 to 100 times, e.g., 10 to 30 times larger.

Examples of the amounts of SMS used in the invention are 0.2, 0.4, 0.8 and 1.6 mg of SMS per 20 mg of powder.

Preferably, the powder has a particle size of 10 to 250 microns.

The powdered pharmaceutical composition prepared according to the invention can be used directly, such as a powder in unit dosage form. If desired, the powder may be placed in a capsule, such as hard gelatin capsules. The contents of the capsule can be administered using e.g. airway-25 control.

:: In the process of the invention, other excipients may also be included in the compositions. Some excipients useful in certain compositions have been described above, and it is to be understood that these excipients may also be included in other compositions of the invention. For example, sugars such as lactose, stabilizers and isotonic agents may be included in the powder forms in equally preferred amounts as desired.

If desired, according to the invention, an absorption enhancer, in particular a non-ionic enhancer suitable for application to the nasal mucosa, may also be included in the compositions. However, in the context of the present invention, a surprising finding has been made to the suggestion previously made in connection with nasal administration of peptides, e.g. nasally administered insulin, that the use of a surfactant generally improves nasal absorption or may even be a prerequisite for therapeutically adequate levels of bioavailability. In particular, and surprisingly, it has been found that nasal SMS 10 compositions can be prepared without the inclusion of an absorption enhancer. This finding provides a particular advantage in avoiding the disadvantages that would otherwise be encountered in the preparation of effective nasal compositions when surfactants with irritating side effects have to be used.

When it is nevertheless desired to use a nasally acceptable absorption enhancer, agents capable of promoting absorption through the nasal mucosa may be added. Such promoters include nasally acceptable surfactants or surfactants. Such surfactants include: i) Bile acids and their salts, such as sodium taurocholate, sodium deoxycholate and sodium glycocholate, s-glycodeoxycholate, s-cholate, s-tau:> rodeoxycholate.

ii) Cationic surfactants such as long chain amine condensates with ethylene oxide and quaternary ammonium compounds, for example cetyltrimethylammonium bromide and dodecyldimethylammonium bromide. lii) Anionic surfactants such as alkyl benzene sulfonates; N-acyl-n-alkyl taurates, α-olefin sulphonates, sulphanated linear primary alcohols and sulphanated polyoxyethylene straight-chain alcohols, iv) Non-ionic surfactants such as polyoxy-ethylene long-chain alkylated phenols, polyoxyethylene carboxylic acid esters including glycerol esters of natural fatty acids, propylene glycol, sorbitol and polyoxyethylene sorbitol esters e.g.

Polysorbate 80R.

v) Amphoteric surfactants such as imidazole carboxylates, sulfonates, etc .; and vi) Phospholipids such as phosphatidylcholine, etc.

When it is desired to use a surfactant, preferred nasal ethers of polyoxyalkylene high alcohols are preferred. Such ethers are, for example, ethers of the formula I 15

RO - [- (CH2) n-O-] - xH I

wherein RO is a residue of a higher alcohol, in particular a higher alkanol or an alkylphenol such as lauryl or cetyl alcohol, or a sterol residue, in particular a lanosterol, dihydrocholesterol or cholesterol residue, and also mixtures of two or more such ethers. Preferred polyoxyalkylene ethers for use in accordance with this invention are polyoxyethylene and polyoxypropylene ethers (i.e., where n is 2 or 3 of the above formula), especially polyoxyethylene and polyoxypropylene lauryl, cetyl and cholesteryl ethers, as well as two or more such ethers. alloys.

The hydroxy group of the terminal alkylene unit of such ethers may be partially or completely acylated, e.g. with an acyl residue of aliphatic carboxylic acids such as acetic acid.

Preferred ethers used in accordance with this invention have a hydrophilicity-lipophilicity balance (HLB group number) of about 10 to about 20, especially about 12 to 16.

16 93307

Particularly suitable ethers for use according to the invention are those in which the average number of repeating units of the polyoxyalkylene unit (x in the above formula) is on average 4 -5 75, more preferably 8-30, particularly suitably 16-26.

Ethers can be obtained according to known methods. A wide range of such products are commercially available and are sold, for example, by Solchan of Amerchol, KAO Soap, ICI and Atlas Ema-10 lexR, BrijR and LaurethR, and CetomacrogolR of Croda.

Examples of polyoxyalkylene ethers suitable for use in accordance with this invention are as follows: (POE = polyoxyethylene ether: POP = polyoxy-15 cypropylene ether: x = average number of repeating units per POP / POE unit).

1. Cholesteryl ethers: 1.1 Cellulan “C-24 - POE, x = 24.

2. Ethers of lanolin alcohols: 20 2.1 Cellulan ”16 - POE, x = 16.

2.2 cells ”25 - POE, x = 25.

2.3 Solulan ”16 - POE, x = 75.

2.4 Solulan ”PB-10 - PPE, x = 10.

2.5 Cellulan ”98 - POE, x = 10 - partially acetylated 25 2.6 Cellulan” 97 - POE, x = 9 - fully acetylated • 3. Lauryl ethers: 3.1 Emalex ”709 / Laureth” 9 - POE, x = 9.

3.2 Laureth ”4 / Brij” 30 - POE, x = 4.

30 3.3 Laureth ”23 / BrijR35 - POE, x = 23.

4. Cetyl ethers: 4.1 Cetomacrogol ”-POE, x = 20-24.

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

17 93307

Suitable ethers for use in accordance with this invention are polyoxyethylene cholesteryl ethers, i.e. compounds of formula I above wherein n = 2 and RO is a cholesterol residue, especially ethers having an average number of repeating units in the polyoxyethylene unit of 16 to 26. , most preferably about 24.

Such ethers are preferably completely free of contaminants, especially other polyoxy-sialkylene ethers. Preferably, they contain at least 75%, more preferably at least 85%, and most preferably at least 90% by weight of pure polyoxyethylene cholesteryl ether.

The suitable viscosity of the compositions prepared by the method of the invention depends on the particular mode of administration, e.g. whether it is administered as nasal drops or as a nasal spray.

A suitable viscosity for nasal drops is about 2 to 400 x 10’3 Pa.s. The viscosity of the nasal sprays should preferably be less than 2 x 10 ~ 3 Pa.s.

When surfactants, e.g., polyoxyalkylene ether, are used in the compositions of the invention, the amount used will vary depending on which particular surfactant is selected, the particular route of administration (e.g., drop or spray) and the effect desired. However, in general, the amount is in the range of about 0.01 to 100, more preferably about 1 to 75, most preferably about 1 to 60, mg / ml.

The compositions prepared by the method of the invention may be administered in any suitable form. Suitable forms have been described above, but it is to be understood that other preparations may be prepared in an analogous manner or analogously to e.g. methods described in the literature. They may be packaged for administration in a conventional manner, suitably in a nasal dispenser, preferably so as to provide a predetermined dose of SMS. Compositions to be administered as drops 18 93307 may conveniently be placed in a bottle having, e.g., a conventional closable pipette cap, e.g. containing a pipette or the like, which suitably dispenses a fully defined volume of composition black. The compositions to be administered as a spray may be placed in a suitable spray device, e.g. a pump sprayer, an aerosol bottle or the like. The spray device must have suitable means for introducing the spray into the nostril. Preferably, it should have means to ensure that a fully defined volume of composition is obtained per application (i.e., per spray unit). If desired, the spray can be bottled by pressure into a new type of aerosol device. The device preferably delivers a measured dose. The propellant may be a gas or a liquid, e.g. fluorinated and / or chlorinated hydrocarbons. The spray composition may be mixed with a liquid propellant. Stabilizing and / or suspending agents may be present. If desired, the powder or liquid may be packaged in a soft or hard gelatin capsule. The delivery device-20 may have means for opening the capsule.

The amount of active ingredient, i.e. SMS, in the compositions of the invention may, of course, vary depending on various factors such as which particular dosage form is chosen (i.e. whether the SMS is free, salt, solvate or complex), the condition being treated, desired frequency of administration and desired effect. The bioavailability of the compositions prepared according to the invention can be determined by conventional means, e.g. as described by way of example below.

Doses may be selected to be as effective as those obtained by injection, e.g. in the treatment of any of the above symptoms. The amount of active ingredient is generally selected to provide effective treatment when administered (e.g., 1-5 drops or spray units) 35 times or 2-4 times daily, suitably twice or more suitably once daily. For this purpose, the active ingredient is suitably present in a concentration such that the amount of free SMS is about 0.1 to 3, suitably about 0.1 to 1, more preferably about 0.6 to 1, mg per administration. Examples of SMS doses are 0.2 mg, 0.4 mg, 0.8 mg and 1.6 mg.

5 The individual drops or powders suitably have a volume of about 0.05 ml and the spray units suitably have a volume of about 0.05 to 0.2 ml, e.g. about 0.1 ml.

Thus, the compositions suitably contain an average of about 20, suitably about 15, more preferably about 10 to 2.0 mg of 10 free SMS per milliliter, e.g. about 6.0 mg of free SMS / ml. When a salt, solvate or complex of SMS is used, the amount of drug component is correspondingly higher. Thus, when SMSact is used, the liquid compositions of this invention may contain e.g.

15 7.4 mg SMSac / ml (approx. 6.0 mg free SMS).

The following examples illustrate the method of the invention for preparing liquid compositions for use in a nasal spray dispenser.

Further details on the properties of the excipients can be found in Pharmacopoeia, H.P. Fiedler, Lexicon der Hilfsstoffe, Editio Cantor, Aulendorf, 1981 and manufacturers' brochures.

Example 1: Preparation of a nasal liquid spray:

Composition 25 Ingredient Amount of substance / ml final composition

A B

1. SMSac 7.796 mg * 3.19 mg + 5% 0.390 mg 0.16 mg excess -------- -------- 30 8.186 mg 3.35 mg 2. Glucose 50.0 mg 50.0 mg 3. 0.1N HCl pH 4.2 to pH 4.2 4. Benzalkonium chloride 0.11 mg 0.11 mg 35 5. H 2 O (injection purity) to a final volume of 1.0 ml * = 6.315 mg free SMS 20 93307

Manufacturing:

Components 1, 2 and 4 are mixed with water by conventional means, a 5% excess of SMSac is added to cover filtration losses. Component 3 is then added to bring the pH 5 to 4.2 and water (5) is added in the amount required for the desired final volume. The mixture is stirred for 5 min and filtered (0.2 micron holes) and placed in Rexo vessels under CO 2 gas. The result is a clear and colorless solution with a final pH of 4.2 ± 0.5 and is suitable for nasal spray administration using a spray dispenser giving about 0.095 ml / spray unit (= about 0.6 mg / free SMS / spray unit in Example IA and 0.25 mq / free SMS / spray unit in Example IB).

Example 2: Preparation of a nasal liquid spray:

Example IA is repeated otherwise, but ground SOLULAN C42 (Polyoxyethylene- (24) -cholesteryl ether) 3.0 mg / ml per final composition is added to components 1, 2 and 4 of the first preparation step.

20

Bioavailability TEST USING THE PREPARATIONS OF EXAMPLES 1 AND 2

The experiment was performed on 12 healthy volunteers (4 women, 8 men, mean age 31.5 years, 25 mean weight 68 kg, mean length 183 cm) according to the principles set out in the Tokyo Declaration of Amendment (1975) of the Declaration of Helsinki (Liittorekisterl 40, page 16056, April 9, 1975).

Individuals with known hepatic or renal impairment, heart failure, or fluid and electrolyte disturbances have been excluded from the study. Other grounds for exclusion include pregnancy and previous allergic reactions. Chronic symptoms of constipation, diarrhea or acute symptoms related to the gastrointestinal tract at the time of the study, or acute or chronic inflammation of the sinuses, as well as acute inflammation of the airways, are also grounds for exclusion.

An EEC study (12 channels) was conducted before the start of the experiment. Laboratory tests (blood: red blood cell count, hemoglobin, white blood cell count, red blood cell sedimentation rate, platelet count, postprandial glucose; serum: total protein and electrophoresis, sodium, potassium, creatinine, uric acid, S-GOT, S-GOT, -GT, LDH, alkaline phosphatase, cholesterol, bilirubin, α-amylase; urine: pH, 10 protein, glucose, sediment) were performed before and after the study.

Each subject receives two doses containing: 1. 0.6 mg of free SMS as a nasal spray using the composition of Example IA; and 2. 0.6 mg of free SMS as a nasal spray using the composition of Example 2.

Doses were administered randomly in a sequential order. The dosing interval was at least 3 days.

The drug is given in the morning after a light breakfast that did not contain caffeinated beverages. Each subject was instructed to administer a nasal spray to the right nostril, keeping the head upright. The nose is cleaned by swallowing before intranasal administration. During and after the administration of the substance, persons hold their breath for 10 seconds. Drink at least 100 ml of water or fruit tea every hour to maintain satisfactory urinary excretion.

30 Blood samples are taken immediately before taking the SMS and 5 ', 10', 15 ', 20 *, 30 *, 40', 50 ', 60', 75 ', 90 *, 2 h, 2.5 h, 3 h, 4 h, 5 h, 6 h and 8 h after taking the drug. They are taken through a catheter inserted into the elbow vein at the beginning of the experiment and placed in empty 35 tubes kept on ice, centrifuged after about 15-30 minutes at 4 ° C, and the serum frozen at -20 ° C until analyzed.

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Urine samples are collected before taking the drug and then at 0-2 h, 2-4 h, 4-6 h, and 6-8 h intervals. The total volume of the urine sample is measured and about 5 ml of urine is frozen at -20 ° C until analyzed.

Blood pressure and pulse are measured immediately before, and 1 h, 2 h, 3 h, 4 h, 5 h, 6 h, and 8 h after taking the drug.

Concentrations of SMS 201-995 in serum and current-10 are analyzed by a radioimmunoassay with a sensitivity limit of 0.2 ng / ml.

SCORE

The administered compositions are well tolerated, side effects (abdominal hypermotility / fat stool) were observed in only 4 of 12 subjects, and in all cases were only mild and lasted for up to 2 hours.

Bioavailability levels based on serum levels and cumulative excretion in urine suggest that the therapeutic level of serum SMS is achieved using both compositions and that treatment by nasal administration of either composition is suitable for long-term clinical use.

Example 3: Preparation of liquid SMS nasal spray:

The preparation is prepared analogously to Example 1 and contains: mg / ml 1. SMSac 11.55 1 30 + 5% excess 0.55 2. Glucose 50 3. HCl 0.1N to pH 4.2 4. Benzalkonium chloride 0.11 mg 5. H 2 O (injection purity) 1 to a final volume of 35 ml

* = 11 mg free SMS

9 23 93307 2.5 ml of the solution is placed under CO2 gas in a 3.5 ml glass lifter fitted with a nasal spray mechanism. This gives 1 mg SMS per press.

Example 4: Preparation of nasal SMS lyophilisate insert:

The lyophilisate insert (stopper) is prepared from the following: mg (4A) 1 mg (4B) 1 10 SMSac 0.316 0.315

Lactose 2.0 1.0 HPMC (Pharmacoat 606) 3.0 HPMC (Methocel E5) 1.5 PEG (MW 4000) 1.5 15 1) corresponds to 0.25 mg free peptide

Preparation of nasal insert from hydroxypropylmethylcellulose: 30 g of pure water are heated to 70 ° C. 1.5 g of HPMC are added (in Example 4A and 0.75 g of HPMC 20 plus 0.75 g of PEG 4000 in Example 4B). The suspension is cooled to room temperature and 1 g of lactose (200 mesh) is added (Example 4A and 0.5 g of lactose in Example 4B). SMS is dissolved in 15 g of pure water. The liquids are mixed and the volume is made up to 50 ml with water. The solution is filtered through a 0.2 micron filter and pipetted in 0.1 ml aliquots into wells (5 mm) on an aluminum plate.

The plate is cooled to -35 ° C for 4 hours, then lyophilization is started at -10 ° C for 40 hours and continued at + 15 ° C for 24 hours (in Example 4A and started at -10 ° C for 66 hours and continued for 24 hours). At + 10 ° C in Example 4B).

The resulting lyophilized pieces are carefully transferred from the plate after raising the temperature of the lyophilizer to room temperature and placed in a 1 ml plunger syringe with a 3 mm cut-off from the needle side. Each piece weighs approximately 5 24 93307 mg.

The resulting insert is stable and easily soluble in water. It is a homogeneous lyophilisate, about 5 mm in diameter and about 6 to 7 mm in length. In the electron-5 cloning microscope, it appears to be arranged in film layers with long, parallel pore channels about 5 to 10 microns in diameter. The edge layer of the lyophilisate is about 50 microns thick and has a fine, foamy, porous structure.

10 EXAMPLE 5: Preparation of Nasal SMS Powder:

A powder (particle size 38 to 68 μm (screened)) containing 0.3 mg of SMSac (= 0.25 mg of free SMS) and 19.7 mg of microcrystalline cellulose-15 (AVICEL PH 101) (= Example 5A) or lactose Example 5B). This is packaged in a capsule that is dispensed into the nose using a blower.

Bioavailability experiments in monkeys: The compositions were administered in nasal doses of 0.5 mg SMS to groups of 4 rhesus monkeys. Achieved pharmacokinetic parameters:

Cp maximum t maximum AUC (0-6 h) 25 (ng / ml) hours ng ml "1 h

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 30 Example 5B 19.96 0.25 32.14 EXAMPLE 6: Preparation of nasal lyophilisate inserts:

Lyophilisate inserts A and B were prepared analogously to Example 4 and contained: 93307 25 mg (6A) mg (6B) SMSac 1.20 1.20 + 5% excess 0.06 0.06

Lactose 1.0 2.0 5 HPMC (Methocel E5) 1.5 3.0 PEG 4000 1.5 H 2 O (Injection purity) to a final volume of 1 ml.

Lyophilizates (length 5 mm, diameter 5 mm) were well tolerated locally and systemically.

10 EXAMPLE 7; Preparation of nasal powders:

Prepared nasal powders containing: mg (7A) mg (7B) 15 SMSac 1.32 1.32 + 5% excess 0.07 0.07

Microcrystalline cellulose (Avicel PH 101 particle size 38 to 68 microns) 18.61 20 HPMC (Methocel E5) particle size 38 to 68 microns - 18.61

A total of 20 20 25 These powders were prepared in batches of about 300 unit doses by mixing SMS and a quarter of the polymer. The mixture is screened. The rest of the polymer is added and then the mass is mixed thoroughly.

If desired, the SMS can be dissolved in an aqueous solution of alcohol 30 and mixed with the polymer. The resulting suspension or solution is lyophilized or spray dried to. a powder is formed.

The particles of the final powder have a diameter of about 20 to 250 microns.

35 These powders are packaged in a capsule which can be dispensed into the nose by means of a blower. 4 presses give 1 mg of SMS in 18 mg of powder.

26 93307

Nasal powders were well tolerated locally and systemically.

Bioavailability TEST USING 5 PREPARATIONS ACCORDING TO EXAMPLES 6 AND 7

The study was performed on 12 healthy and volunteer individuals (3 (Example 6) or 4 (Example 7) women, and 9 or 8 men, respectively, mean age 26 and 27 years, mean weight 69 kg, mean length 175 and 178 cm) 10 according to their principles. presented in the Tokyo Declaration of Amendment to the Declaration of Helsinki (1975) (Federal Register 40, page 16056, April 9, 1975).

Individuals with known hepatic or female dysfunction, heart failure, or fluid and electrolyte disturbances have been excluded from the study. Other grounds for exclusion include pregnancy and previous allergic reactions. Chronic symptoms of constipation, diarrhea or acute gastrointestinal symptoms or acute or chronic inflammation of the sinuses, as well as acute inflammation of the airways, at the time of the study are also grounds for exclusion.

An EEC study (12 channels) was conducted before the start of the experiment. Laboratory tests (blood: red blood cell count, hemoglobin, white blood cell count, red blood cell sedimentation rate, platelet count, postprandial glucose; serum: total protein and electrophoresis, sodium, potassium, creatine, uric acid-po, S-GOT, S-GOT, -GT, LDH, alkaline phosphatase, cholesterol, bilirubin, α-amylase; urine: pH, protein, glucose, sediment) have been performed before and after the study.

Each person receives two doses, including:

1. 1 mg of free SMS administered in a nasal insert or as 35 nasal powders using Example 6 or 7A

compositions, respectively, and 2. 1 mg of free SMS administered in a nasal insert or 27,9307 as a nasal powder using the compositions of Example 6B or 7B, respectively.

The doses were administered randomly in the prescribed inventive order. The dosing interval was at least three days. The drug was administered in the morning after a light breakfast that did not contain caffeinated beverages.

Nasal inserts were inserted into the right nostril using an applicator. For insertion of gelatin capsules (powders) into the nose 10, they were placed in a ventilator commonly used for asthma medications (Insuflator Intal * nasal, Fisons). Four puffs are given alternately to the right and left nostrils. After each blow, the person inhales the metered powder. Prior to dosing, one of the researchers cleaned the nostrils while the person was in a sitting position.

Blood samples are taken immediately before taking the SMS and 5 ', 10', 15 ', 20', 30 ', 40', 50 ', 60', 75 ', 90', 2h, 2.5 h, 3 h, 4 h, 5 h, 6 h, 8 h, 10h, and 11 h after taking the drug. They are taken through a catheter inserted into the elbow vein at the beginning of the experiment and placed in empty tubes kept on ice, centrifuged for about 15-30 minutes at 4 ° C, and the serum frozen at -20 ° C until analyzed.

25 Blood pressure and pulse are measured immediately before and 1 h, 2 h, 3 h, 4 h, 5 h, 6 h and 8 h after taking the drug.

Concentrations of SMS 201-995 from serum (powders) versus plasma (inserts) are analyzed by a radioimmunological method with a sensitivity limit of 0.2 to 0.1 ng / ml.

Bioavailability levels based on serum and plasma levels and cumulative urinary excretion suggest that a therapeutic level of SMS is achieved using all compositions and that treatment by nasal administration of either composition is suitable for long-term clinical use.

Pharmacokinetic parameters SMS nasal (dose = 1.0 mg) 5 means

Example 6A 6B 7A 7B

T max (min) 35.0 20.0 15.0 30.0 10 Cp (Tmax) (ng / ml) 1.4 2.5 26.1 3.2 AUC (0 1 - 270 ') 227.0 334.0 2066.0 560.0 (ng1min / ml) ·

Claims (4)

A process for preparing an octreotide-containing pharmaceutical composition, characterized in that a nasal pharmaceutical composition is prepared in the form of nasal drops, nasal sprays, nasal powders or nasal inserts, wherein in the process a) the nasal the powder form is prepared by mixing 10 octreotide with at least one nasally acceptable solid adjuvant selected from a group belonging to lactose as well as water-absorbing and water-insoluble cellulose whose average particle size is 5 to 80 microns, or alternatively by mixing til other nasally acceptable excipients selected from a group including hydroxypropylmethyl cellulose and polyethylene glycol; or b) the nasal spray or nasal drop form is prepared by mixing octreotide in solution with at least one nasally acceptable excipient selected from a group including glucose, benthalkonium chloride and water, or alternatively by mixing the polyoxyethylene carbonyl ether solution and adjusting the pH tili approx. 4 -5 with a suitable acid; or c) the nasal insert form is prepared by mixing octreotide in solution with at least one nasally acceptable excipient selected from a group belonging to lactose, hydroxypropylmethyl cellulose and water, or alternatively by mixing to polyethylene glycol and, if necessary removing the solvent present; and d) alternatively, the composition is brought in a single-dose form or a nasal dosing device is filled with the composition. 35 2. A process according to claim 1, characterized in that the composition is prepared in nasal drop or spray form by mixing 93307 octreotide in an aqueous carrier or diluent by adjusting the pH of the recovered solution to 4-5. with an appropriate acid and carry out phase d). 5 3. A method according to claim 1, characterized in that the composition is reinstalled in the form of a nasal insert. 4. A process according to claim 1, characterized in that the composition is prepared in the form of a nasal powder. > · «· 1