CH672252A5 - - Google Patents

Description

DESCRIPTION

Somatostatin or SRIF is a natural cyclic Te-tradecapeptide, first isolated from hypothalamic tissue from sheep and pigs, which has a strong inhibitory effect on growth hormone (GH). It has now been found to be present in other areas of the central nervous system, as well as in the specialized D cells of the pancreas, stomach and small intestine. From these sites, SRIF inhibits GH and thyreotropic hormone (TSH) secretion on the pituitary gland, exocrine and endocrine secretion (including insulin and glucagon secretion) on the pancreas, and locally in the gastrointestinal tract inhibits secretion of gastrin CCK, VIP and possibly other hormones. Because of these inhibitory effects, SRIF plays an important physiological role in the regulation of gastrointestinal functions, e.g. by reducing gastric secretion, delaying gastric emptying, slowing intestinal motility, decreasing bile flow, increasing mucus production and reducing the blood flow to the intestine.

Several therapeutic uses have been proposed for somatostatin, e.g. in the treatment of acromegaly or in gastrointestinal diseases such as gastrointestinal bleeding. Although SRIF is biologically highly active, it has a very short half-life (2 to 3 minutes) and this, together with the need for i.v. Administration and after i.v. Administration found rebound effect, making this compound unsuitable for prolonged clinical use.

Recently, attempts have therefore been made to develop new analogues and derivatives of somatostatin, in particular oligopeptides which contain fewer amino acids than somatostatin itself, but while retaining one or more of the peptide partial sequence (s) which occur in the somatostatin molecule.

So far, these analogs have all had to be injected e.g. B. i.v. or s.c. be administered in order to obtain a therapeutic effect at non-toxic doses.

A special representative of this class of oligopeptides, which promises therapeutic promise and is now in an advanced stage of clinical investigation, is the compound SMS 201-995 (= octreotide) of the formula

I «

H- (D) Phe-Cys-Phe- (D) -Trp-Lys-Thr-Cys-Thr-ol

This compound, specifically published and claimed in European Patent No. 29,579 (= US 4,395,403), is an octapeptide and has many of the pharmacological properties of SRIF, although it appears to be 15 more selectively the GH and glucagon than the insulin secretions. one inhibits.

This compound can be used particularly in the treatment of acromegaly, diabetic complications and a variety of gastrointestinal diseases including tumors that secrete gastrointestinal hormones (e.g. Vipomas and the like).

When used therapeutically, SMS, like most peptide-like drugs, can of course be used both in free form and as a pharmaceutically suitable salt and / or complex.

Such salts and complexes are also known and in the above. European Patent No. 29,579. SMS can also be in Solvat form, e.g. as a hydrate.

The now preferred form for the clinical use of SMS is the acetate hydrate, also referred to as SMSac, which has a free peptide content of approx. 80 to 88%, e.g. Has 83 to 87%. Unless otherwise stated, “SMS” and “octreotide” in the present description and claims mean both the free peptide and the pharmaceutically suitable salts, especially the acid addition salts, especially the acetate and the pharmaceutically suitable complexes and / or solvate thereof.

«Although SMS offers considerable therapeutic options, there are still problems with the administration of this substance. So far the i.v. or s.c. Administration the only accessible method to get an effective dosage in the clinic. In general, administration is by injection or infusion. Such forms of administration are always troublesome and if the administration is to take place at long time intervals during long-term therapy, it can be very painful and uncomfortable for the patient. Therefore, finding alternative forms of administration for SMS, especially those which enable easy self-application, e.g. for patient outpatient treatment, remains an important goal.

In particular, we have found that nasal administration with such doses which are completely within the limits of tolerability achieves bioavailability which is appropriate for long-term effective treatment of such diseases, for which SMS therapy is suitable is, e.g. the above Diseases, to enable 60.

Since the nasal route is a simple and painless method of administration, which can be repeated regularly and without great inconvenience for the patient, the present invention provides a solution for the above-mentioned. previously existing problems.

The nasal compositions according to the invention are surprisingly very well tolerated, e.g. they only minimally impair the ciliary function.

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The present invention therefore relates to:

1.) A nasal pharmaceutical composition containing octreotide (SMS).

2.) A method of making a nasal pharmaceutical composition.

The pharmaceutical compositions can be prepared in a conventional manner using carriers compatible with the nasal mucosa, e.g. as described below. The pharmaceutical compositions can be formulated for topical administration to the nasal mucosa and be able to produce a systemic effect of the SMS. The formulations can be liquid or in the form of an insert or powder.

Compositions as defined under 2.) above are e.g. liquid compositions containing SMS together with a liquid diluent or carrier suitable for administration to the nasal mucosa.

Such compositions are preferably suitable for administration as a nasal spray or as drops.

Aqueous solutions are particularly suitable as liquid compositions 2.). The solutions to be used for nasal administration preferably have a slightly acidic pH, e.g. from about 4 to 5, especially 4.2. The required level of acidity is e.g. achieved by adding HCl or another suitable mineral or organic acid. The compositions intended for nasal administration are preferably isotonic or substantially isotonic. Preferred additives in order to obtain the desired isotonicity are nasally compatible sugars such as glucose, mannitol or sorbitol or nasally compatible inorganic salts, particularly NaCl, particularly preferred are glucose, ribose, mannose, arabinose, xylose or other aldoses or glucosamine.

The compositions according to the invention can also contain other conventional ingredients or carriers, e.g. Stabilizers or preservatives included. Preferred preservatives are sodium methyl mercurio thiosalicylate (= thiomersal) and benzalkonium chloride.

A suitable amount of the preservative is between 0.05 to 0.2 mg / ml e.g. 0.1 mg / ml.

Another aspect of the invention relates to porous nasal inserts which contain SMS dispersed therein. The invention further relates to solid nasal inserts consisting of a porous matrix which contains gelatin and / or hydroxypropyl methyl cellulose and SMS.

The nasal insert can be made in any conventional way, e.g. by a) generating a distribution of the SMS in a porous matrix containing gelatin and / or hydroxypropyl methyl cellulose, e.g. by freeze-drying a liquid containing a matrix-forming polymer and SMS

or b) distribution of the SMS in a nasal application, e.g. By soaking a sponge with an aqueous solution, e.g. at room temperature and evaporation of the solvent.

Under the expression "nasal use" z. B. to understand a device shaped and adapted for insertion and retention in the naris; a device which is intended for introduction into the Naris; or which is shaped to correspond substantially to the inner surface of the Naris; or which is provided with aids which facilitate the introduction into the Naris and / or the retention in the Naris; or which is provided with an applicator to facilitate the introduction into the Naris; or which is provided with guidelines for introduction to the Naris. The insert can be held in the naris, but can be flushed out through the nasal mucus, and can be constructed for the release of the active ingredient in the same place in the naris. Suitable nasal inserts are e.g. Plugs, tampons and the like. It is advisable to choose the volume and porosity of the insert so that it is held in the naris, but does not significantly hinder breathing. A range is suitable e.g. from about 0.05 to about 1 cm3, e.g. from about 0.5 to about 0.8 cm3. The application can e.g. be cylindrical, conical, spherical or cube-shaped.

The SMS can be attached to the insert, e.g. by absorption on its surface, or in use, e.g. by absorption, or by any other suitable means, e.g. in combination with one or more nasally acceptable diluents or coatings, e.g. solid or semi-solid coatings, on the surface of the insert. If the insert itself is composed of a soluble or semi-soluble material, e.g. water-soluble polymers, or from another material degradable in the Naris, e.g. from a nasally acceptable protein material such as gelatin, the SMS may be in solid form, e.g. as a lyophilisate, dispersed in use, e.g. distributed in the matrix.

Preferably the SMS is installed in the insert, e.g. recorded, e.g. by absorption, suitably distributed in the volume of the insert.

The inserts according to the invention are able to deliver the peptide contained to the surface of the nasal mucosa. For this purpose they are preferably shaped to correspond to the inner surface of the Naris, e.g. so that they allow maximum contact between the surface of the insert and the nasal mucosa. If the SMS is placed inside the application, e.g. by absorption, it is suitable to improve the properties of the insert, e.g. choose the absorption properties of the material from which it is made so as to ensure rapid diffusion of the peptide to the surface of the insert, in parallel with the progressive uptake of the peptide on the surface of the insert through the nasal mucosa.

If the active ingredient is retained within the insert, e.g. by absorption, the insert can be composed of any suitable, e.g. nasally acceptable material which can form a porous matrix or reticular structure in the interstices of which the peptide is held e.g. can be absorbed. The material is expediently elastic, so that it can be kept in the naris without discomfort. It can e.g. B. made of fiber material such as cotton, wool or spongy material such as natural or synthetic sponges.

When administered, the material may swell slightly, e.g. increase about 50% in volume. The material from which the insert is made is e.g. a water soluble polymer. The polymer is preferably easily wettable through the nasal mucosa. In the Naris it can be biodegradable and even dissolve slowly, e.g. in a day or more. It may also be necessary to remove it after the dose of the active substance has been taken. An example is a lyophilized, absorbable gelatin sponge. If desired, the matrix can dissolve when the dose of the active ingredient has been taken up or shortly afterwards. Examples include: water-soluble acrylate polymers and cellulose derivatives such as e.g. Hydroxypropyl cellulose and especially hydroxypropyl methyl

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cellulose. As an alternative, water-insoluble microcrystalline cellulose can also be used.

The properties of the matrix material used, e.g. Viscosity or molecular weight should be chosen so that the resulting use is easy to handle and store. Typical molecular weights for hydroxypropylmethyl cellulose are from about 9,000 to 15,000 and the viscosity is about 4 to 15 cp. for a 2% solution.

Another suitable base material is sponge-like gelatin material. Information about absorbable gelatin sponges is given in the U.S. Pharmacopoeia, e.g. for hemostasis in surgical procedures and such sponges are preferred here. Such sponges can be produced, for example, by vigorously striking an aqueous solution of pure gelatin to produce a foam, drying the foam under controlled conditions to obtain a sponge, cutting the sponge and sterilizing the pieces obtained. Suitable dimensions are from approx. 5 x 5 x 5 to approx. 10 x 10 x 10 mm. The sponge is squeezed by hand before use and is reabsorbed in a few hours. A particularly suitable sponge-like material for use in the manufacture of the nasal inserts according to the invention is the product SPONGOSTANR, available from A / S Ferrosan, 5 Sydmarken, DK-2860 Soeborg, Denmark.

Other polymers are hydroxypropyl cellulose and polyvinyl pyrrolidone.

As mentioned above, the insert preferably has a porous structure. It is beneficial that the nasal mucosa can wet the insert and the active ingredient can diffuse through the pores in the insert onto the surface of the naris. The pores of the insert can have a diameter of, for example, a few microns to approximately 100 microns. The pore size can e.g. from about 5 to about 10 microns. The pores can be twisted in spongy material. If the insert is made by freeze drying, the pores can be approximately linear.

The inserts preferably contain water-soluble sugar or similar carriers in order to provide the insert with a stable structure. Suitable sugars are e.g. Lactose, sucrose and mannitol. The weight ratio of sugar to other material is preferably between approximately 0.1 to 1 and approximately 10 to 1.

A preferred insert contains a water soluble polymer such as hydroxypropylmethyl cellulose and lactose. Under the electron microscope it is clear that a lyophilized sample is composed of laminar layers, each containing pores. The pores are practically distributed over the entire sample.

If the SMS is recorded within the mission, e.g. by absorption, it is convenient to use this active ingredient in a diluted form, e.g. as a composition containing the active ingredient together with a nasally acceptable liquid, diluent or carrier therefor. Such a composition is suitable, which contains the active ingredient in solution, suspension, dispersion or the like. Such a composition preferably contains the active ingredient in aqueous solution. The insert is preferably produced under practically microorganism-free or sterile conditions. In a preferred variant, the solution of the active ingredient is lyophilized. The insert can be pre-formed or e.g. during freeze drying from a solution of the feed.

Freeze drying can be carried out under the usual conditions, preferably at low temperatures, e.g. from about -100 "C to about -10 CC. A usual pressure, e.g. from about 0.01 mm to about 0.2 mm Hg, is appropriate.

Freeze drying can result in an outer layer with very fine pores, which can be spongy. 5 This layer can be approximately 10 to 100 microns thick. If desired, the formation of this layer can be avoided by freeze drying at very low temperatures. As an alternative solution, the layer can be removed by rubbing.

According to the invention, the nasal compositions can also be in the form of a powder, z. B. lactose or water-absorbing, water-insoluble or water-soluble polymers can be used as carriers. The following can be mentioned as usable water-soluble and water-absorbing polymers:

Polyacrylates, such as sodium, potassium or ammonium polyacrylate; low cellulose alkyl ethers such as e.g. Methyl, hydroxyethyl, hydroxypropyl or Na carboxymethyl cellulose; Polyvinylpyrrolidone, amylose and preferably 20% polyethylene glycol with a molecular weight of 1000 to 8000, and hydroxypropylmethyl cellulose.

The following may be mentioned as examples of water-absorbing, water-insoluble polymers:

water-absorbent, water-insoluble celluloses e.g. 25 microcrystalline cellulose, α-cellulose and cross-linked Na carboxymethyl cellulose; water-absorbing, water-insoluble starches such as hydroxypropyl starch, carboxymethyl starch; water-absorbing, water-insoluble proteins, such as gelatin, casein; water-absorbent, water-insoluble resins 30 such as gum arabic, tragacanth and glucomannan, crosslinked vinyl polymers such as crosslinked polyvinylpyrrolidone, crosslinked carboxyvinyl polymer or its salts, crosslinked polyvinyl alcohol and polyhydroxyethyl methyl acrylate.

35 Of these polymers, the water-absorbent, water-insoluble celluloses and the crosslinked vinyl polymers are preferred, the water-absorbent, water-insoluble celluloses are particularly preferred, and very particularly the microcrystalline cellulose.

The preferred polymers are said to have the same properties as mentioned above for the nasal inserts or are known per se for administration in nasal powders.

The hydroxypropylmethyl celluloses preferably have a methoxy content of 28 to 30% and a hydroxypropoxy content of 7 to 12% (percentages by weight). A preferred example is the Methocel E5 brand. The viscosity is preferably 1 to 50 cP (2% aqueous solution at 20 °).

The average degree of polymerization for the preferred polymers, especially for the microcrystalline cellulose, is approximately 200 to 2000, preferably 200 to 300. The preferred molecular weights are approximately 20,000 to approximately 100,000, e.g. 30,000 to 50,000. The average particle size is preferably about 5 to 80 µm, e.g. 30 to 70 µm. The preferred average size of the particles is 50 µm. A specific weight of approx. 260-300 g / l is favorable for a product that is not compressed. The microcrystalline cellulose can be obtained by mechanical treatment of polysaccharides consisting mainly of 60 glucose units, e.g. natural cellulose, optionally in an acidic environment, can be obtained. Their manufacture is e.g. in U.S. Patent 2,978,446.

Preferred forms are the AVICEL products (registered trademark of FMC Corporation). The material used in the examples is the trademark Avicel PH 101 (registered trademark) available from FMC Corporation, Marcus Hook, USA. It complies with the regulations

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for microcrystalline cellulose in the USP / National Formulary XXI.

These powders can be obtained by mixing the SMS with the particles, e.g. with the polymer base, can be produced in the usual way. The particles preferably have a size and / or specific weight similar to that given above for the microcrystalline cellulose. If desired, the particles can be coated. The polypeptide can be in solution, e.g. in aqueous or alcoholic solution, mixed with the particles and then the solvent is distilled off, e.g. by freeze drying or atomization.

Such drying can be carried out in the usual way, e.g. as described above for the nasal inserts. This results in an SMS cover. Alternatively, the mixture can be compressed or granulated and then pulverized and / or sieved. If desired, the powder can first be made as an insert as previously described and then pulverized.

In general it is desirable to use an amount of particles which is more than 5 times, especially 10 to 100, e.g. 10 to 30 times larger than the amount of SMS. For example, 20 mg powder contains 0.2; 0.4; 0.8 or 1.6 mg SMS.

The powder preferably has a particle size of 10 to 250 μm.

The powdery pharmaceutical composition can be used directly as a powder for a unit dosage form. If desired, the powder can be in capsules, e.g. be filled into hard gelatin capsules. These capsules can then e.g. be administered by means of an insufflator. The compositions according to the invention can contain further carriers. Some carriers have been previously described for specific compositions, but these carriers may also be present in other compositions of the invention.

For example, sugars such as lactose, stabilizing and / or preserving substances, isotonizing compounds can be present in the powders, if desired in the same preferred amounts.

If desired, the compositions may also contain an absorption promoter suitable for administration to the nasal mucosa, particularly a non-ionic absorption promoter.

However, it has surprisingly been found that, although hitherto nasal administration of peptides, e.g. of insulin, the use of a surfactant generally improves nasal absorption or is even an absolute necessity to achieve bioavailability sufficient for therapeutic use, the presence of a surfactant in the case of SMS has little or no effect on absorption. In particular, and surprisingly, it was found that effective nasal SMS compositions which do not contain an absorption promoter can be produced. This knowledge has the advantage that the disadvantages otherwise associated with nasal formulations, which are caused by the irritating side effects of the surface-active agents used, can be avoided.

If a nasally acceptable absorption promoter is nevertheless required, compounds which promote absorption through the nasal mucosa can be added. Such absorption promoters include nasally acceptable surfactants or surfactants.

Such surfactants include:

1. Bile acids and their salts, such as sodium taurocholate, sodium deoxycholate, sodium glycocholate, Na-glycodes-oxycholate, Na-cholate and Na-taurodeoxycholate.

2. Cationic surfactants, such as condensation products from long-chain amines and ethylene oxide, and quaternary ammonium compounds, such as cetyl trimethylammonium bromide and dodecyldimethylammonium bromide.

3. Anionic surfactants such as alkylbenzenesulfonates; N-acyl-n-alkyl taurates, a-olefin sulfonates, sulfated linear primary alcohols and sulfated polyoxyethylene (straight chain) alcohols.

4. Non-ionic surfactants, such as polyoxyethylene alkylphenols, polyoxyethylene straight chain alcohols, esters of long chain carboxylic acids, including glycerol esters of natural fatty acids, propylene glycol. Sorbitol, polyoxyethylene sorbitol esters, e.g. Polysorbate 80R.

5. Amphoteric surfactants such as imidazole car-boxylates, sulfonates, etc. and

6.phospholipids such as phosphatidylcholines, etc. Particularly preferred are nasal polyoxyal

kylene ethers of higher alcohols, e.g. of the general formula I.

RO -T (CH.) -O -f- H (I)

u 2 n J x wherein RO is the residue of a higher alcohol, especially a higher alkanol such as e.g. Lauryl or cetyl alcohol or an alkylphenol, or a sterol, especially Lanoste-rol, dihydrocholesterol or cholesterol, and mixtures of two or more such ethers. Preferred polyoxyalkylene ethers useful in the invention are polyoxyethylene and polyoxypropylene ethers (i.e., where n is formula 2 or 3 above), especially lauryl, cetyl and cholesterol polyoxyethylene and polyoxypropylene ethers, and mixtures of two or more such ethers. The hydroxyl group on the terminal alkylene radical of this

0.e. Polyether can be partially or fully acylated, e.g. with acyl residues of aliphatic carboxylic acids, e.g. Acetic acid.

Preferred polyethers usable in this invention have a hydrophilic-lipophilic ratio (HLB group number) of about 10 to about 20, especially about 12 to 16.

Particularly suitable polyethers for use in the invention are those in which the mean value of the repeating units in the polyoxyalkylene part (x in the formula above) is between 4 and 75, particularly between 8 and 30 and very particularly between 16 and 26. The polyethers can be obtained according to known methods. A large selection of such products are commercially available and z. B. sold by Amerchol under the brand name Solulan®, by KAO Soap, LCI and Atlas under the brand names Emalex®, Brij® and Laureth® and by Croda under the brand name Cetomacrogol®.

Examples of polyoxyalkylene ethers suitable for use in the invention are e.g. (POE = polyoxyethylene ether; POP = polyoxypropylene ether; x == mean value of the repeating units in the POE / POP part)

1. Cholesteryl ether:

1.1 Solulan® C-24 - POE, x = 24

2. Ether of lanolin alcohols:

2.1 Solulan® 16 - POE, x = 16.

2.2 Solulan® 25 - POE, x = 25.

2.3 Solulan® 75 - POE, x = 75.

2.4 Solulan® PB-10 - PPE, x = 10.

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

2.6 Solulan® 97 - POE, x = 9 - completely acetylated.

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3. Lauryl ether:

3.1 Emalex® 709 / Laureth® 9 - POE, x = 9.

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

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

4. Cetyl ether:

4.1 Cetomacrogol® - POE, x = 20 to 24.

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

Preferred polyethers for use in the invention are cholesteryl polyoxyethylene ethers, i.e. Polyether of formula I, in which n = 2 and RO is a cholesterol residue, especially those polyethers, in which the number of repeating units in the polyoxyethylene part is 16 to 26, particularly approximately 24.

Such polyethers are preferably free of impurities, especially other polyoxyalkylene ethers. They preferably contain at least 75%, particularly preferably at least 85% and very particularly preferably at least 90% (weight) of the pure cholesteryl polyoxyethyl ether.

The desired viscosity of the compositions according to the invention depends on the administration form concerned, e.g. whether nasal drops or a nasal spray are administered.

For nasal drops a viscosity of approx. 2 to approx. 400 x 10 ~ 3 Pa.S. suitable. A viscosity of less than x 10 ~ 3 Pa.S. is suitable for nasal sprays.

If a surfactant, e.g. If a polyoxyalkylene ether is used, the amount present in the compositions according to the invention will depend on the surface-active agent used, on the mode of administration (e.g. drops or spray) and on the desired effect.

In general, however, the amount present will be between about 0.01 to about 100, especially between about 1 and about 75 (preferably up to about 15) and very particularly between about 1 and 60 mg / ml hegen.

The compositions according to the invention can be administered in any suitable form. The preferred forms have been described above, but it should be understood that other formulations can be prepared in an analogous manner or analogous to the methods described in the literature. They can be packaged for administration in the usual way, preferably in a sodium applicator, particularly in such a way that a certain SMS dose is delivered. For administration as drops, the compositions are conveniently taken up in a container, e.g. B. provided with a conventional drip cap, which e.g. contains a pipette or the like and preferably dispenses a certain volume of the compositions per drop. For administration as a spray, the compositions are placed in a suitable atomizer, e.g. in a pump sprayer, aerosol device or similar device. The nebulizers should be provided with suitable devices for delivering the spray to the nasal mucosa. They are preferably provided with devices which allow the delivery of a practically equal volume of composition per actuation (i.e. per spray unit). If desired, the spray can be introduced under pressure into a new aerosol device. It is convenient that the device administer a metered dose. The propellant can be a gas or a liquid, e.g. fluorinated and / or chlorinated hydrocarbons. The spray composition can be suspended in a liquid propellant. Stabilizing and / or suspending substances can be present. If desired, a

Powder or a liquid can be taken up in a soft or hard gelatin capsule. The applicator can be provided with a device for breaking open the capsules.

The amount of active ingredient, i.e. SMS, in the compositions according to the invention will of course depend on various factors, e.g. B. of the selected form of the drug (z. B. SMS in free form or as a salt, solvate or complex), the disease to be treated, the desired frequency of administration and the desired effect. The bioavailability of the compositions according to the invention can be determined in a conventional manner, e.g. as described below in the examples. The doses can be chosen so that they are equipotent to the usual injections, e.g. in the treatment of the above Diseases. The amount of active ingredient is generally chosen to be an effective treatment when e.g. Allows 1 to 5 drops (or spray units) once or 2 to 4 times a day. It is preferably administered twice, particularly once per day. For this purpose, the active ingredient is preferably present in an amount such that a dose of free SMS from about 0.1 to about 3, preferably from about 0.1 to about 1, very particularly from about 0.6 up to 1 mg per administration.

Examples of SMS dosages are 0.2 mg, 0.4 mg, 0.8 mg and 1.6 mg.

An appropriate volume for the individual drops or powder is approx. 0.05 ml and for the spray units approx. 0.05 to approx. 0.2 ml, e.g. 0.1 ml. The compositions according to the invention therefore contain, for example, approximately 2.0 mg to approximately 20, preferably up to approximately 15, particularly up to approximately 10 mg of free SMS / ml, e.g. 6.0 mg free SMS / ml.

If a salt, solvate or complex from SMS is used, the amount of SMS available is correspondingly larger. If SMSac is used, the liquid compositions according to the invention will therefore contain approximately 7.4 mg SMSac / ml (= approximately 6.0 mg free SMS).

The following examples illustrate the preparation of the liquid compositions according to the invention, suitable for use in a nasal spray applicator.

Further details about the carriers are from the pharmacopoeia, from H.P. Fiedler's "Lexicon of auxiliary materials" (Edition Cantor, Aulendorf, 1981) and available from the brochures of the manufacturers.

Example 1: Nasal liquid spray

Together

component

Amount / ml of the composition

settlement

A

B

1.

SMSac_

7.796 mg *

3.19 mg

+ 5% surplus

0.390 mg

0.16 mg

8.186 mg

3.35 mg

2nd

Glucose

50.0 mg

50.0 mg

3rd

0, IN HCl to pH 4.20

up to pH 4.20

4th

Benzalkonium

chloride

0.11 mg

0.11 mg

5.

Water for

Injections up to 1 ml final volume

* = 6.515 mg free SMS

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Manufacturing

Components 1, 2 and 4 are mixed in water in the usual way, a 5% excess of the SMS being added to compensate for losses in the filtration. Then component 3 is added to pH 4.2 and water to the desired final volume. The mixture is stirred for 5 minutes, filtered (0.2 (jm filter) and filled into Rexo containers with CC> 2 gassing. The resulting solution is clear and colorless, has a final pH of 4.2 ± 0, 5 and is suitable for administration as a nasal spray from a nebulizer which contains approx. 0.095 ml per spray unit (= approx. 0.6 mg free SMS per spray unit for example 1A and 0.25 mg free SMS per spray unit for example 1B delivers.

Example 2:

Nasal liquid spray

Example 1A is repeated, but with the addition of 3.0 mg / ml end product powdered Solulan C24 (polyoxyethylene (24) cholesterol ether) to components 1, 2 and 4 in the first stage of the preparation.

Bioavailability for Examples 1 and 2

The experiments are carried out with 12 healthy volunteers (4 female, 8 male, average age 31.5 years, average weight 68 kg, average height 183 cm) according to the Tokyo Manifesto (1975) of the Helsinki Manifesto (Federai Register 40, p. 16 056, April 9, 1975).

People with known damage to liver or kidney function, heart failure or fluid and electrolyte disorders are excluded. Other exclusion criteria are pregnancy and previous allergic reactions. Chronic constipation or diarrhea symptoms, acute symptoms related to the gastrointestinal tract or acute or chronic sinusitis as well as acute respiratory infections during the tests are also grounds for exclusion.

Before the investigations begin, an EEG (12 leads) is carried out. Laboratory tests (in blood: blood cells (white and red) count, hemoglobin, sedimentation rate, platelet count, post-prandial glucose; in serum: total proteins and electrophoresis, sodium, potassium, creatinine, uric acid, SGOT, SGPT, 8-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 tests.

Each person receives two administrations containing:

1) 0.6 mg of free SMS nasally administered as a spray using the composition of Example 1A; and

2) 0.6 mg of free SMS nasally administered as a spray using the composition of Example 2.

It is administered in a randomized cross-over. The interval between administrations is at least three days. The active ingredient is administered in the morning after a light breakfast without caffeinated drinks. Each person is informed that the nasal spray should be placed in the right nostril with the head in an upright position. Before intra-nasal administration, the nostrils are cleaned by brushing the nose. During and after administration of the active substance, people refrain from breathing for 10 seconds. At least 100 ml of water or fruit tea are drunk every hour to ensure adequate urine output.

Blood samples are taken just prior to SMS administration and 5 ', 10', 15 ', 20', 30 ', 40', 50 ', 60', 75 ', 90', 2h, 2.5h, 3h, 4h, 5h , 6h and 8h after administration.

They are withdrawn through a catheter, which is placed in the forearm vein at the beginning of the examination, placed on ice in empty test tubes, centrifuged about 15 to 30 minutes later at 4 ~ C and the serum frozen at -20 ° C until analysis .

Urine samples are taken before administration of the active ingredient and afterwards between 0 and 2, 2 and 4, 4 and 6 and 6 and 8 hours. The total volume of each urine sample is measured and approximately 5 ml of urine is frozen at -20 ° C until analysis.

Blood pressure and heart rate are checked immediately before the drug is administered and 0.1, 2, 3, 4, 5, 6 and 8 hours after the administration.

SMS 201-995 concentrations in serum and urine are measured using radioimmunoassay methods (detection limit: 0.2 ng / ml).

Results

The compositions as administered are well tolerated, with only 4 of the 12 test persons having side effects (hypermotility in the abdomen / fatty stool) which were only weakly pronounced and of a maximum duration of 2 hours.

Bioavailability data based on serum levels and cumulative urinary output show that therapeutic SMS serum levels are achieved using both compositions and that treatment with either composition by nasal administration is suitable for long-term clinical use.

Example 3:

Nasal liquid SMS spray

This spray is produced analogously to the spray described in Example 1 and contains mg / ml

40

1.

2nd

3rd

4th

5.

SMSac

+ 5% surplus

glucose

HCl 0.1 N

Benzalkonium chloride H2O for injections

11.55 *

0.55 50

up to pH 4.2

0.11 mg to 1 ml final volume

45

11 mg free SMS

2.5 ml of the solution are introduced under COi gas into a 3.5 ml glass dispenser equipped with a nasal nebulizer. This results in 1 mg of free SMS per actuation.

5S ■ Example 4:

SMS nasal lyophilisate insert

A lyophilisate insert (graft) is made containing:

60

mg (4A) 1

mg (4B)

SMSac 0.316

Lactose 2.0

HPMC (Pharmacoat 606) 3.0 65 HPMC (Methocel E5)

PEG (MG 4000)

1 equivalent of 0.25 mg free peptide

0.315 1.0

1.5 1.5

672 252

Manufacture of a nasal insert made of hydroxypropylmethyl cellulose

30 g of pure water are heated to 70 ° C. and 1.5 g of HPMC (in the case of Example 4A) or 0.75 g of HPMC and 0.75 g of PEG 4000 (in the case of Example 4B) are then added. The suspension was cooled to room temperature and 1 g of lactose (200 mesh) (Example 4A) or 0.5 g of lactose (Example 4B) was added. The SMS is dissolved in 15 g of pure water. The liquids are mixed and water up to 50 ml is added. The solution is filtered through a filter with 0.2 μm openings and 0.1 ml quantities thereof are pipetted into the depressions (5 mm) of an aluminum plate.

The plate is cooled to -35 ° C over 4 hours, after which the lyophilization is initially at 40 ° C for 40 hours and then at +15 = C for 24 hours (Example 4A), respectively. is initially carried out at -10 ° C for 66 hours and then at +10 ° C for 24 hours (Example 4B). The resulting lyophilized blocks are carefully removed from the plate after the temperature has been increased in the lyophilizer to room temperature and introduced into a 1 ml syringe which has been cut off approx. 3 mm from the end point. Each block weighs approximately 5 mg.

The insert obtained is stable and easily soluble in water. It is a uniform lyophilisate with a diameter of approx. 5 mm and a length of approx. 6 to 7 mm.

Under the electron microscope it turns out that it consists of laminar ordered layers with long parallel pore channels of approx. 5 to 10 | in diameter. The lyophilisate is surrounded by an approx. 50 Jim thick edge layer with a fine, foam-like, porous structure.

Example 5:

SMS nasal powder

A powder (particle size 38-68 pm (sieved) is prepared, containing 20 mg; 0.3 mg SMSac (= 0.25 mg free SMS) and 19.7 mg microcrystalline cellulose (Avicel PH 101) (Example 5A), or lactose (example 5B) which is placed in capsules which are administered nasally with an insufflator.

Bioavailability in monkeys

Compositions containing 0.5 mg SMS were administered nasally to groups of 4 rhesus monkeys.

Pharmacokinetic parameters obtained:

Example 6: (continued)

Cpmax (ng / ml)

tmax St.

AUC (0-6 pcs) ngml-1 pcs

Example 4A

23.60

0.25

37.25

Example 1B

2.60

0.25

13.16

Example 4B

9.54

0.25

24.80

Example 5A

55.75

0.25

77.83

Example 5B

19.96

0.25

32.14

Example 6:

Nasal lyophilisate inserts

Lyophilisate inserts A and B were produced analogously to Example 4. They contain:

mg (6A.)

mg (6B)

SMSac

+ 5% excess lactose

1.20 0.06 1.0

1.20 0.06 2.0

mg (6A)

mg (6B)

s HPMC (Methocel E5) PEG 4000

H20 for injections up to 1 ml final volume.

1.5 1.5

3.0

io The lyophilisates (length 5 mm, diameter 5 mm) were well tolerated locally and systemically.

Example 7:

Nasal powder

Nasal powders A and B were prepared containing:

mg (7A)

mg (7B)

SMSac

+ 5% excess microcrystalline cellulose (Avicel pH 101) -25 (particle size 38-68 µm) HPMC (Methocel E5) (particle size 38-68 µm)

Total

1.32 0.07

18.61

20th

1.32 0.07

18.61

20th

These powders are made in an amount sufficient for 300 unit doses by mixing the SMS with 35 about a quarter of the polymer. The mixture was then sieved, the rest of the polymer added and the mass mixed thoroughly.

If desired, the SMS can be dissolved in an aqueous alcoholic solution, which is then mixed with the polymer. A powder is then produced from the resulting suspension or solution by freeze or spray drying.

The powder obtained has a particle size of approximately 20 to 250 μm.

45 These powders are filled into capsules, which can be administered nasally using an insufflator. Through 4 operations, 1 mg of SMS in 18 mg of powder is administered.

Local and systemic tolerability are good for the nasal powder.

Bioavailability for Examples 6 and 7

The experiments are carried out with 12 healthy volunteers (3 example 6) or 4 (example 7) female and 9 resp. 8 male-55 loans, average age 26, resp. 27 years, average weight 69 kg, average size 175 resp. 178 cm) carried out according to the guidelines laid down in the Toyko amendment (1975) of the Helsinki Manifesto (Federai Register 40, p. 16 056.9 April 1975).

6o People with known damage to liver or kidney function, heart failure or fluid and electrolyte disorders are excluded. Other exclusion criteria are pregnancy and previous allergic reactions. Chronic constipation or diarrhea 65 symptoms, acute symptoms related to the gastrointestinal tract or acute or chronic sinusitis as well as acute respiratory infections during the tests are also grounds for exclusion.

672 252

Before the investigations begin, an EEG (12 leads) is carried out. Laboratory tests (in blood: blood cells (white and red) count, hemoglobin, sedimentation rate, platelet count, post-prandial glucose; in serum: total proteins and electrophoresis, sodium, potassium, creatinine, uric acid, SGOT, SGPT, y-GT, LDH , alkaline phosphatase, cholesterol, bilirubin, a-amylase; in urine: pH, proteins, glucose, sediment) are carried out before and at the end of the tests.

Each person receives two administrations containing:

1) 1 mg of free SMS nasally administered as a spray or powder using the composition of Example 6A rep. 7 A and

2) 1 mg of free SMS nasally administered as a spray or powder using the composition of Example 6B or 7B.

It is administered in a randomized cross-over.

The interval between administrations is at least three days. The active ingredient is administered in the morning after a light breakfast without caffeinated drinks. Before intra-nasal administration, the nostrils are cleaned by brushing the nose.

The nasal inserts are inserted into the right nostril with an applicator. For the nasal administration of the gelatin capsules (powder), they are placed in an insufflator, as is usually used for anti-asthmatic active ingredients (Insufflator Intal® nasal, Fisons). Four shots are administered alternately into the right and left nostrils, starting with the right nostril. After the impact, the test person will inhale the administered powder briefly. The insufflations are carried out by one of the persons performing the tests on the seated test person.

Blood samples are taken just prior to SMS administration and 5 ', 10', 15 ', 20', 30 ', 40', 50 ', 60', 75 ', 90', 2h, 2.5h, 3h, 4h, 5h , 6h, 8h, 10h and 13 after administration.

s They are withdrawn through a catheter, which is placed in the forearm vein at the beginning of the examination, placed on ice in empty test tubes, centrifuged about 15 to 30 minutes later at 4: C and the serum is frozen at -20 ° C until analysis Blood pressure and heart rate are checked immediately before the administration of the active ingredient and 0.1, 2, 3, 4, 5, 6 and 8 hours after the administration. SMS 201-995 concentrations in serum (powder) resp. in the plasma (inserts) are measured using radioimmunoassay methods i5 (detection limit: 0.02 - 0.1 ng / ml).

Bioavailability data based on serum resp. Plasma levels and cumulative urine output show that therapeutic SMS serum levels are achieved using all compositions and that treatment with all compositions by nasal administration is suitable for long-term clinical use.

25th

example

Pharmacokinetic parameters SMS nasal (dose = 1.0 mg) median values 6A 6B 7A

7B

30 Tmax (min) Cp (max) (ng / ml) AUC (0-720 ') (ng * min / ml)

35.0 1.4

20.0 2.5

227.0 334.0

15.0

26.1

2066.0

30.0 3.2

560.0

35

40

45

50

55

60

65

Claims (10)

672 252 PATENT CLAIMS 1. Nasal pharmaceutical compositions which contain octreotide as active ingredient. 2. A composition according to claim 1, containing 0.1 to 3 mg octreotide in one dose. 3. A composition according to claim 1 or 2 in the form of an aqueous solution. 4. A composition according to claim 1 or 2 in the form of a nasal insert. 5. A composition according to claim 1 or 2 in the form of a powder. 6. A composition according to claim 5, wherein the powder contains microcrystalline cellulose. 7. A composition according to claim 5 or 6 containing 0.2 to 1.6 mg octretide in 20 mg powder. 8. A composition according to any one of the preceding claims in a nasal applicator. 9. A process for the preparation of a nasal octreotide-containing pharmaceutical composition, characterized in that octreotide is mixed with a nasal carrier and the compositions obtained are processed into a unit dosage form or introduced into a nasal applicator. 10. The method according to claim 9, characterized in that microcrystalline cellulose is used as a nasal carrier.