CA1322331C - Galenical formulations - Google Patents

Abstract

Novel Galenical Formulations Abstract Nasal octreotide compositions in liquid, powder or insert form are disclosed. Such compositions are capable of systemic action and are useful for treating e.g. disorders with an aetiology comprising or associated with excess GH secretion or gastro-intestinal disorders.

Description

100-69~8 NOVEL GALENICAL FORMULATIONS

The present invention relates to a novel means for the ad-ministration of the somatostatin analogue SMS 201-995 as well as to novel ~alenic compositions comprising this analogueO

Somatostatin or SRIF is a naturally occurring cyclic tetradeca-peptide, fîrst isolated from ovine and porcine hypothalamic tissue, having potent growth hormone (GH) inhibitins activity.
It has since also been found to be pr~sent in other areas of the central nervous system as well as in the specialised D-cells of the pancreas, stomach and small intestine. From these locations SRIF acts on the pituitary to inhibit secre-tion of GH and thyroid stimulating hormone (TSH), on the pan-creas to inhibit exocrine and endocrine secretion (including ~
secretion of insuli-n and glucagon), and locally in the gastro- -intestinal (GI) tract where it inhibits release of gastrin secretion~ CCK, VIP and possibly other hormones. Through the latter i`nhi~iting effects SRIF plays an important physiologi-cal role in modulation gastro intestinal function, e.g. ~y reducing gastric acid secretion, delaying stomach evacuation, slowing intestinal motility, decreasing blle flow, increasing mucous production and reducing splanchnic ~lood flow.

Various proposals have been made for the therapeutic applica-tion of thi~ compound, e.gO in the treatment o~ acromegaly or gastrointestinal disorders such as gastro-întestinal bleeding.
However, although biologically highly active,SRIF has a very short half life (2 to 3 minutes) and this, coupled with the .. . . . . . . . .

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-2- l00-6948 1 7`22S31 concomitant need for i.v. administration and the rebound phenomena observed at the end of i~v. administration~
renders this substance unsuitable for long-term cl;nical use.
More recently therefore, research has concentrated on the development of novel analogues and derivatives of somato-statin-these being oligopeptide compounds comprising sub-stantially fewer amino acid residues than somatostatin it-self, but incorporating one or more partial peptide sequen- i ces occurring in the somatostatin molecule.

Hitherto all these analogues have to be administered by in-jection, eOg~ iovo or sOcO administration, in order to pro-vide a therapeutically effect at non-toxic doses.

A particular analogue which shows especial therapeutic pro-mise and is no~ in an adYanced stage of clinical testing is the compound SMS 201-995 (hereinafter "SMS") of formula H-(D)Phe-Cys-Phe~(D)Trp-Lys-T~r-Cys-Thr-ol The generic name for SMS is octreot{de.

This compound ~hich is specifically disclosed and claimed in European patent noO 0029579 (= USP 4,395,403), is an octa-peptide possessing many of the same pharmacological properties as SRIF~ though apparently somewhat more selective in inhibi-ting GH and glucagon rather than insulin release. Par~icular conditions for which use of this compound is proposed include treatment of acromegaly, diabetic complications and a variety of GI disorders including GI hormone secreting tumours (e.g.
VIPomas and the like) .

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. ' ' '' ' For the purposes of therapeutic application SMS, like most other peptide drugs~ may of course be administered as such, iOeO in free form, or in pharmaceutically acceptable salt and/or complex formO The SMS additi0nally or alternatively may be~in solvate form, eOgO a hydrate.

The current form of Ghoice for clinical application of SMS
is the acetate hydrate referred to herein as SMSac, which has a free peptide content of ca. 80 to 88%, e.g 83 to 87%.
Unless otherwise indicated the terms "SMS" and "octreotide" as used throughout the present application and claims understood as designating both the free peptide and its pharmaceutically acceptable salts, in par~icular acid addi-tion salts, especially the acetate, as wel1 as pharmaceutically acceptable complexes and/or solvates thereofO

Though of very considerable therapeutic potential, practical difFiculties are encountered in relation to administration of SMS; ioVo or sOcO administration has hitherto been the only route available permitting effective dosaging in clinic.
Generally administration by injection or infusion is practiced.
Such means of ad~inistration are always inconvenient and where long term therapy is required with administration at regular intervals, can cause considerable pain and inconvenience to the patient. The finding of alternative means oF administration for SMS, in particular means which would per~it ready self-application ~y the patient, eO~O for the purposes o~ out-patient treatment, has accordingly remained a major objective.
In accordance ~ith the present invention it has now surprising ly been found that eFfective trea~ment w;th SMS can be obtained on nasal administration9iOeO via application to the nasal mu-cosae In particular it has been found tha~ on nasal admini--4_ 100-6948 stration at dosage levels wh;ch are well within the range of tolerability, b;oavailability levels are achieved which are entirely adequate to permit effective long term treat-ment of conditions for which SMS therapy is to be employed, eOgO such as hereinbefore set forth.
Since the nasal route provides a simple and painless mode of administrationt ~hich may be repeated on a regular basis with no great inconvenience to the patient, the present in-vention accordingly meets previously existing needs as dis-cussed aboveO The nasal compositions of the invention rn~y besurprisingly very well tolerated, e.g. having a minimal effect on ciliary functionO
In accordance with the foregoing the present invention pro-vides:-i) A method of administering octreotide (SMS) to a subject requiring treatment therewith, e.g. for the purposes of treating disorders with an aetiology comprising or asso-ciated with excess GH secretion or of treating gastro-intestinal disorders, for example as hereinbefore speci-~o fied, ~hich comprises administering octreotide (SMS) via the nasal route; as well as ii) A nasal pharmaceutical composition comprising octreotide (SMS), and iii) A process for the p~eparation of a nasal pharmaceutical compo~ition which comprises working up octreotide ~SMS) with nasal excipients.

The pharmaceutical composition may be formulated in conven-tional manner using excipients compatîble with the nasal mucosae, e.~. as described hereina-fterO

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~' The pharmaceutical compositions may be formulated for local administration to the nasal mucous membrane9 and capable of providing a systemic ac~ion of SMS. The formu-lation may be e.g. a liquid, an insert or a powder.

Compositions as defined under ii) above are for example liquid composition~ comprising SMS together with a liquid diluent or carrier suitable for application to the nasal mucosaeO
Such compositions are pre~erably adapted for ad~inistration lo in nasal spray or in drop form.

Appropriate liquid compositions ii) are in particular aqueous solutionsO For the purposes of nasal application such solutions will preferably have a mildly acid pH e.g.
of from about 4 to 5, preferably about 4-2. The required degree of acidity is conveniently achteved~ e.g. by the addition of HCl or other appropriate mineral or organic acidO For the purposes of nasal administration such compo-sitions will also preferably be isotonic or substantially isotonic. Preferred additives for achieving the desired degree of isotonicity înclude nasally acceptable sugars such as glucose, mannitol or sorbitol or nasally acceptable inorganic salts in particular NaCl. In accordance with the present invention the preferred addit1ve for achieving the desired degree of isotonicity is glucose, ribose, mannose, arabinose, xylose or another aldose, Gr glucosamine.

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-6- l00-694~

'` 1 32233 1 The compositions of ~he present invention may ,also contain further ingredîents or excipients known in the art for example stabilizing and/or preserving agents. Preferred preserving agents for use in the composi~ions of the in-vention are sodium methylmercurithiosalicylate (=Thiomersal)and benzalkonium chlorideO Suitably any such preserving agent is present in an amount of from ca~ 0.05 to 0.2 mg/ml e.gO ca O O o l mg/ml.

In another aspect the present invention provides a porous solid nasal insert having SMS dispersed therein. In yet another aspect the present invention provides a solid nasal insert comprising a porous matrix comprising gelatine and/o'r hydroxypropylmethylcellulose and SMS therein.

The na~al insert may be produced by any conventional method, eOgO by a) producing a distribution of SMS throughout a porous matrix comprising gelatine and/or hydroxypropyl-methylcellulose~ e~gO by Iyophilising a liquid containing a polymer capable of forming a matrix, and SMS; or b) distributing a SMS throughout a nasal insert, for example by soaking a sponge in an aqueous solution at eOg. room temperature and evaporating off the solvent.

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~ 32233 1 By the term "nasal însert" is to he understood, e.g. a deYice which.is sized, shaped and adapted for placement and retenti`on ;nto the naris: intended for insertion into the naris; or which is formed, sh.aped or ot~er~ise adapted for insertion into and/or retention in the naris; or which is sh.aped to suhstantia11y conform to the internal surface of the nari:s; or ~hich is provided ~ith means to Faciliate insertion into andlo'r retention in the naris; or which is provided with a dispenser device tc faciliate insertion lo into th.e naris, or which is provided toget~er with instruc- ;
tions to effect insertion into the naris. The insert may be retained in the naris~ but flushed by the nasal mucous, and may ~e designed to release the active agent at the same place in the naris. Suitable nasal insert types include nasal plugs~
tampons and the lik.eO Conveniently the volume and porosity of the i~nsert are chosen such that it is retained in the naris, but ~reathing is not signifi`cantly inhibited. Suitable dimension~ are eOg. from about 0.05 to about 1 cm3, e.g. about 0.5 to about 0.8 cm3. The shape may be approximately e.g. a 20 cylinder, a cone, a cube or sphereO .

Th.e SMS may he carried on the insert, e.g. ~y adsorption onto the surface thereof, or in the insert, e.g. ~y absorption, or hy any other conven~ent means, e.g. carried in combination with. one or more nasally acceptahle d~luents or vehicles in the form of a coating, e~g. solid or semi~-solid coating, upon th.e ~.urface on the insert.

Alternatively, ~here the insert itself comprises a soluble or semi-solu~le m~terial, e.g. water-solub.le polymers, or material other~ise degrada~le ~thin the naris9 for example a nasally acceptable proteinaceous material such as gelatin, the SMS may he present in solid form, e.g. in the form of .. .. .
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1 3~2331 lyophilisate dispersed within the insert, e.g. distributed throughout the matri~

Preferably SMS is carried, e.g. retained by absorp~ion, in the insert and is suitably distributed t~roughout the lnsertO

Inserts in accordance with the invention are capa~le of re-leasing the peptide carried to the surface of the nasal mucosa. For this purpose they will preferably be so shaped or formed as to conform to the internal surface of the naris, e.gO so as to enahle maximum contact 6etween ~e surface of the insert and the nasal mucosaO Moreo~er, where the SMS is retained in the insert, eOg. by absorption, its characteristics e.g. the ab~orption characteristics of the material of which it is comprised, ~ill suitably be such as to allow ready passage of the peptide to the sur~ace o~ the insert Followiny progressive uptake by the nasal mucosa from the insert sur-faces.

Where agent is retained, e.g, by adsorption, in the insert, the insert may comprise any appropriate, e~g. nasally acceptable material, proYîding a porous matri~ or reticulum in the in~er-stices of ~hich the peptide may he retained, e.g. absorbed.
The material ~s conveniently elastic so it can be retained in the naris ~ithout discomfort~ It may be for example, fibrous materi~l, such as cotton ~ol or sponge material, such as natural or synthetic sponge, If desired, the material may s~ell a little, e.g. increase in volume by about 50~ 9 on administrat~on.

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-9- 1 00-6g~8 The material from which the insert l5 made -may be for example a ~ater soluble polymer. Preferably tfie polymer is easily wettable by the nasal mucousO rn the nari`s ;t may be biodegrada61e and, it may even dis;solve slowly, e.g~ over up to one or ~ore days. It may have to 6e removed after the dose of active agent has been admlnistered. An example îs lyophilised absorbable gelatine sponge. If desired the matrix may dissolve by the time or shortly after the dose of active agent has been administeredO Examples include water lo soluhle acrylate polymers and cellulose derivatives such as cellulose, e~g.hydrcxypropylcellulose and espec;allyhydroxypropylmethyl cellulose.Alternatively water-insoluble crystalline cellulose may be u~ed.
The characteristîcs of the matrix mater;al used, e.g.
Yiscosity or molecular weight should be chosen such that these resultant insert is easy to handle and store. Typical molecular weights ~or hydroxypropyl methylcellulose are from a~out 9,000 to 15,000 and a viscosity e.g. 4 to around 15 cp, for a 2% solutionO

Another suitahle material is a gelatin sponge material. Speci-fications have heen laid down in the U5 Pharmacopoeia for ab-sor~sable gelatine sponges, e.g. for hemostatis in surgical procedures and such sponges are preferred. Such sponges may bSe produc~d~ e.y. hy vigorously wh~pping and aqueous solutian of pure gelatine to produce a foam~ dry~ng the foam under controlled conditions to give a Sponge, cutting up the sponge and sterilizing the cut-up pieces. ~uita6sle sizes a~e from about 5 x 5 x 5 to about 10 x 10 x lQ mmO The sponge is compressed 6y hand 6efore use and is resorbed over a few hours.
An especially sui~able sponge ma~erial for use in the prepara-tion of nasal inserts in accordance ~iths the inven~ion is the product SPONGOSTANR available from AlS Ferrosan, 5 Sydmarken, DK-286Q Soe60rg, Denmark.

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-lO- l00-6948 Alternative polymers are eOg. hydroxypropylcellulose or polyvinylpyrrolid.one.

As indicated above the inser~ prefera~ly has a porous struc-tureO Conveniently the nasal mucous can wet the insert and the active agent may diffuse through the pores in the insert to the surface of the naris.

The pores of the insert may have a diameter of for example a few. microns to about lO0 micronsO The pores of a lyophi-lised absorbable gelatin sponge may ~e for example from about 5 to lO0 microns. The pore size may for example from about 5 to about lO micronsO

In sponge material the pores may be ~ortious~ When the ins:ert i.s produced under lyophilisation the pores may be approximately linear.

Preferab.ly the insert contains a ~ater-soluble sugar or l~ke excipient to provide a stable structure to the insert.
Examples of suitahle sugars include lactose~saccharose,and mannitolO Preferably the weight ratio sugar to other material is from about O.l to l to about lG to l.

A preferred i~nsert comprises a ~ater-soluble polymer such as hydroxypropylmethyl cellulose ~nd lacto~e. Under electron micro~copy a lyoph.ilised sample appears to co.mprise laminar sfieets each. having pores thereinO The pores extend substan-tially throughout th.e sample.

Where the S~S is reta;ned in th.e insert, e.g. by absorption, it will conveniently b.e carried in dilute form, e.g. in the form of a composition comprising the active agent together with a nasally acceptable fluid, eOg. liquid, diluent or vehicle therefor Suitably such compositions will comprise the agent in the form of a solution, suspension, dispersion .. ,.~ ~ . . . ~
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-ll- l00-6948 1 32233 t or the like. Preferahly such compositions w;ll comprise the agent in aqueous solution.

The insert is preferably formed under substantially micro-organism-free or sterile conditionsO
s In one preferred variante a solution of the active agent is lyophilisated~ the insert may be preformed or formed during the lyophilisation process, e.g. from a solution of the insert materialO

Tbe lyophilisation may be effected under conventional con-ditions, preferably at low temperatures, e.g ca. about -lO0C to about -lOC. Conventional pressures,eOg.ca.about OoOl mm to about 0.2 mm mercury~may be used.

Lyophilisation may produce an outer layer of very fine pores which may be spongy. This outer layer may be about l0 to lO0 mi`crons thick. If desired its formation may be avoided by effecting the lyophilisation at Yery lo~ temperature.
Alternatively it may be removed by rub~ing.

In another a~pect the nasal compositions of the invention may be in the form of a powder, e.g. based on lactose or wa~er-absorbing, water-insoluble or water-soluble polymers.

As water-absorbing and water-soluble polymers to be used in the invent~on may be mentioned:-Polyacrylates such as sodium polyacrylate, potassium poly-acrylate and ammonium polyacrylate; lower alkyl ethers of cellulose such as methyl cellulose, hydroxyethyl cellulose 9 hydroxypropyl cellulose and sodium oarboxymethyl cellulose;
polyvinyl pyrrolidone, amylose and prefera~ly po~yethylene-glycol eOgc of MW from lO00 to 8000, and hydroxypropyl-methyl celluloseO

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-12- 100~6948 1 3223~ 1 As the desirable examples of water-absorbing and water-insoluble ba~e, the following may be mentioned:-They include, for ins~ance, ~ater-absorbing and water-in-soluble celluloses such as microcrystalline cellulose, cellulose, a-cellu~ose, and cross-linked sodium carboxy-methyl cellulose, water-absorbing and water - insoluble starches such as hydroxypropyl starch, carboxymethyl starch, water-absorbing and water-insoluble proteins such as gelatin, casein, ,. .i~; water-absorbing and water-insoluble gum~ such as gum arabic, tragacanth gum and glucomannan; and cross-linked vinyl polymers such as cross-linked polyvinyl pyrrolidone, cross linked carboxy-vinyl polymer or its salt, cross-linked polyvinyl alcohol and polyhydroxyethylmethylacrylateO Of these mentioned above, water-absorbing and water-insoluble celluloses and cross-linked vinyl polymers are desirable, and water-abosrbing and water-insoluble celluloses are more desirable and microcrystalline cellulose is especially desirable.

The preferred polymers have characteristics as mentioned above for the na~al inserts or are conventionally employed for nasal powder administrationO

Pre~erred hydroxypropylmethyl celluloses have a 28-30 per cent metho~yl content and a 7 . -12 weight per cent hydroxyo.
propoxyl content~ A preferred example is brand Methocel E5 Viscosities are preferably from 1 to 50 cP (2% aqueous solution at 20)o Preferably the mean polymerisation number of the preferred polymers 9 microcrystalline cellulose, ;s from about 200 to 2000 9 preferably 200 to 300O Preferred mean molecular weights are from about 20,000 to about 1009000 e.g. 30,000 to 50~000O

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-l3- lO0 6948 Preferably the mean particle size is from about 5 to about 80 microns 9 eOg 30 to 70 microns, The preferred average particle size is 50 microns. Conveniently the untapped specific gravi~y is eOgO about 260 - 300 g/l. Conveniently the microcrystalline cellulose is ob~ained by mechanical treatment of glucose-based polysaccharides, e.g. native cellulose, optionally with acidic treatment. Their prepa-ration is described for example in USP 2,978,446.

Preferred forms are the AVICEL brand (Registered Trade Mark of FMC Corporation). The material used was the brand Avicel PH lOl ~Registered Trade Mark) available from FMC
Corporation, Marcus Hook9 USA. It complies with specifi-cations given for microcrystalline cellulose in USP/National Formulary XXIo lhese powders may be prer~red by mix~ng the SMS w~th the particles, eOgO a polymer base in conventional manner. The ;`
particles preferably have a particle size and/or specific gravity as given above for ~icrocrystalline celluloseO
If desired the par~icles may be coated. The polypept;de may be in solution, eOg. 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 the conventional conditions, e.g, as described above with respect to the inserts. This gives a -coating of octreotideO 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 eOgO as described above and ~hen pulverized.

It is desirable in general to use a ~article weight which is more than 5 times the weight of SMS, especially lO to 1009 eOg~ lQ to 30, timesO

-l4- lO0 ~948 ~ 32233 1 Examples of loadings of SMS are 002, 004, 008 and 106 mg SMS per 20 mg powderO
Preferably the powder has a particle size of from lO to 250 micronsO
The powdery pharmaceutical composition can be directly used as a powder for a unit dosage form.
If desired the po~der can be filled in capsules such as hard gelatine capsulesO The contents of the capsule may be administered using eOgO an insufflatorO
The composit;ons of the invention may contain other exci-pientsO Some excipients have been described above for parti-cular composi~ions, and it is to be understood that these excipients may also be present in other compositions of the inventionO For example sugars, such as lactose, stabilizing agents, isotonic agents may be present in the powder form, if desired in the same preferred amounts.
If desired the compositions of the invention may also contain an ab~orption promoter, in particular a non-ionic promoter, suita~le for application to the nasal mucosae. However, in 20 accordance with the present invention it has surprisingly been found that, whereas where nasal ad~inistration of pep-tides ha~ prevîously been proposed in the art, e.g. in the case of nasally administered insulin, use of a surface active agent generally improYes nasal resorp~ion or may indeed be a 25 prerequisite for the achievemen~ of bioavailability levels suf~cient for therapeutic utilityO It has In particular and mos:t surpri~si:ngly ~een found that nasal SMS compositions may fie prepared w~ich contain no absorption promoter. This particular finding has the especial advantage of permitting avoidance uf disadvantages otherwise encountered in the pre-paration of effective nasal formulations, resulting fro~
irritant side-effects of surface active agents necessarily employed~

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-l5- l00-694~

Where use of a nasally acceptable absorption promoter is none the less desired, eOg. substances capable of promo-ting absorption via the nasal mucosae may be added. Such promoters include nasally acceptable surface active agents or tensidesO Such surface active agents include:-iO Bile acids and salts thereof, such as sodium taurocho-late,sodium deoxycholate and sodium glycocholate,s-gly-codeoxycholate,~-cholate,s-taurodeoxycholateO
iiO Cationic surfactants,such as long chain amine candensates with ethylene oxide and quaternary am~onium compounds, for example cetyl trimethyl ammonium bromide and dodecyl dimethyl ammonium bromideO
iiiO Anionic surfactants such as alkylbenzenesulfonates, N-acyl-n-alkyltaurates, a-olefin sulfonates, sulfated linear primary alcohols and sulfated polyoxyethylene straight chain alcohols.
ivo Non-ionic surfactants, such as polyoxyethylenated alkyl-phenols, polyoxyethylene straight chain alcohols, long chain carboxylic acid esters including glycerol esters of natural fatty acids, propylene glycol, sorbitol and polyoxyet~ylene sorbitol esters, eOgO Polysorbate 80R.
v. Amphoteric surfactants, such as imidazoline carboxylates, sulfonate~ etcO o . o 9 and vi. Phospholipids, such as phosphatidyl choline etc.

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-l6- l00-6948 Where use of a surface active agent i~ desired, use of nasally applica~le polyoxyalkylene ~igh alcohol ethers is preferred. Suc~ ethers are e.g. those of formula I

R-[-(CU2)n~~]~xH

wherein R0 is the residue of a higher alcohol especially a higher alkanol or alkylphenol 9 such as lauryl or cetyl alcohol, or a sterol residue, especially a lanosterol, dihydrocholesterol or cholesterol residue, as well as mixtures of two or more such ethers. Preferred polyoxyalkylene ethers for use in accordance ~ith the invention are polyoxyethylene and polyoxyethylene and polyoxypropylene et~ers (i.e. wherein n in the formula bove is 2 or 3) in particular polyoxyethylene and polyoxypropylene lauryl,cetyl and choles~eryl ethers as well as mixtures of two or more such ethers.

The hydroxy group at the end alkylene unit of such ethers as aforesaid may be partially or completely acylated, by e.g.
acyl residues of aliphatic carboxylic acids, `such as acetic acid.

Preferred ethers for use in accordance ~ith the invention have a hydrophilic-lipophilic balance (HL~ ~roup number) of fro~ a~out lO to ahout 20, especially from about l2 to about l6.

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, , ,. ' ' l7- lOO-6g48 Especially suitable ethers for use in accordance with the inven-tion are those wherein the average number of repeating units in the polyoxyalkylene moiety (x in the formula above) is from 4 to 75, suitably 8 to 309 more especially 16 to 26. The ethers may be `~
obtained in accordance with known techniques. A wide variety of such products are commercially available and e.g. offered for sale e.g. by the company Amerchol under the trade~name Solulan , the companies KAO Soap, ICI and Atlas under the trade-names Emalex~ Brij~and Laureth~and from the company Croda under the trade-name Cetomacrogol~
.
Examples of polyoxyalkylene ethers suitable for use in accordance with the invention are as follows:
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(POE = polyoxyethylene ether: POP = polyoxypropylene ether: x =
average No. of repeating units in the POP/POE moiety), . `: , :, , '' ,: , :. ` '~ ' ~ .

--l8- 100-6948 1, Cholester~ ethers.

1.1 Solulan~ C-24 - POE, x = 24.

2. Ethers of Lanolin alcohols:

2.1 Solulan~ 16 - POE, x = 16.
2.2 Solulan~ 25 - POE, x = 25.
2.3 Solulan~ 16 - POE, x = 75 .
2.4 Solulan~ PB-10 - PPE, x = 10.
2.5 Solulan~ 98 - POE, x = 10 - partially acetylated.
2.6 Solulan~ 97 - POE, x = 9 - fully acetylated.

3. Iauryl ethers:

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 ethers:

4.1 Cetomacrogol~- POE, x - 20 to 24.

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

; Preferred ethers for use in accordance with the present invention are polyoxyethylene cholesteryl ethers, i.e. of the above formula I wherein n = 2 and RO is a cholesterol residue, especially such ethers wherein the number of repeating units in the polyoxyethy-lene moiety is from 16 to 26~ most preferably about 24, :, ;
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-l9- 100-6948 More preferably such ethers are substantially free from conta-minents in pdrticular from other polyoxyalkylene ethers. Most preferably they comprise at least 75 %, more preferably at least 85 %, and nost preferably at least 90 % by weight of pure poly-oxyethylene cholesteryl ether.

Desired viscosity for the compositions of the invention will de-pend on the particular form for administration, e.g. ~hether administration is to be by nasal drops or nasal spray.

For nasal drops an appropriate viscosity is from about 2 to 400 x ~0 3 PaOs, For nasal sprays the viscosity may preferably be less than 2 x l~ 3 Pa.s.

Where a surfactant, e.g. polyoxyalkylene ether, is employed in the compositions of the invention, the amount used will vary depending on the particular surfactant chosen, the particular mode of administration ~e.g. drop or spray) and the effect `
desired. In general however~ the amount present will be of the order Of f~om ab~ut O.Ol to lO~,more preferably about 1 to 75, most preferably from about l to 60~mg/ml.

Compositions in accordance with the present invention may be ad~inis~ered in any appropriate formO Th2 preferred forms have been described above, but it is to be understood that other formulations may be made in analogous manner or in analogy to, e g. methods described in the literature~ They may be packa~ed far administration in conventional manner, preferably in a nasal applicator, conven ;ently in such a way as to deliver a fixed dose of SMS, For admi- ;
nistration in drop form such compositions will suitably be put up ... ~ , . . . .

-20- l00-6948 in a container provided e.g. with a conventional dropper/
closure device, eOgO comprising a pipette or the like, preferably delivering a substantially fixed volume of com-position/drop~ For administration as a spray, such composi-tions will be put up in an appropriate atomising device,e.gO in a pump-atomiser, aerosol or the likeO The atomi~
sing device will be provided with appropriate means for delivery of the spray to the naris. Preferably it will be provided with means ensuring delivery of a substantially fixed volume of composition/actuation (i.e. per spray-unit)~
If desired the spray may be bottled under pressure in a novel aerosol deviceO Conveniently the device administers a metered dosaye. The propellant may be a gas or a liqu;d, eOg a fluorinated and/or chlorinated hydrocarbon, The spray composition may be suspended in a liquid propellant. Stabi-lizing and/or suspending agents may be present ~f desired a powder or liquid may be filled into a soft or hard gelatine capsule. The applicator may have means to break open the capsule.

20 The amount of active ingredient~ iOeO SMS, in ~he composi- ;
tions of the invention may of course vary depending on a variety oF factors such as the particular drug-form chosen (i.e. whether the SMS is in ~ree, salt,solvate,or complex form) the condition to be treated, the desired frequency of admi-nistration and the effect desiredO The bioavailability of the compositions of the invention may be determined in conven-tional manner e.g. as described in the examples hereinafter.
Doses may be chosen to be equipotent to the injection route, for~ O treatment in one of the indications mentioned above. The amount of active ingredient will generally be chosen to provide effective treatment on administration (e.g.
of l to 5 drops~ or spray-uniks) once or 2 to 4 x /day.

~- - - .. , . . . :
.

, . - .; .. ... ~ , , . , ~ . . , .. . ~ ..
. .

~ 100 6948 conveniently twice or more convenien~ly once a-day. For this purpose the active ingredient is suitably present in an c~ncentxation such as to provide a free SMS anniant of from about Ool to about 3, preferably from abou~ 0.1 to about 1, more preferably about 006 to l,mg per administration.Examples of dosages of SMS are 002 mg, 0.4 mg, 0.8 mg and 1.6 mg.

Individual drops or powders su.i~ably have a volume of ca.
0005 ml and spray units sui~ably ca. 0.05 ~o caO 002 ml, eOg. caO 0.1 mlO
~ompositions thus suitably comprise from caO 20, pre-ferably caO 15, more preferably ca. 10 to caO 200 mg free SMS/ml ~ eOgo caO 600 mg free SMS/ml.Where a salt~solvate or complex of SMS is employed the amount of drug substance present will be correspondingly greaterO Thus where SMSac is employed, liquid compositions in accordance with the present invention may comprise e.g. ca. 7.4 mg SMSac/ml (= caO 600 mg free SMS~o The following examples are illustrative of the preparation of liquid compositions in accordance with the present in-vention9 suitable for use in a nasal spray applicatorO

Further details of the characteristics of excipients may beobtained from Pharmacopeia, ~I.P Fiedler, Lexikon der Hilfsstoffe, Edi~io Can~or, Aulendorf, 1981 and manufacturer's brochures.

. . . ~ . ', .' : . : :
' ' - ' ' : . . '..... . ' :'.. , . '' EXAMPLE 1: Nasal li~uid sera~
Comeosi~ion 1 3 2 2 3 3 1 INGREDIENT QUANTITY/ml end composition _ _ A B
SMS ac 0OOOO.O 70 796 mg* 3019 mg ~ 5 % excess~. 0.390 mg 0016 mg 8.186 mg 3035 mg 2 0 Glucose Ou.O.O 50-0 mg 50.0 mg OolN HClo~oooo to pH 4.20 to pH 4~20 Benzalkonium ;
chloride 0.11 mg nvll mg 5ù H20 (i njection grade) O. to an end volume of l.O ml * = 6.315 mg free SMS

Production Components l, 2 and 4 are mixed in water ;n conventional manner, a 5% excess of SMSac being added to allow for loss in filtra-tionOComponent 3 is then added ~o bring the pH to 4.2 and further water (5) added to provide the desired end-volume.
The mixture is stirred for 5 mins,and filtered (0.2 micron holes) and f~lled with C02-gassing into Rexo-containers. The resultant solution is clear and colourless has an end pH of 4.2 ~ 0.5 and is suitable for admin1stration as a nasal spray -from a spray dispenser device delivering caO 00095 ml /spray-unit (= caO Ou6 mg/free SMS/spray unit for Example lA and 0025 mg/free SMS/spray unit for Exa~ple lB~.

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

. , . . - .
,..... . . . . . ... .

-23- l00-6948 B~IoAv-AILABILITy STUDY for EXAMPLES 1 and 2 The investigation is carried out on 12 healthy volunteers (4 females, 8 males, average age 31.5 years, average weight 68 kg, average height 183 cm) in accordance with the guidelines laid down in the Tokyo Amendment (1975) of the Declaration of Helsinki (Federal Register 40, p. 16056, April 9, 1975).

Excluded are subjects with known impairment of hepatic or renal function, heart failure or disorders of fluids and electrolytes.
Further exclusion criteria are pregnancy and previous history of allergic reactions. Chronic symptoms of constipation, diarrhea or acute symptoms related to the gastrointestinal tract or acute or chronic sinusitis as well as acute infections of the respiratory tract at the time of the study are also a ground for exclusion.

An EEC (12 leads) is performed before commencing the investigation. Laboratory test (in blood: red blood cell count, hemoglobin; white blood cell count, erythrocyte sedimentation rate, platelet count, post prandial glucose; in serum: total protein and ~lectrophoresis, sodium, potassium, creatinine, uric acid, SGOT, SGPT, ~-GT, LDH, alkaline phosphatase, cholesterol, bilirubin, a-amylase; in urine: pH, protein, glucose, sediment) are done before and at the end of the study.

Each subiect receives two administrations comprising:
1. 0.6 mg free SMS administered nasally in spray form employing the composition of example lA; and 5 2. 0 6 mg free SMS administered nasally in spray form employing the composition of example 2.
Administration is effected in randomized cross-over sequence. The interval between administrations is at least three days. ThP drug -24- l00-6948 3 ~ ~

is given in the morning after a light breakfast without caffein-containing beverages~ Each subject is instructed to administer the nasal spray with the head in the upright position into the right nostril. Before intra-nasal administratioil the nostrils are cleaned by blowing the nose~ During and after administration of the substance the subjects refrain from taking breath for 10 seconds. At least 100 ml of water or fruit tea are drunk every hour in order to maintain a satisfactory urinary output.

Blood samples are taken immediately before SMS application, 5', lO 10', 15', 20', 30', 40', 50', 60', 75', ~0', 2 h, 2.5 h, 3 hv 4 h, 5 h, 6 h, and 8 h after drug administration They are drawn through a catheter introduced in the cubital vein at the begin-ning of the study and are put on ice in empty tubes, centrifuged about 15 - 30 minutes later at 4C and the serum is deep-frozen at -20DC until analysed.

Urine samples are collected beforé drug's administration and then between 0 h - 2 h, 2 h - 4 h, 4 h - 6 h, and 6 h - 8 h, The total ~olume of each urine sample is measured, and about 5 ml of the urine are deep-frozen at -20C until analysed Blood pressure and heart rate are monitored immediately before, l h, 2 h, 3 h, 4 h, 5 h, 6 h, and 8 h after drug application.

SMS 2n1-995 concentrations in serum and urine are analysed using radioimmunoassay technique providing a limit of detection of 0.2 ng/ml - :,. . ,.: , ~ -:
. .: :. :. :. ~ :
. ~ . , , .. .~... : . ; . .

-25- l00-6948 RESULTS

The compositions as administered are well tolerated~ with side-effects (hypermotility in the abdomen/fatty stool) recorded in 4 out of 12 subjects only9 and being in all cases of slight inten-sity only and with a maximum duration of 2 hours.

Bioavailability levels based on serum level concentration and cumulative urinary excretion indicate that therapeutic SMS serum levels are achieved employ;ng both compositions and that treat-ment via nasal administration of either composition is suitable ~0 for long term clinic application.

- :- ,. ..

--26- 100 694~

( EXAMPLE 3: Nasal SMS liguid sera~ 1 3223 ~1 This is made up analogously to ~hat descri~ed in Example 1 and contains:-mg/~il 1, SMS ac 11.55 *
+5% excess 0.55 2. Glucose 50 3. HCl O.lN to pH 4.2 4O Benzalkonjum chloride Ooll mg H20 (injection grade) to an end volume of 1 ml * = 11 mg free SMS
2.5 ml of the solution is filled under C02 gas into a 3.5 ml ~lass dispenser f~tted with a nasal spray deYice. Th;s gives 1 mg free SMS per actuation.
EXAMPLE 4: SMS nasal l~oehilisate insert _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ 15 A lyophilisate insert (plug) is made comprising the following:-mg ~4A) mg (4B) SMSac 0.316 1) 0~3~51) Lactose 200 1.0 HPM0 (Pharmacoat~ 606) 3.0 -20 HPMC (Methocel E5) 105 PEG (MW 4000) 1.5 1) Equiva1ent to 0~25 mg free pepti~e .
,~ ~
.: -; ` ~ ';' . ' ' ` ' .: . . -.
;
.
... :~:

Preearaticn of nasal insert from hydroxyeroeylmethyl _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ cellulose 30 9 of pure water are heated to 70Co 1.5 9 of HPMC (in the case of example 4A and 0.75 9 HPMC plus 0.75 9 PEG 4000 in the case of example 4B) are added. The suspension is cooled to room temperature, and 1 g of lac~ose (200 mesh) (in the case of example 4A and O.S g of lactose in the case of example 4B) are added. 15 g of pure water are used to dissolve the SMS. The liquids are mixed and water lo added to 50 ml. The solution is filtered through 0.2 m;cron holes, and pipetted in 0.1 ml lots into depressions (5 mm) in an aluminîum plate.

The plate is cooled to -35C for 4 hours, then lyophilisa-tion starts for 40 hours at -10C and continues for 24 hours at + 15C (in the case of example 4A and starts for 66 hours at -lO~C and continues for 24 hours at + 10C in the case of example 4B)o The resultant lyophilisated blocks are, after raising the temperature in the lyophilisater to room temperature, care- -fully removed from the plate and inserted into a 1 ml syringe (fitted with a plunger) the needle end of which;has been cut off a~out 3 mm from the and. Each block weighs about 5 mg.

The resultant insert is stable and easily disolvable in water. It is a uniform lyophilisate sized about 5 mm in diameter and about 6 to 7 mm in lengthO Under the electron microscopy it appears as a laminar ordered sheet system with long parallel pore channels of diameter about 5 to 10 microns. The edge of the lyophilisate is a layer of abou~
50 microns having a fine, foam-like, porous structure.

,. . .. .. . . ..
,, ,:
, .: :: .:

1 ~2331 EXAMPLE 5: SMS nasal yowder . _ _ _ _ _ _ _ _ A powder (particle size 38-68 ym (sieved~) is made up containing per 20 mg 0.3 mg SMS ac (= 0.25 mg ~ree SMS) and 19.7 mg microcrystalline cellulose (AVICEL PH 101) (= Example 5A) or Lactose (= Example 5B). This is filled into a capsule which - is nasally administered by an insufflator.

Bioavailability Trials in Monke~s ________ ___ _ ___ __ ____ _ _ _ Compo~itions were administered nasally to groups of 4 rhesus monkeys at a dose of 0.5 mg SMSo Pharmacokinetic parameters obtained:
Cpmax t max AUC (0 - 6 hr) (ng/ml) hr ng ml 1 hr Example 4A23060 0.25 37025 Example lB2060 0025 13.16 Example 4B9054 0025 24.80 Example 5A55.75 0.25 77083 Example 5B19096 0025 32.14 .. . .

., :.~ . , EXAMPLE 6: Nasal lyoehilisate inserts ~ 3~ ~31 .. . ~ ~
Lyophilisate inserts A and B were made in analogous manner to Example 4 containing:-mg (6A) mg (6B) SMS ac 1O20 1O20 5% exces~ 0.06 0.06 ~actose 1.0 2~0 HPMC (Methocel E5) 1.5 3.0 10~ H20 (injection grade) up to the end volume of 1 m1O

The lyophilisates (length 5 mm, diameter 5 mm) were locallyand systemically well tolerated.

EXAMPLE 7: Nasal eowders Nasal powders A and B were prepared containing:-~ mg (7A) mg (7B~
SMS ac 1O32 1O32 + 5% exces~ 0.07 0.07 Mi crocrystal 1 i ne cel 1 u-lose (Avicel PH 101 - 18~61 --particle size 38-68 mi crons ) HPMC (Methocel E5) -- 18.61 particle size 38-68 microns To~al 20 20 These powders were prepared in a charge ~or about 300 unit doses by mixing the.SMS and about one quarter of the polymer. The mixture is sieved. The remainder of the polymer is then added and the mass is mixed thoroughly.

" . ., ;

:, .
.

1 3~331 If desired the SMS may be disso1ved in an aqueous alcohol;c solution and this is mixed with the polymer. The resul~ant suspension or solution is freeze-or spray-dried to give a powder~

The final powder has a particle d;ameter from about 20 to about 250 microns a These powders are filled into a capsule which can be nasally administered by an insuf~lator. 4 actuations admini-ster 1 mg SMS ;n 18 mg powderO
Local and systemic tolerability were good for the nasal powders.

BIOAVAILABILITY STUDIES for examples 6 and 7 -The investigation has been carried out on 12 healthy volunteers 3 (Exo6) ~ or 4 (Ex~7) females-,and 9 or 8 males respectively,average age 26 and 27 years, average weight 69 kg~ average height 175 and 178 cm) in accordance with t~e guidel;nes la-id -down in the Tokyo Amendment (1975) of the Declaration of Helsinki (Federal Register 40, pO 16056~ April 9, 1975).

Excluded are subjects with known impairment of hepatic or renal function, heart failure or disorders of fluids and electrolytes, Further exclusion criteria are pregnancy and previous history of allergic reactions. Chronic symptoms of constipation, diarrhea or acute symptoms related to the gastrointestinal tract or acute or chronic sinusitis as well as acute infections of the resp;ratory tract at the time of the study are also a ground for exclusion~

, ~ . ' ! ', ~ , ~
.., ,' ~ ' 1 3~2~
An EEC (12 leads) is performed before commencing the investi-gation, Laboratory test (in blood: red blood cell count, hemoglobin, white blood cell count, erythrocyte sedimenta-tion rate~ platelet count, post prandial glucose; in serum:
total protein and electrophoresis, sod;um, potassium, creatinine, uric acid, SGOT, SGPT, gamma-GT, LDH, alkaline phosphatase, cholesterol, bilirubin, a-tlmylase: in urine:
pH, protein, glucose, sediment) are done before and at the end of the studyO

lo Each subject receives two administrations comprising:
1. 1 mg free SMS administered as a nasal insert or a nasal powder employing t.he composition of examples 6 or 7A respectively, and 20 1 mg free SMS administered as a nasal insert or a nasal powder employing the composition of example 6B
or 7B respectivelyO

Administration is effected in randomized cross-over sequence.
The interval bet~een administrations is at least three days.
The drug is given in the morning after a light breakfast without caffein containing beveragesO

The nasal inserts were administered into the right nostril with an applicator. For the nasal administration of the gelatine capsules tpowders) these are put into an in-sufflator as usually used for antiasthmatic drugs ~Insufla-tor Intal nasal, Fisons)O Four puffs are administeredalternatively into the right and left nostril starting with insufflation into the right nostril. After each puff the sub~
ject inhales the administered powderO Before administration the n~strilS were eleaned by one of the investigators the subject being in the sitting position, , ,.; ~ :
.. . ~ .
, .

1 ~22331 Blood samples are taken immediately before SMS application, 5', 101J 15'~ 20', 30', 40'g 50', 60', 75', 90', 2 h, 2.5 h, 3 h, 4 h, 5 h, 6 h, 8 h, 10 and 11 h, aFter drug admini- :
strationO They are drawn through a catheter ;ntroduced in the cubital vein at the beginning of the study and are put on ice in empty tubes, centrifuged about 15 - 30 minutes later at 4C and the serum is deep-fro2en at -20C until analysed~

Blood pressure and heart ra~e are monitored immediately before, 1 h~ 2 h, 3 h, 4 h, 5 h, 6 h, and 8 h after drug applicationO

SMS 201-995 concentrations in serum (powders) resp. plasma (inserts) are analysed using rad;o;mmunoassay techniques providing a limit of detection of 002 - Ool ng/ml.

Bioavailability levels based on serum and plasma level concentration and cumulative urinary excretion ;ndicate that therapeutic SMS serum levels are achieved employing all com-positions and that treatment via nasal administrat;on of either composition ;s suitable for long ter~ clinic applica-tion.

Pharmacokinet;c parameters SMS nasal (dose - 1.0 mg) med;an values Exampl.e . 6A 6B 7A 7B
.
Tmax (min) 35.0 20.0 l5.0 30.0 Cp (Tmax) (ng/ml) 104 2a5 2601 3.2 AUC (0'-720') (ng*m;n/ml) 2270033400206600 560.0 ~ ;~ . ,.~: .
- . : - ......... . 1:; . ::

Claims (24)

1. A nasal pharmaceutical composition comprising octreotide together with a solid or liquid diluent or carrier.

2. A composition according to claim 1 adapted to contain from 0.1 to 3 mg octreotide per dose.

3. A composition according to claim 1 adapted to contain from 0.1 to 1 mg octreotide per dose.

4. A composition according to claim 1 adapted to contain from 0.6 to 1 mg per dose.

5. A composition according to claim 1,2,3 or 4 in the form of a liquid.

6. A composition according to claim 5 in the form of an aqueous solution.

7. A composition according to claim 1,2,3 or in the form of a nasal insert.

8. A composition according to claim 1 in the form of a powder.

9. A composition according to claim 8 containing particles coated with a layer of octreotide.

10. A composition according to claim 8 wherein the powder comprises particles containing hydroxypropylmethyl cellulose.

11. A composition according to claim 8 wherein the powder comprises particles containing lactose.

12. A composition according to claim 8 wherein the powder comprises particles containing microcrystalline cellulose.

13. A composition according to claim 8,9,10,11 or 12 comprising from 0.2 to 1.6 mg octreotide per 20 mg powder.

14. A composition according to claim 8. comprising 0.2 mg octreotide per 20 mg powder.

15. A composition according to claim 8 comprising 0.4 mg octreotide per 20 mg powder.

16. A composition according to claim 8 comprising 0.8 mg octreotide per 20 mg powder,

17. A composition according to claim 8 comprising 1.6 mg octreotide per 20 mg powder.

18. A composition according to claim 8,9,14,15,16 or 17 wherein the weight ratio of octreotide to particles there-of is from 1 to from 10 to 100.

19. A composition according to claim 1,2,3 or 4 in unit dosage form.

20. A composition according to claim 19 in a capsule.

21. A composition according to claim 1,2,3 or 4 in a nasal applicator.

22. A composition according to claim 21 in an aerosol device.

23. A composition according to claim 22 wherein the aerosol device contains a liquid propellant.

24. Use of the octreotide composition of claim 1,2,3,6,8,9, 14,15,16 or 17 for administration of a therapeutically effective amount to the nasal mucosa.