WO1993017037A1 - Treatment of acute migraine or cluster headache attacks - Google Patents

Abstract

Nasal administration of a somatostatin peptide analogue or derivative for treating acute attacks of migraine or cluster headache.

Description

TREATMENT OF ACUTE MIGRAINE OR CLUSTER HEADACHE ATTACKS

The present invention relates to a new use, in particular a new use for the compound group comprising somatostatin analogues and derivatives, in free form or in pharmaceutically acceptable salt or complex form, said compound group being referred to herein-after collectively as COMPOUNDS OF THE INVENTION.

By the terms "somatostatin analogue or derivative" as used herein is meant any straight-chain or cyclic polypeptide derived from that of the naturally occurring tetradecapeptide somatostatin wherein one or more amino acid units have been omitted and/or replaced by one or more other amino acid radical(s) and/or wherein one or more functional groups have been replaced by one or more other functional groups and/or one or more groups have been replaced by one or several other isosteric groups. In general, the term covers all modified derivatives of the naturally occurring somatostatin peptide which exhibit a qualitatively similar effect to that of the unmodified somatostatin peptide, e.g. they bind to somatostatin receptors and decrease hormone secretion.

Cyclic, bridge cyclic or straight-chain somatostatin analogues or derivatives are known. Such compounds and their preparation are described in European patent applications 29,579; 215,171;

203,031 and 214,872. Preferred COMPOUNDS OF THE INVENTION are compounds of formula I

wherein

A is C_1-12alkyl, C_7-10phenylalkyl or a group of formula RCO-, whereby

i) R is hydrogen, C_1-11alkyl, phenyl or C_7-10phenylalkyl, or ii) RCO- is a) an L- or D-phenylalanine residue optionally ring-substituted by halogen, NO₂, NH₂, OH, C_1-3alkyl and/or C_1-3alkoxy; b) the residue of a natural or a non natural α-amino-acid other than defined under a) above, or of a corresponding D-amino acid, or c) a dipeptide residue in which the individual amino acid

residues are the same or different and are selected from those defined under a) and/or b) above, the α-amino group of amino acid residues a) or b) and the N-terminal amino group of dipeptide residues c) being optionally mono- or di-C_1-12alkylated or substituted by C_1-8alkanoyl or benzyl;

A' is hydrogen or C_1-3alkyl,

Y₁ and Y₂ represent together a direct bond or

each of Y₁ and Y₂ is independently hydrogen or a radical of

formulae (1) to (5) -CO-NHR_c

(3)

wherein

R_a is methyl or ethyl

R_b is hydrogen, methyl or ethyl

m is a whole number from 1 to 4

n is a whole number from 1 to 5

R_c is (C_1-6)alkyl

R_d represents the substituent attached to the α-carbon atom of a natural or non natural α-amino acid (including hydrogen) R_e is (C_1-5)alkyl

R_a' and R_b' are independently hydrogen, methyl or ethyl,

R₈ and R₉ are independently hydrogen, halogen, (C_1-3)alkyl or

(C_1-3)alkoxy,

p is 0 or 1,

q is 0 or 1, and

r is 0, 1 or 2,

B is -Phe- optionally ring-substituted by halogen, NO₂, NH₂, OH, C_1-3alkyl and /or C_1-3alkoxy (including pentafluoro- alanine), or naphthylalanine C is (L)-Trp- or (D)-Trp- optionally α-N-methylated and optionally benzene-ring-substituted by halogen, NO₂, NH₂, OH, C_1-3alkyl and/or C_1-3alkoxy,

D is Lys, Lys in which the side chain contains O or S in

β-position, γF-Lys or δF-Lys, optionally α-N-methylated, or a 4-aminocyclohexylAla or 4-aminocyclohexylGly residue

E is Thr, Ser, Val, Phe, Tyr, Ile or an aminobutyric or aminoisobutyric acid residue

G is a group of formula

wherein

R₇ is hydrogen or C_1-3alkyl,

R₁₀ is hydrogen or the residue of a physiologically acceptable, physiologically hydrolysable ester,

R₁₁ is hydrogen, C_1-3alkyl, phenyl or C_7-10phenyl-alkyl,

R₁₂ is hydrogen, C_1-3alkyl or a group of formula -CH(R₁₃)-X₁, R₁₃ is CH₂OH, -(CH₂)₂-OH, -(CH₂)₃-OH, or -CH(CH₃)OH or represents the substituent attached to the α-carbon atom of a natural or non natural α-amino acid (including hydrogen) and

X₁ is a group of formula -COOR₇, -CH₂OR₁₀ or

wherein

R₇ and R₁₀ have the meanings given above,

R₁₄ is hydrogen or C_1-3alkyl and

R₁₅ is hydrogen, C_1-3alkyl, phenyl or C_7-10phenylalkyl, and

R₁₆ is hydrogen or hydroxy, with the proviso that

when R₁₂ is -CH(R₁₃)-X₁ then R₁₁ is hydrogen or methyl, wherein the residues B, D and E have the L-configuration, and the residues in the 2- and 7-position and any residues Y₁ 4) and Y₂ 4) each independently have the (L)- or (D)- configuration, in free form or in pharmaceutically acceptable salt or complex form.

Phenylalkyl as A or R is preferably phenethyl.

In the compounds of formula (I), the following significances are preferred either individually or in any combination or

sub-combination:

1.1. When R has the meaning a) this is preferably a') an L- or D-phenylalanine or -tyrosine residue. More preferably a') is an L- or D-phenylalanine residue.

1.2. When R has the meaning b) or c) the defined residue is preferably lipophilic. Preferred residues b) thus b') are α-amino acid residues having a hydrocarbon side chain, e.g. alkyl with 3, preferably 4, or more C atoms, e.g. up to 7 C-atoms, or a naphthyl-methyl or heteroaryl side chain, e.g. pyridyl-methyl or indol-3-yl-methyl, said residues having the L- or D-configuration. Preferred residues c) are dipeptide residues in which the individual amino acid residues are the same or different and are selected from those defined under a') and b') above.

1.3. When RCO has the meanings a), b) or c), the α-amino group of amino acid residues a) and b) and the

N-terminal amino group of dipeptide residues c) is preferably non-alkylated or mono-C_1-12 alkylated, especially -C_1-8 alkylated, more especially -methylated. Most preferably the N-terminal is non-alkylated.

1.4. Most preferably R has the meaning a) especially the meaning a').

2. B is B', where B' is Phe or Tyr.

3. C is C, where C is (D)Trp.

4. D is D', where D' is Lys, MeLys, especially Lys.

5. E is E', where E' is Ser, Val or Thr, especially Thr.

6. G is G', where G' is a group of formula

especially a group of formul

(in which case R₁₁=H or CH₃). In the latter case the moiety -CH(R₁₃)-X₁ preferably has the L-configuration.

6.1. R₁₁ is preferably hydrogen. 6.2. As the substituent attached to the α-carbon atom of a natural or non natural amino acid (i.e. of formula H₂N-CH(R₁₃)-COOH), R₁₃ is preferably -CH₂OH,

-CH(CH₃)-OH, -(CH₂)₂-OH, -(CH₂)₃-OH, isobutyl, butyl, naphthyl-methyl or indol-3-yl-methyl. It is especially -CH₂OH or -CH(CH₃)OH.

6.3. X₁ is preferably a group of formula

or -CH₂-OR₁₀, especially of formula -CH₂-OR₁₀ and R₁₀ is preferably hydrogen or, as an ester residue, formyl, C_2-12 alky1carbony1, C_8-12 phenylalkylcarbonyl or benzoyl. Most preferably R₁₀ is hydrogen.

Individual compounds suitable for use in accordance with the present invention are the following somatostatin analogues:

The COMPOUNDS OF THE INVENTION may exist e.g. in free form, salt form or in the form of complexes thereof. Acid addition salts may be formed with e.g. organic acids, polymeric acids and inorganic acids. Such acid addition salt forms include e.g. the hydrochlorides and acetates. Complexes are e.g. formed from compounds of the invention on addition of inorganic substances, e.g.

inorganic salts or hydroxides such as Ca- and Zn-salts, and/or an addition of polymeric organic substances.

COMPOUNDS OF THE INVENTION have, on the basis of observed activity, e.g. inhibition of GH secretion in rats and/or inhibition of pancreatic and gastric secretion in rats, e.g. as described in EP-B-29579, been found to be useful e.g. in the treatment of acromegaly, complications of diabetes mellitus or gastro-intestinal disorders.

It has also been reported that injections of octreotide can alleviate chronic, life disrupting headache associated with acromegaly and prolactinoma (G. Williams et al, Brit. Med. J., 295, 247-248, 1987). This kind of chronic headache is related to the presence of pituitary tumors. Although other factors in addition to the space occupying effects of the tumor may be involved, it is accepted that this chronic headache has a pathogenesis distinct from that of migraine or cluster headache according to the International Classification of headache disorders, cranial neuralgias and facial pain, Cephalalgia 1988, 8 suppl. 7, 1-96. Even more the usual treatments proposed for headache and migraine are so far generally ineffective in the management of headache associated with acromegaly and

prolactinoma. Migraine is a familial disorder characterized by periodic commonly unilateral, throbbing headaches which begin in

childhood, adolescence or adult life. Migraine episodes usually have one or more of the following characteristics; episodic nature lasting 4-72 hours, unilateral location, accompanying nausea, pulsating characteristic of pain, photophobia and phonophobia, autonomic disturbances and tenderness of the scalp on the side of the headache. One main aspect of the treatment consists in pharmacologically aborting acute attacks.

Unfortunately, current therapy is limited in some cases by inadequate efficacy and disagreable side effects. There thus exists a need for acute treatment of migraine attacks.

Cluster headache is a craniofacial pain syndrome which can be distinguished clinically from migraine. Attacks of headache occur in clusters during a period of weeks or months followed by often prolonged painfree periods. Between 1 and 4 attacks of 10-240 min duration may occur in a single day. There also exists a need for adequate treatment of cluster headache attacks.

In accordance with the present invention, it has now surprisingly been found that COMPOUNDS OF THE INVENTION, when administered nasally, have a fast onset of action in the treatment of acute attacks of migraine or cluster headache in subjects who do not suffer from pituitary tumors.

In accordance with the particular findings of the present invention, there is provided in a first aspect:

1. A method for treating acute attacks of migraine or cluster headache in a subject in need of such therapy comprising administering nasally to said subject a therapeutically effective amount of a COMPOUND OF THE INVENTION. As alternative to the above, the present invention also provides:

2. A COMPOUND OF THE INVENTION for nasal use in the treatment of acute attacks of migraine or cluster headache.

3. A COMPOUND OF THE INVENTION for use in the manufacture of a nasal pharmaceutical composition for use in the treatment of acute attacks of migraine or cluster headache.

4. A nasal pharmaceutical composition for use in the treatment of acute attacks of migraine or cluster headache, comprising a COMPOUND OF THE INVENTION together with one or more diluents or carriers adapted for nasal administration.

The COMPOUNDS OF THE INVENTION are administered in the form of a composition adapted for nasal administration. They may be administered in the form of liquid or solid, e.g. in nasal spray, drop, gel or powder form, or nasal inserts.

Liquid nasal compositions may comprise a COMPOUND OF THE

INVENTION together with a liquid diluent or carrier suitable for application to the nasal mucosa, e.g. water or aqueous saline. Such compositions may contain further ingredients or excipients, e.g.

- a substance for adjusting the pH, preferably tp a mildly acid pH, e.g. of from about 4 to 5, preferably about 4.2, for example a mineral or organic acid, e.g. HCl,

- a substance for adjusting isotonicity, e.g. glucose, ribose, mannose, arabinose, xylose, glucosamine or NaCl,

- a stabilizing and/or preserving agent, e.g. thiomersal,

benzalkonium chloride, cetrimide, paraben etc. Such a preserving agent may be present in an amount of from ca. 0.05 to 0.2 mg/ml.

Suitable nasal inserts include e.g. a device which is sized, shaped or adapted for placement and retention into the naris e.g. nasal plugs, tampons and the like, breathing being not significantly inhibited. The COMPOUND OF THE INVENTION may be carried on the insert, e.g. by adsorption onto the surface thereof or in the form of a coating, and/or in the insert, e.g. by absorption or by any other convenient means. The COMPOUND OF THE INVENTION may be carried in combination with one or more nasally acceptable diluents or carriers. The material from which the insert is made may be for example a porous material, e.g. a polymer capable of forming a porous matrix, e.g. gelatin, acrylate polymers, hydroxypropyl cellulose, hydroxypropylmethyl cellulose (HPMC), or a fibrous material such as cotton wool or sponge material. Such nasal inserts are e.g. disclosed in UK Patent Application 2,176,105 A, the contents of which relating to the nasal inserts being incorporated herein by reference.

Preferably the COMPOUNDS OF THE INVENTION may be administered in the form of a powder.

Examples of nasal powdered compositions suitable for the treatment according to the invention may be based on a carrier such as lactose or water-absorbing, water-insoluble,

water-swellable or water-soluble polymers. Examples of such polymers are e.g. polyacrylates such as sodium polyacrylate, potassium polyacrylate and ammonium polyacrylates; lower alkyl ethers of cellulose such as methyl cellulose, hydroxyethyl cellulose, hydroxypropyl cellulose and sodium carboxymethyl cellulose; polyvinyl pyrrolidone, amylose and preferably polyethyleneglycol e.g. of MW from 1000 to 8000, hydroxypropylmethyl cellulose, microcrystalline cellulose, cellulose, α-cellulose, and cross-linked sodium carboxymethyl cellulose, water-absorbing and water-insoluble starches such as hydroxypropyl starch, carboxymethyl starch, water-absorbing and water-insoluble proteins such as gelatin, casein; water-absorbing and water-insoluble gums such as gum arabic, tragacanth gum and glucomannan; and cross-linked vinyl polymers such as cross-linked polyvinyl pyrrolidone, cross-linked carboxyvinyl polymer or its salt, cross-linked polyvinyl alcohol and polyhydroxyethylmethylacrylate. Of these mentioned above, water-absorbing and water-insoluble celluloses and cross-linked vinyl polymers are desirable, and water-absorbing and water-insoluble celluloses are more desirable and microcrystalline cellulose is especially desirable.

Preferably the mean polymerisation number of the preferred polymers, microcrystalline cellulose, is from about 200 to 2000, preferably 200 to 300. Preferred mean molecular weights are from about 20.000 to about 100.000 e.g. 30.000 to 50.000.

These powders may be prepared by mixing a COMPOUND OF THE

INVENTION with the particles, e.g. a polymer base in conventional manner.

If desired the particles may be coated. The COMPOUND may be in solution, e.g. an aqueous or alcoholic solution when being mixed with the particles and the solvent evaporated, e-g. under freeze-drying or spray drying. Such drying may be effected under conventional conditions. Alternatively the mixture may be compacted or granulated and then be pulverized and/or sieved. If desired the powder may be produced in the form of an insert e.g. as described above and then pulverized.

Preferably the powder has a particle size of from 10 to

250 microns. The powdery pharmaceutical composition can be directly used as a powder for a unit dosage form. If desired the powder can be filled in capsules such as hard gelatine capsules. The contents of the capsule may be administered using e.g. an insufflator. The nasal powder may contain other excipients. Some excipients have been described above. For example sugars, such as lactose, stabilizing agents, isotonic agents may be present in the powder-form.

If desired the nasal powder to be used according to the invention may also contain an absorption promoter, in particular a non-ionic promoter, e.g. a non-ionic surfactant, suitable for application to the nasal mucosae.

Compositions adapted for nasal administration are disclosed e.g. in GB-A-2, 193,891, the contents of which being incorporated herein by reference. A particularly preferred nasal composition for use in the method of the invention is a powdery composition comprising a water-absorbing, water-insoluble diluent or carrier, e.g. microcrystalline cellulose.

An example of such a powdery composition is a composition comprising from 2.2 to 1.6 mg of a COMPOUND OF THE INVENTION, particularly octreotide, per 20 mg powder.

Utility of the COMPOUNDS OF THE INVENTION in the nasal treatment of acute attacks of migraine or cluster headache as hereinabove specified, may be demonstrated clinically, for example in accordance with the method hereinafter described. 84 patients either male or female, age 18 to 60, having at least a one year history of migraine without aura are submitted to a double-blind, cross-over, placebo-controlled clinical study.

The diagnosis of migraine without aura fulfills the criteria of the International Headache Society's Headache Classification Committee (Appendix G).

Patients are included who have a mean monthly frequency of 2 to 6 attacks of migraine without aura/month during 3 months prior to entering the study period. Preferably the clinical trial excludes:

- patients having a different type of cephalalgia, e.g.

tension-type headaches

- patients having less than 2 migraine attacks per month or more than 6 migraine attacks per month

- females who are pregnant, breast-feeding or not using medically accepted contraceptive measures

- patients suffering from one of the following disorders:

* diabetes

* obstruent intestinal tumor

* hepatic and renal insufficiency

* known cholelithiasis

* rhinopharyngeal pathology

* asthma

* serious psychiatric disorders

Each patient receives three medication boxes containing each one capsule and an insufflator. Two capsules contain the compound to be tested, in powder form and at various concentrations; the third capsule is a placebo capsule. All three capsules are identical in their aspect. The migraine attack is treated within 3 hours following its onset. Migraine attacks are rated

1 = slight migraine attack

2 = moderate migraine attack

3 = severe migraine attack

Only migraine attacks rated a 2 or 3 are treated. The patient administers to himself a total of 6 puffs, which permits to empty the capsule. Administration is made alternatively in each nostril (3/nostril). The patient uses the box corresponding to the particular attack (box labelled no. 1 for the first attack, no. 2 for the second migraine attack and no. 3 for the third attack). Two hours after administration, the patient is allowed to take another migraine medication, except for a nasal medication, if its symptoms have not improved.

At the study inclusion, the physician records the migraine history of the patient, the results of neurologic and

craniocervical examination and blood pressure.

The patient rates the severity of the migraine attack

1) by choosing a score between 0 and 3

0: no headache

1: mild headache allowing a normal activity

2: moderate headache impairing the normal activity but without interruption or need to lay down 3: severe headache which necessitates to interrupt the normal activity or to lay down

2) by placing a mark on a visual analog scale of 100 mm

This rating is done immediately before the nasal administrations, and then 30, 60, 120 minutes, 8 and 24 hours after the nasal administration. The patient records also: the total duration of the migraine attack; whether he needs a complementary medication; the existence of nausea and/or vomiting before and 2 hours after the treatment; rebound of migraine within the 24 hours after the treatment.

In this study, patients treated nasally with a COMPOUND OF THE INVENTION at a dosage of 0.5 to 2 mg exhibit a significant to complete relief within 2 hours after the nasal administration. With Octreotide, for example, there is obtained an onset of action within 10 to 20 minutes after nasal administration at the above indicated dosage.

In a similar study comprising 48 patients with cluster headache, similarly good results are obtained when the COMPOUNDS OF THE INVENTION are administered nasally at a dosage of 0.5 to 2 mg.

Daily dosages required in practicing the method of the present invention will, of course, vary depending on a variety of factors, for example the particular COMPOUND OF INVENTION chosen, the particular condition to be treated and the effect desired. In general however satisfactory results are indicated to be obtained at a dosage for nasal administration from about 3.5 μg/kg to about 300 μk/kg animal body weight. In larger mammals, for example humans, an indicated daily dosage is in the range of from ca. 0.25 to 2 mg nasally. Suitable unit dosage forms for nasal administration thus comprise from ca. 0.25 to 2 mg active compound together with one or more pharmaceutically acceptable diluents or carriers therefor.

The following is illustrative of the preparation of a composition for nasal administration in accordance with the invention.

EXAMPLE 1: Nasal liquid spray

Composition

INGREDIENT QUANTITY/ml end composition 1. Octreotide acetate 7.796 mg*

+ 5 % excess 0.390 mg

8.186 mg

2. Glucose 50.0 mg

3. 0.1 N HCl to pH 4.20

4. Benzalkonium chloride 0.11 mg

5. H₂O (injection grade) to an end volume of 1.0 ml * = 6.315 mg free peptide

EXAMPLE 2: Nasal liquid spray

Example 1 is repeated but with addition of 3.0 mg/ml end composition powdered SOLULAN C24 (Polyoxyethylene-(24)-cholesteryl ether) together with components 1, 2 and 4 in the first production step. EXAMPLE 3: Nasal lyophilisate insert

A lyophilisate insert (plug) is made comprising the following: mg

Octreotide acetate 0.315¹⁾

Lactose 1.0

HPMC (Methocel E5) 1.5

PEG (MW 4000) 1.5

¹⁾ Equivalent to 0. 25 mg free peptide

EXAMPLE 4: Nasal powder

A nasal powder is prepared containing:

mg octreotide ac 1.32

+ 5% excess 0.07

Microcrystalline cellulose (Avicel PH 101- 18.61

particle size 38-68 microns)

Total 20

This powder is prepared in a charge for about 300 unit doses by mixing octreotide and about one quarter of the cellulose. The mixture is sieved. The remainder of the cellulose is then added and the mass is mixed thoroughly.

The final powder has a particle diameter from about 20 to about 250 μ. This powder is filled into capsules. Local and systemic tolerability is good for this nasal powder.

Claims

1. A method for treating acute attacks of migraine or cluster headache in a subject in need of such therapy comprising, administering nasally to said subject a therapeutically effective amount of a somatostatin peptide analogue or derivative, in free form or in pharmaceutically acceptable salt or complex form.

2. A nasal pharmaceutical composition for use in the treatment of acute attacks of migraine or cluster headache, comprising a somatostatin peptide analogue or derivative, in free form or in pharmaceutically acceptable salt or complex form, together with one or more diluents or carriers adapted for nasal administration.

3. A somatostatin peptide analogue or derivative, in free form or in pharmaceutically acceptable salt or complex form, for use in the manufacture of a nasal pharmaceutical composition for use in the treatment of acute attacks of migraine or cluster headache.

4. A method, composition or use according to claim 1, 2 or 3, wherein the somatostatin peptide analogue or derivative is a compound of formula I

wherein

A is C_1-12alkyl, C_7-10phenylalkyl or a group of formula RCO-, whereby

i) R is hydrogen, C_1-11alkyl, phenyl or C_7-10phenylalkyl, or ii) RCO- is a) an L- or D-phenylalanine residue optionally ring-substituted by halogen, NO₂, NH₂, OH, C_1-3alkyl and/or C_1-3alkoxy; b) the residue of a natural or a non natural α-amino-acid other than defined under a) above, or of a corresponding D-amino acid, or c) a dipeptide residue in which the individual amino acid

residues are the same or different and are selected from those defined under a) and/or b) above, the α-amino group of amino acid residues a) or b) and the N-terminal amino group of dipeptide residues c) being optionally mono- or di-C_1-12alkylated or substituted by C_1-8alkanoyl or. benzyl;

A' is hydrogen or C_1-3alkyl,

Y₁ and Y₂ represent together a direct bond or

each of Y₁ and Y₂ is independently hydrogen or a radical of

formulae (1) to (5)

-CO-NHR_c

(3)

wherein

R_a is methyl or ethyl

R_b is hydrogen, methyl or ethyl

m is a whole number from 1 to 4

n is a whole number from 1 to 5

R_c is (C_1-6)alkyl

R_d represents the substituent attached to the α-carbon atom of a natural or non natural α-amino acid (including hydrogen)

R_e is (C_1-5)alkyl

R_a' and R_b' are independently hydrogen, methyl or ethyl,

R₈ and R₉ are independently hydrogen, halogen, (C_1-3)alkyl or

(C_1-3)alkoxy,

P is 0 or 1,

q is 0 or 1, and

r is 0, 1 or 2,

B is -Phe- optionally ring-substituted by halogen, NO₂, NH₂, OH, C_1-3alkyl and /or C_1-3alkoxy (including pentafluoro- alanine), or naphthylalanine

C is (L)-Trp- or (D)-Trp- optionally α-N-methylated and

optionally benzene-ring-substituted by halogen, NO₂, NH₂, OH, C_1-3alkyl and/or C_1-3alkoxy,

D is Lys, Lys in which the side chain contains 0 or S in

β-position, γF-Lys or δF-Lys, optionally α-N-methylated, or a 4-aminocyclohexylAla or 4-aminocyclohexylGly residue E is Thr, Ser, Val, Phe, Tyr, Ile or an aminobutyric or amino- isobutyric acid residue

G is a group of formula

wherein

R₇ is hydrogen or C_1-3alkyl,

R₁₀ is hydrogen or the residue of a physiologically acceptable, physiologically hydrolysable ester,

R₁₁ is hydrogen, C_1-3alkyl, phenyl or C_7-10phenyl-alkyl,

R₁₂ is hydrogen, C_1-3alkyl or a group of formula -CH(R₁₃)-X₁, R₁₃ is CH₂OH, -(CH₂)₂-OH, -(CH₂)₃-OH, or -CH(CH₃)OH or represents the substituent attached to the α-carbon atom of a natural or non natural α-amino acid (including hydrogen) and

X₁ is a group of formula -COOR₇, -CH₂OR₁₀ or

wherein

R₇ and R₁₀ have the meanings given above,

R₁₄ is hydrogen or C_1-3alkyl and

R₁₅ is hydrogen, C_1-3alkyl, phenyl or C_7-10phenylalkyl, and

R₁₆ is hydrogen or hydroxy, with the proviso that

when R₁₂ is -CH(R₁₃)-X₁ then R₁₁ is hydrogen or methyl, wherein the residues B, D and E have the L-configuration, and the residues in the 2- and 7-position and any residues Y₁ 4) and Y₂ 4) each independently have the (L)- or (D)- configuration, in free form or in pharmaceutically acceptable salt or complex form.

5. A method, composition or use according to claim 1, 2 or 3 wherein the somatostatin peptide analogue or derivative is selected from

6. A method, composition or use according to claim 1, 2 or 3 wherein the somatostatin peptide analogue or derivative is in the form of a nasal powder.