CA2050905A1

CA2050905A1 - Therapeutic aerosol formulations

Info

Publication number: CA2050905A1
Application number: CA002050905A
Authority: CA
Inventors: George R. Felt; Mark P. Warchol
Original assignee: Individual
Current assignee: Rorer International Holdings Inc
Priority date: 1989-02-23
Filing date: 1990-02-21
Publication date: 1990-08-24
Also published as: FI913899A0; WO1990009781A1; FI913899A7; AU5194990A; JPH05508616A; EP0460064A4; EP0460064A1

Abstract

Disclosed are self-propelled therapeutic aerosol compositions, and a process for the preparation thereof, comprising a micronized, water soluble, propellant insoluble homogeneous complex of a drug and an extender suspended in a propellant mixture.

Description

Wo90/0978~ PCT/US~0/00928 2 ~ J ~

THER~PEIJ~IC AEROSOL FORMULATIONS

Backqround o~ the Invention 1. Field of the Invention The present inverltion relates to a novel therapeutic self-propelled aerosol ~ormulation ~or inhalation. ~ore particularly, it relates to a therapeutic ~ormulation o~ the dispersion or ~u~pen~ion ~ype comprising: a phy~iologically active solid drug and a solid exkender or aarrier ~or the drug suspended in a chloro~luorocarbon propellant mixture.

The present in~ention also relates to a process for the preparation of self-propelled aerosol ~ormulation intended for inhalation wherein the preparative steps include: dissolving a solid drug and a solid extender or carrier in a solvent;
lyophilizing the solution to obtain a powder; micronizing and s~spending the powder in a propellant mixture. -~
. .
The preferred embodiment of the present invention relates to a self-propelled aerosol formulation for inhalation wherein the active drug is a poIypeptide having calcitonin activity for the treatment of bone diseases.
Inhalation therapy involves direct deposition of medication onto the airway of a patient by the nasal or oral ;
routes. This method o~ delivery o~ medication is therapeutically ound and is well accepted in the prior art.
Among the benefits of the method are: the rapid medication .

,, . . ~ .. ... .. , .... .. ,, . i .

WOgO/09781 PCT/VS90/00928 20~0 ~ a~ -2-effects essential in the treatment of life threatening afflictions, such as certain allergic and asthmatic conditions; the reduction of systemic side effects;
convenience and cost as compared to, for example, intravenous or intramuscular administration; and self-administration of certain drugs such ~s the pharmaceutically active peptides that cannot be taken orally for reason of decomposition in the gastrointestinal tract.

Inhalation therapy can be used for the treatment of a variety of diseases requiring physiologically active drugs such as insulin, calcitonin, interferons, vaccines, decongestants, antiasthmatics and the like.

2. Descriptlon of the Prior Art ., Delivery o~ medication in aerosol form to a pati~nt has been proved to be an important therapeuticall~ sound module.
Its effectiveness, howev~r, i~ dcpendent upon several key ~actors including particle stability, adequate penetration and deposition into the respiratory tract, precise dosage to provide uniform results, and non-irritation to the tracheobronchial tree.

Particle penetration and deposition are believed to maximized by the use of a particle size range of from about 2 to about 10~. Particles less than 2~, although reach the alveoli, deposit minimally and are likely to be exhaled Particles 10~ or greater do not enter the respiratory tract ~ -and are deposited in the oropharynx. Comminuting solid drugs ;.
to obtain the desired particle size range poses no problem in the prior art. However, the requirements of particle stability, precise dosage and non-irritation have not been, in general, quite satisfactorily met. Generally described, the hereto~ore proposed and/or utilized aerosol formulations, are micronized drug particles suspended in a propellant mixture.
Customarily, the ~ormulations also contain a surfactant, a solvent or a dispersing agent to prevent agglomeration or sedimentation o~ the suspended particles. Despite the w090/09781 ~ PCT~US90/OQ92~

-3- 20~0~0~
presence of thes~ agents the drug particles tend to form agglomerates, floating flocculants or sedimentary precipitations during extended shelf-life resulting in destruction or clogging of the dispensing mechanism, and when administered, uneven distribution and non-uniform dosage of the drug in the tracheobronchial tree of the patient. In addition, certain solvents and surfactants tend to cause irritation on extended use of the formulations~

Another major problem associated with these type of formulations is the handling and metering of the microgram quantities of the active drug required for the intended therapeutic purpose. During the manufacturing process resulting in the metering of the drug into the dispensing containers the amounts metered varies because of adsorption, absorption and agglomeration ~actors. To minimize ~his problem and al~o to more closely reach the opkimum size range o~ particle size, ~he prior art incorporate~ a b~ol~gically inert or compatible parki~ula~e agent in~o inhalahla aero~ol ~ormulations such as into bronohodllator, ~toroid, and nicotine formulatiorls. Whlle this approach is suitable to substantially solve the metering and particle size problems, it also tends to result in an unhomogeneous mixture wherein the inert particles of the extender are not uniformly and intimately mixed with the active drug particles. The lack of homogeneity is dependent on the comminuting and mixing process and will vary even from batch to batch of the product made.
Respective specific gravities of the drug and the extender used will also greatly influence the homogeneity o~ the finished product ultimately resulting in the delivery of non-uniform dosagPs. It is, therefore, an object of the present invention to provide self-propelled therapeutic aerosol ~ormulations for oral and/or nasal applications which satisfy the above-discussed requirements. It is a further object of the invention to provide, as the preferred embodiment, calcitonin containing sel~-propelled aerosol formulations for the treatment o~ various bone diseases.
.
.

.
.. . ~ . . . . . , ~ .. . . .

WO 90/0978] PCI~US90~0092~

2 ~ a O 9 5 Y_OF TH~: INVENTION

According to the present invention, there is provided a self-propell~d therapeutic aerosol formulation for oral and/or intranasal application comprising:

a) from about 0.01 to about 5.0% w/w, and preferably ~rom about 0.1 to about 3.0~ w/w, of a homogeneous complex o~
at least one actlve drug and a pharmaceutically acceptable extender, wherein said active drug comprises from about 0.1 to .
about 25.0~ w/w of said homogeneous drug/extender complex;

b) from about 0.1 to about 3.0% w/w of a solvent and/or surfactant; and c) from about 92 to about 9g.89~ w/w o~ a pharmaceutically acceptable propellant mixture having a density of about 1.33 to about 1.~0 gm/cc~

Wherein said homogeneous complex is insoluble in said propellant mixture and is present in the form of micronized solid particles of which at least 90% w/w has an ef~ective .
particle diameter of about 2 to about 10~ and having a density of about 1.33 to about 1.40 gm/cc. .

In preparing the therapeutic aerosol formulations of the :-present invention, the active drug and the pharmaceutically acceptable extender are dissolved in water, the resultant solution is lyophilized forming a homogeneous complex wherein the drug and extender molecules are in intimate contact with each other. The so obtained powder is comminuted to the desired particle size, then combined with a small amount of solvent and/or surfactant, followed by metering into aerosol containers and adding the propellant mixture thereto.

WO ~/09781 PCT/VS9~ 92 ~5~ ~ 9 ~
Detailed Descri~tion of the Invention In accordance with the present invention, the desired self-propelled therapeutic formulations can be obtained as described above and as will be further explained and exemplified in detail.
Extenders The extenders serve as carriers and diluents for the a~tive drugs in the formulations and comprise about 75 to 99.9~ of the drug/extender homogeneous complex. The extender must be a solid, water soluble, propellant insoluble, pharmaceutically acceptable material, 50 that it can be dissolved in an aqueous solution together wlth the active drug, lyophilized and the so obtained homogen~ous complex comminut~d to the desired particle sizc.

We have ~ound the amino acld DL-Méthionine to ~unction extremely well in the formulations according to the present invention. However, other water soluble hydrocarbon insoluble pharmaceutically acceptable agents which are in, or can be made into, a solid form, are also applicable, such as:
. :
a) other amino acids, including D or L-Methionine, glycine, alanine, valine, leucine, isoleucine, phenylalanine, tyrosine, serine, cystein, aspartic acid, glutamic acid, arginine, lysine, asparagine, histidine, tryptophan and proline;

b) monosaccharides, such as, D-allose, D-altrose, fructose, galactose, glucose, inositol, D-mannose and sorbose;

c) disaccharides, ~uch as, sucrose, cellobiose, lactose, maltose, melibiose, trehalose and turanose;

d) polysacchaxides, such as, dextrin, glycogen and starch; and .

WO ~0/09781 PC~/~S90/00~28 ~ 9i~5 ` -6- ~
e) peptides and proteins, such as the widely used dipeptide, Aspartame.

Solvents and/or Surfactants ,~
The present invention utilizes from about 0.1 to about 3.0% w/w of a solvent and/or surfactant to help maintain a stable suspension. ~he solvents used include alcohols, prePerably ethyl alcohol; while the surfactants include nonionic, cationic and anionic sur~ace active agents, the pre~erred being oleic acid.

The Propellant Mixture The propellant mixture comprises from about 92 to about 99.89% w/w o~ the total ~ormulation having a density o~ about 1.33 to 1.~0 gm/cc and consists o~ a 90/10 mixtur~ o~
dichlorodi~luorometh~ne and dichlorotetra~luoroethane, or a 90/10 mixture o~ dlchlorodi~luoromethane an~
trichloro~luorome~hanc, sold und~x the trade name~ Dymel 12, Dymel 114 and Dymel 11 respectively.

The Active ~ruqs The active drug comprises from about 0.1 to about 25.0~
w/w of the drug/extender homogeneous complex. Drugs in solid form and drugs that can be made into a solid form and are soluble in aqueous solutions and insoluble in the hydrocarbon mixtures hereindescribed are contemplated for use in accordance with the present invention.

While the invention is applicable to several -pharmaceutically potent classes of drugs, it is especially suitable for delivery o~ bronchodilators, cardiovascular drugs, hormones and enzymes. Illustrative exa~ples include bronchodilatora, such aY

Ipratropium bromide = 3-~3-hydroxy~l-oxo-2-phenylpropoxy)-8-,., .. ,., , , . . . , .. , . . ~, .,. . ~ :
:,, ., .:: .- . :::. . . .: . . , .. ,, ... .. . , : . ~:
.. : ... ~ : ...... . : .,.... .. .:. ;, . .. : .:

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

9o/~s78l PCT/US90/00928 ~7~ 2 ~ 3~ 9V~
methyl-8~ methylethyl)-3-azonicabicyclo[3.2.1]octane bromide;

Metaproterenol sulfate = 5-[1-hydroxy-2-[(1-methylethyl)-amino]ethyl]1,3-benzenediol sulfate;

Terbutaline sulfate = 5-[2-[(1,1-dimethylethyl)amino]-1-hydroxyethyl]-1,3-benzenediol sulfate;

Bitolterol mesylate = 4-methylbenzoic acid 4-[2-[(1,1-dimethylethyl)aminoJ-l-hydroxyethyl]-1,2-phenylene ester mesylate;

Isoproterenol hydrochloride = 4-[l-hydroxy-2-[~l-methyl-ethyl)amino]ethyl]-1,2-benzenediol hydrochloride;

Epinephrine hydrochloride ~ 4-~1-hydroxy-2(methylamino)-ethyl]-1,2-benzenediol hydrochloride;

Albuterol sul~ate ~ a~
dimethylethyl)amino]methyl]-4-hydroxy-1,3-benzenedimethanol sul~ate; and .
Theophylline = 3,7-dihydro-1,3-dimethyl-lH-purine-2,6-dione.

Cardiovascular drugs, such as: :
.:
Clonidine hydrochloride = 2,6-dichloro-N-2-imidazolidinyli-denebenzeneamine hydrochloride; .

Terazosin hydrochloride = 1-(4-amino-6,7-dimethoxy-2-~uina-zolinyl)-4t(tetrahydro-~-~uranyl~carbanyl)]piperazine hydrochloride;

~ hydrochloride = 1_(4_amino-6,7-dimethoxy-2-quina-zolinyl)-4-(2-furoyl)piperazine hydrochloride;
.
Tolazoline hydrochloride ~ 4,5-dihydro-2-~phenylmethyl)-lH-imidazole monohydrochloride;

Labetalol hydrochloride = 5- L l-hydroxy-2-[(1-methyl-3-phenylpropyl)amino]ethyl~salicylamide monohydrochloride;

Captopril = 1-[~2S)-3-mercapto-2-methylpropionyl]-L-proline; ;

Verapamil hydrochloride = ~-[3-[[2-(3~4-dimethoxyphen ethyl]-methylamino]propyl]-3,~-dimethoxy-a(l-methylethyl)benzene-acetonitrile hydrochloride;

Diltia~em hydrochlorid~ ~ 3-(acetyloxy)-5-~2-~dlme~hyl-mlno)ethyl]-2,3-d~hydro-2-(~-methoxyphenyl)-1,5-benzothiaxepin-4(5~)~one hydrochloride;

Propranolol hydrochloride = 1-(isopropylamino)-3-(1-napthyl-oxy)-2-propanol hydrochloride;

Bretylium tosylate = (o-bromobenzyl) ethyl dimethylammonium p-toluene solfonate;

Lidocaine hydrochloride = 2-(diethylamino)-2',6'-acetoxyl-idide monohydrochloride;

Mexilitine hydrochloride = l-methyl-2-(2,6-xylyloxy)-ethyl-amine hydrochloride:

Disopyramide phosphate = ~-~2-diisopropylamino)ethyl]-~phenyl-2-pyridineacetamide phosphate:

Procainamide hydrochlorida = p-amino-N-~2-(diethylamino)-ethyl]-benzamide hydrochloride;

.,.... , . ~ .. .. .

.. ` . ` , :

.. , , ` , . . .
:' . " ' ` . , : ` : . .:, ' . ' ~ ` , ~

WO90/09781 P~T/US90/00928 ~ -9- 2 ~ S
Flecainide acetate = N-(2-piperidinylmethyl)-2,5-bis(2,2,2-trifluoroethoxy)benzamide ~onoacetate;

Tocainide hydrochloride = 2-amino-N-(2,6-dimethylphenyl)-propanamide hydrochloride;

Methoxamine hydrochloride ~ aminoethyl)-2,5-dimethoxy-benzenemethanol hydrochloride;

Minoxidil - 6~ piperidinyl)-2,4-pyrimidinediamine-3-oxide;

Metoprolol tartrate = 1-(isopropylamino)-3-~p-(2-methoxy-ethyl)phenoxy]-2-propanol (2:1) dextro-tatrate salt;

Hydro~lumethiazide = 3,4-dihydro-6-(trifluoromethyl)-2H-1,2,4-benzothiadiazine-7-sulPonamide~ dioxide;

Amrinone laotate ~ 5-amino~3,~'-bipyridine]~6tlH)-on~
lactate;

Ethaverine hydrochloride ~ (3,4- ..
diethoxyphenyl)methyl]-6,7-diethoxyisoquinoline hydrochloride:
and :

Papaverine hydroch}oride = 1-[(3,4-dimethoxyphenyl)methyl]-6,7-dimethoxyisoquinoline hydrochloride.
.
The preferred embodiment of the invention utilizes calcitonin as the active polypeptide ~or the treatment of bone diseases.
.
Calcitonin Calcitonin is a pol~peptide hormone involved in the control of calcium metabolism in the body. All known natural calci~onin peptides contain an amino acid sequence of 32 amino acids, of which the seven at the amino terminal en.d of the , . .. .. . . .

W~ ~/09~8l PCT/USgO/00928 2~s~g~ -10- ~
peptide chain are held in a cyclic configuration by a sulphur or carbon bridge and the carboxyl terminal residue consists of proline amide. The natural calcitonins include the salmon, eel, bovin, porcine, ovine, rat and human calcitoninO The detailed structure within the peptide chain of the hormone varies among di~ferent species and while the hormones, and their derivatives and analogues found in various species are of interest for use in the present invention, salmon calcitonin is of special interest in view of its relatively hydrophilic character and its stabillty. Salmon calcitonin has the following formula:

H-Cys-Ser-Asn-Leu-Ser-Thr-Cys-Val-Leu-Gly-Lys-Leu-Ser-Gln-Glu-Leu-His-Lys-Leu-11 12 13 1~ 15 16 17 1~ 19 Gln-Thr-Tyr Pro-Arg-Thr-Asn-Thr-Gly~

Ser-Gly-rrhr-pro-N~
2~ 30 3~ 32 In U.S. Pat. Nos. 3,926,938, 4,062,815, 3,929,758, 4,033,940, 4,336,187, 4,388,235, 4,391,747 and 4,401,593 are disclosed improved synthesis o~ calcitonin including the salmon calcitonin referred to above.

Human, salmon and porcine calcitonin have been available for therapeutic use for several years. For example, synthetic salmon calcitonin is marketed by Armour Pharmaceutical Co.
under the tradename CALCIMAR in a sterile, lyophilized form reconstitutable! ~or subcutaneous or intravascular injection for the treatment of bone diseases.

The level of hypocalcemic activity of calcitonin varies from species to species. Salmon and chicken calcitonin have a potency of about 4,000 to 6,000 MCR ~Medical Research Council) U/mg peptide; eel calcitonin about 2,000 to 4,000 MRC U/mg peptide; rat 400 MRC U/mg; while bee~, sheep, hog and man about 100 to 200 MRC U/mg peptide.

.. . . , , , , ~ .
,: ; . ; , . . . , . ~ . ;

W090/09781 2 ~ 5 0 9 ~ ~ PCT/l)S90/00928 Calcitonin used by the present invention may be obtained from Armour Pharmaceutical Co., from natural sources, or by synthetic routes known in the art. The synthesis can be performed by classical peptide synthesis as well as by solid phase synthesis.

In addition to the above-described calcitonin, the present invention encompasses synthetic calcitonin peptides having biological activity o~ the same type as those above-described. Such synthetic calcitonin are disclosed, along with processes Por p~eparation thereof in the ~ollowing U.S.
Pat. Nos.

~,388,235 4,604,238 4,391,747 4,605,514 4,397,7~0 ~,605,515 ~,401,593 ~,606,85~
4,414,149 ~,622,3~6 4,444,681 ~,622,3~7 ~,451,395 4,622,38~
4,469,636 4,632,978 4,497,731 4,639,509 4,497,732 4,639,510 ~,528,132 4,639,511 4,537,716 4,650,854 4,597,900 4,659,804 4,604,23~ 4,732,969 4,604,237 4,746,728 Synthetic calcitonin analogues disclosed in these patents are incorporated herein by reference as if set out in full herein. This list is not intended to be exhaustive of all U.S. Patents covering synthetic calcitonin analogues, but is representative of the analogUes useful in the present invention; nor is the invention limited to the compounds disclosed in the listed patents.

In accordance for the foregoing, the following analogues of calcitonin constitute specific active ingredients used in . .

.. ; .. .. ...

WO90~09781 PCT/US9~/00928 ~r ~9~5 - 12- ~
the various suppository formulations o~ the present invention: ~ -. .
l. Des Asparagine-3-Calcitonin having the structures~

(a) H-Cys-Ser-Leu-Ser-Thr-Cys-Val-Leu-Gly-Lys-Leu-Ser-Gln-Glu-Leu-His-Lys-Leu-Gln-Thr-Tyr-Pro-Arg-Thr-Asn-Thr-Gly-Ser-Gly-Thr-Pro-NH2; and .. . .. .
(b) Cys-Ser-Leu-Ser-Thr-Cys-Val-Leu-Gly-Lys-Leu-Ser-Gln-Glu-Leu-His-Lys-Leu-Gln-Thr-Tyr-Pro-Arg-Thr-Asp-Val-Gly-Ala-Gly-Thr-Pro-NH2.

2. [16-Alanine~ Calcit~nin having the following structures:

~a) Cys-Ser-Asn-Leu-Ser-Thr-Cys-Val-Leu-Gly-Lys-Leu-Ser-Gln-Glu-Ala-His-Lys-Leu-Gln-Thr-T~r-Pro-Arg-Thr-~sn-Thr-Gly-Ser-Gly-Thr-Pro-NH2 (Salmon);

(b) Cy~-Ser-Asn-Leu-Ser-Thr-Cy~-Val-Leu-Gly-Lys-Leu~Ser-Gln-Glu-Ala-His-Lys-Leu-Gln-Thr-Tyr-Pro-Arg-Thr-Asp-Val-Gly-Ala-Gly-Thr-Pro-NH2 (Eel); and ; (c) Cys-Gly-Asn-Leu-Ser-Thr-Cys-Met-Leu-Gly-Thr-Tyr-Thr-Gln-Asp-Ala-Asn-1ys-Phe-His~
Thr-Phe-Pro-Gln-Thr-Ala-Ile-Gly-Val-Gly- `~ :~
: Ala-Pro-NH2 (Human).

:~ 3.~ Des 2-Glycine 8-Des 22-Calcitonin having the structures~

a)- H-Cys-Asn-Leu-Ser-Thr-Cys-Gly-Leu-Gly-Lys-Leu-Ser-Gln-Glu-Leu-His-Lys-Leu-Gln-Thr-Pro-Arg-Thr-Asn-Thr-Gly-Ser-Gly-Thr-Pro-NH2 (Salmon); and . :

W~90/097~1 PCT/US90J00928 -13- 2 ~ 3 ~ 9 ~'3 (b) H-Cys-Asn-Leu-Ser-Thr-Cys-Gly-Leu-Gly-Lys-Leu-Ser-Gln-Glu-Leu-His-Lys-Leu-Gln-Thr-Pro-Arg-Thr-Asp-Val-Gly-Ala-Gly-Thr-Pro-Nh2 (Eel).

4. Des-13-Serine-Calcitonin having the following structures:

(a) Cys-Ser-Asn-Leu-Ser-Thr-Cys-Val-Leu-Gly-Lys-Leu-Gln-Glu-Leu-His-Lys-Leu-Gln-Thr-Tyr-Pro-Arg-Thr-Asn-Thr-Gly-Ser-Gly-Thr-Pro-NH2;

(b) Cys-Ser-Asn-Leu-Ser-Thr-Cys-Val-Leu-Gly- :~
Lys-Leu-Gln-Glu-Leu-His-Lys-Le-l-Gln-Thr-Tyr-Pro-Arg-Thr-Asp-Val-Gly-Ala-Gly-Thr-Pro-NHz, and (c) Cy~-Gly-Asn-Leu~Ser-Thr-Cys-Met L~u~Gly-Thr~Tyr-Gln Asp-Phe~A~n Ly~-Pha~lis-The-Phe-Pro-Gln-Thr-Ala-Ile-Gly-Val-Gly-Ala-Pro-NH2.

5. Des-21-Threonine-Calcitonin having the ~ollowing structures: .

(a) Cys-Ser-Asn-Leu-Ser-Thr-Cys-Val-Leu-Gly-~ys-Leu-Ser-Gln-Glu-Leu-His-Lys-Leu-Gln- :
Tyr-Pro-Arg-Thr-Asn-Thr-Gly-Ser-Gly-Thr~
Pro-NH2 (Salmon);
.
(b~ Cys-Ser-Asn-Leu-Ser-Thr-Cys-Val-Leu-Gly-~ys-Leu-Ser-Gln-Glu-Leu-His-Lys-Leu-Gln-Tyr-Pro-Arg-Thr-Asp-Val-Gly-Ala-Gly-Thr-Pro-NH2, (Eel); and ~ .
(c) Cys-Gly-Asn-Leu-Ser-Thr-Cy6-Met-Leu-Gly-Thr~Tyr-Thr-Gln-Asp-Phe-Asn-Lys-Phe-His-Phe-Pro-Gln-Thr-Ala-Ile-Gly-Val-Gly Ala-Pro-NH2 ~Human). . ;: .
::

WO90/09781 PCT/VS9~/00928 :

~ 3~

6. ~Gly2, Ser3, Gly8! .des-~y~2] Calcitonin having the following structures:

, . . . _ . _ (a) Cys-Gly-Ser-Leu-Ser-Thr-Cys-Gly-Leu-Gly- ~ ;
Lys-Leu-Ser-Gln-Glu-LPu-Mis-Lys-Leu-Gln-Thr-Pro-Arg-Thr-Asn-Thr-Gly-Ser-Gly-Thr-Pro-NH2; and .
(b) Cys-Gly-Ser-Leu-Ser-Thr-Cys-Gly-Lue-Gly-Lys-Leu-Ser-Gln-Glu-Leu-His-Lys-Leu-Gln-Thr-Pro-Arg-Thr-Asp-Val-Gly-Ala-Gly-Thr-Pro-NH2. :;

7. Des-4-Leucine-Calcitonin having the following structures: ~

. ....__ . _ (a) Cys-Ser-Asn-$er-Thr-Cys-Val-Leu-Gly-Lys-Leu-Ser-Gln Glu-Leu-His-Lys-Leu-Gln-Thr-Tyx-Pro-Arg-Thr-A5n-Thr-Gly-Ser-Gly-Thr~Pro-N~l2 (Salmon);
,~ .
(b) Cys-Ser-Asn-Ser-Thr-Cys-Val-Leu-Gly-Lys-Leu-Ser-Gln-Glu-Leu-His-Lys-Leu-Gln-Thr-Tyr-Pro-Arg-Thr-Asp-Val-Gly-Ala-Gly-Thr-Pro-N~2 (Eel); and , .. .. _ (c) Cys-Gly-Asn-Ser-Thr-Cys-Met-Leu-Gly-Thr-Tyr-Thr-Gln~Asp-Phe-Asn-Lys-Phe-His-Thr-Phe-: Pro-Gln-Thr-Ala-Ile-Gly-Val-Gly-Ala-Pro-NH2 (Human).

8. Calcitonin-(1-23)-Peptide Amides having the ~ollowing structures:

.
(a) Cys-Ser-Asn-Leu-Ser-Thr-Cys-Val-Leu-Gly-Lys-Leu-Ser-Gln-Glu-Leu-His-Lys-Leu-Gln-Thr-Tyr-Pro-NH2; and WO90~09781 PCT/US9~/00928 3 ~ ~ 3 (b) Rl R2 Cys-Ser-Asn-Leu-Ser-Thr-Cys~Val-Leu-Gly-Lys-Leu-Ser-Gln~Glu-Leu-His-~ys-Leu-Gln-Thr-Tyr-Pro-NH2.

9. [Des-1-Ami~o,8-Glycine) Calcitonin having the following structures: ~ .

(a) Bmp-Ser-Asn-Leu-Ser-Thr-Cys-Gly-Leu-Gly-Lys-Leu-Ser-Gln-Glu-Leu-His-Lys-Leu-Gln-Thr-Tyr-Pro-Arg-Thr-Asn-Thr-Gly-Ser-Gly-Thr-Pro-N~2 (Salmon); and (b) Bmp-Scr-Asn-Leu-Scr-Thr-Cys-Val-Leu-Gly-Lys-Leu-Scr-Gln-Glu-Leu-His-Lys-Leu-Gln-Thr-Tyr-Pro-Arg-Thr-Asp-Val-Gly-Ala-Gly-Thr-Pro-NH2 (Eel).

10. ~1,7-Di-AlanineJ Calc~tonln having the ~ollowing structures:

(a) Ala-Ser-Asn-Leu-Ser-Thr-Ala-Val-Leu-Gly-Lys-Leu Ser-Gln-Glu-Ala-His-Lys-Leu-Gln-Thr-Tyr-Pro-Arg-Thr-Asn-Thr-Gly-Ser-Gly-Thr-Pro-NH2; and (b) Ala-Ser-Asn-Leu-Ser-Thr-Ala-Val-Leu-Gly-Lys-Leu-Ser-Gln-Glu-Ala-His-Lys-Leu-Gln-Thr-Tyr-Pro-Arg-Thr-Asp-Val-Gly-Ala- -Gly-Thr-Pro-NH2.

11. 8-Methionine Calcitonin having the following structures~
'::
(a) Cys-Ser-Asn-Leu-Ser-Thr-Cys-Met-Leu-Gly-Lys-Leu-Ser-Gln-Glu-Leu-His-Lys- :~
Leu-Gln-Thr-Tyr-Pro-Arg-Thr-Asn-Thr-Gly-Ser-Gly Thr Pro-N~2; and (b) Cys-Ser Asn-Leu-Ser-Thr-Cys-~et-Leu-- Gly-~ys-Leu-Ser-Gln-Glu-Leu-His-Lys-WO90/0978l r~ PCT/US90/OV928 ~o3~9~ - -16- ~
Leu-Gln-Thr-Tyr Pro-Arg-Thr-Asp-Yal-Gly-Ala-Gly-Thr-Pro-NH2. ~

12. Des-2-Serine, 3-Asparagine Calcitonin having the ~ , following structures:

(a) Cys-Leu-Ser-Thr-Cys-Val-Leu-Gly-Lys-Leu-Ser-Gln-Glu-Leu-His-Lys-Leu-Gln-Thr-Tyr-Pro-Arg-Thr-Asn-Thr-Gly-Ser-Gly-Thr-Pro-N~I2; and (b) Cys-Leu-Ser-Thr-Cys-Val-Leu-Gly-Lys-Leu-S,cr-Gln-Glu-Leu-His-Lys-Leu-Gln-Thr-Tyr-Pro-Arg-Thr-Asp-Val-Gly-Ala-Gly-Thr-Pro-NHz.

13. G-Serine, Des-19-Leucine Calcitonin having the ~ollowing structures:

(a) Cys-Ser-Asn-Leu-Ser-SQr-C~-Val~Leu Gly-Lys-Leu-Ser-Gln-Glu-Leu-His-Lys-Gln-Thr-Tyr-Pro-Arg-Thr-Asn-Thr-Gly-Ser-Gly-Thr-Pro-NH2; and (b) Cys-Ser-Asn-Leu-Ser-Ser-Cys-Val-Leu-Gly-Lys-Leu-Scr-Gln-Glu-Leu-His-Lys-Gln-Thr-Tyr-Pro-Arg-Thr-Asp-Val-Gly-Ala-Gly-Thr-Pro-NH2.

:::14. [16,19-Di-Alanine~ Calcitonin having the following ~tructures:
~:
(a) Cys-Ser-Asn-Leu-Ser-Thr-Cys-Val-~eu-Gly- ~' Lys-Leu-Ser-Gln-Glu-Ala-His-Lys-Ala-Gln-Thr-Tyr-Pro-Arg-Thr-Asn-Thr-Gly-Ser-Gly-~hr-Pro-NH2; and - (b) Cys-Ser-Asn-Leu-Ser-Thr-Cys-Val-Leu-Gly-, Lys-Leu-Ser-Gln-Glu-Ala-His-Lys-Ala-Gln-woso/o97~l 2 ~ Pcr/usgo/oo9~8 . . :

Thr-Tyr-Pro-Ary~Thr-Asp-Val-Gly-Ala-Gly- .
Thr-Pro-NH2 .

15. (l-S-Acetamidomethyl Cysteine, 7-Alanine) Calcitonin having the following structures:

(a) SCH2NH-C(O)-CH3 Cys-Ser-Asn-Leu-Ser-Thr-Ala-Val-Leu-Gly-Lys-Leu-Ser-Gln-Glu-Leu-His-Lys-Leu-Gln-Thr-Tyr-Pro-Arg-Thr-Asn-Thr-Gly-Ser-Gly-Thr-Pro-NH2; and :
(b) ScR2NH-c~o)-cH3 Cys-Ser-Asn-Leu-Ser-Thr-Ala-Val-Leu-Gly-Lys-Leu-Ser-Gln-Glu-L~u-His-Lys-Leu-Gln-Th~-Tyr-Pro-Arg-Thr-Asp-Val-Gly-Ala-Gly-Thr-Pro-NH2 .

16. Des-lg-Leucine - Calcitonln Analogs ha~ing the ~ollowing struc~ures:

(a) Cys-Ser-Asn-Leu-Ser-Thr-Cys-Val-Leu-Gly-Lys-Leu-Ser-Gln-Glu-Leu-His-Lys- ; .
Gln-Thr-Tyr-Pro-Arg-Thr-Asn-Thr-Gly-Ser-Gly-Thr-Pro-NH2; and WOgO/~9781 PCTlUS90/00928 ~ ~ -18-. .
(b) Cys-Ser-Asn-Leu-Ser-Thr-Cys-Val-1eu~
Gly-Lys-Leu-Ser-Gln-Glu-Leu-His-Lys- `
Gln-Thr-Tyr Pro-Arg-rrhr-Asp-Val-Gly-Ala-Gly-Thr-Pro-NH2.

17. (Bis-1,7-S-Acetamidomethyl-L-Cysteine) Salmon Calcitonin having the ~ollowing structures:

(a) O O
S-CH2-NH-C-CH3 S-CH2-NH-C~CH3 H-Cys-Ser-Asn-Leu-Ser-Thr-Cys-Val-Leu-Gly-Lys- :
Leu-Ser-Gln-Glu-Leu-His-Lys-Leu-Gln-Thr-Tyr-Pro-Arg-Thr-Asn-Thr~Gly~Ser-Gly-Thr-Pro-NH2; and (b) O O
S-CH2-NH-C-c~l2 S-CHz-NH-C-CH3 H-Cy5-Ser-Asn-Leu-Ser-Thr-Cys~Val-~u-Gly-Lys~
~eu-Ser-Gln-Glu-L~u-~is-Ly~-Leu-Gïn-Thr-Tyr-Pro-Arg-Thr~Asp-Val-Gly-Ala-Gly-Thr-Pro-NH2.

18. 8-Glycine, Des- l9-Leucine-Calcitonin having the ~ollowing structures:
~.

.:
.

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

W0~0~9781 2 ~ PCT~US90/00928 --19-- ' (a) Cys-Ser-Asn-Leu-Ser-Thr-Cys-Gly-Leu-Gly-Lys-Leu-Ser-Gln-Glu-Leu-His-Lys-Gln-Thr Tyr-Pro-Arg-Thr-Asn-Thr-Gly-Ser-Gly-Thr-Pro-NH2 (Salmon);

.. ...
(b) Cys-Ser-Asn-Leu-Ser-Thr-Cys-Gly-Leu-Gly-Lys-Leu-Ser-Gln-Glu-Leu-His-Lys-Gln-Thr-Tyr-Pro-Arg-Thr-Asp-Val-Gly-Ala-Gly-Thr-Pro-NHz (Eel); and (c) Cys-Ala-Ser-Leu-Ser-Thr-Cys-Gly-Leu-Gly-Lys-Leu-Ser-Gln-Glu-Leu-His-Lys-Gln-Thr-Tyr Pro-Arg-Thr-Asp-Val-Gly~Ala-Gly-Thr-Pro-NHz ~Chicken).

19. Des-Leu16-Calcltonin having the follow~ng struatures: ;

(a) Cys-Ser-A~n-Lcu-Ser-Thr-Cys-Val-Leu-Gly-Lys-Leu-Ser-Gln-Glu-His-Lys-Leu-Gln-Thr-Tyr-Pro-Arg-Thr-Asn~Thr-Gly-ser~
Gly~Thr-Pro-NHz (Salmon); .

(b) Cys-Ser-Asn-Leu-Ser-Thr-Cys-Val-Leu-Gly-Lys-Leu-S~r-Gln-Glu-His-Lys-Leu-Gln-, ' ~.

. ^~, , .: ,.,.. ,.,.,.. ,.. . ,.;. .. ... .. , ., , . . . ,,, , .. .. , , , . . . , ~

W090/0978] PCT/US90/00928 Thr-Tyr-Pro-Arg-Thr-Asp-Val-Gly-Ala-Gly-Thr-Pro-NH2 (Eel); and (c) Cys-Gly-Asn-Leu-Ser-Thr-Cys-Met-Leu-Gly-Thr-Tyr-Thr-Gln-Asp-Asn-Lys-Phe-His-Thr-Phe~Pro-Glu-Thr-Ala-Ile-Gly-Val-Gly-Ala-Pro-NH2 (Human).

20. Leucine22 - Falcitonin having the ~ollowing structures:

(a) H-Cys-Ser-Asn-Leu-Ser-Thr-Cys-Val-Leu-Gly-Lys-Leu-Ser-Gln-Glu-Leu-His-Lys-Leu-Gln-Thr-Leu-Pro-Arg-Thr-Asn-Thr-Gly-Ser-Gly-Thr-Pro-N~2 (Salmon); and (b) H-Cys-Ser-Asn Leu-Ser-Thr-Cys-Val-Leu-Gly~Lys-Leu-Ser-Gln-Glu-Leu-Hi~-Ly~Leu-Gln-Thr-Leu-Pro-Arg-Thr-Asp~V~l-Gly-Ala~Gly-Thr-P~o-N~l2 (E~l).

21. Glycine - 8 Calcitonin having the following structures:

(a) H-Cys-Ser-Asn-Leu-Ser-Thr-Cys-Gly-Leu-Gly-Lys-Leu-Ser-Gln-Glu-Leu-His-Lys-Leu-Gln-Thr-Tyr-Pro-Arg-Thr-Asn-Thr-Gly-Ser-Gly-Thr-Pro-NH2; and ~:
`.

wn 90/097~1 2 ~ 5 ~ 9 PCr~US~O/nO92~ ~

-21- ;~
(b) Cys-Gly-Asn-Leu-Ser-Thr-Cys-Gly-Leu-Gly-Thr-Tyr-Thr-Gln-Asp-Phe-Asn-Lys-Phe~His-Thr-Phe-Pro-Gln-Thr-Ala-Ile-Gly-Val-Gly-Ala-Pro-NH2.

22. Glycine8-D-Arqinine24 Calcitonin having the ~ollowing structures:

.
(a) H-Cys-Ser-Asn-Leu-Ser-Thr-Cys-Gly-Leu-Gly-Lys-Leu-Ser-Gln-Glu-Leu-His-Lys-Leu-Gln-Thr-Tyr-Pro-D-Arg-Thr-Asn-Thr-Gly-Ser-Gly-Thr-Pro-NH2 (Salmon); and ;`
: .
~b) H-Cys-Ser-Asn-Leu-Ser-Thr-Cys-Gly-Leu-Gly-Lys-Leu-Ser-Gln-Glu-Leu-His-Lys-Leu-Gln-Thr-Tyr-Pro-D-Arg-Thr-Asp-~lal-Gly-AlawGly-Thr-Pro~NH2 (Eel).

23. L-Tyrosine21 Calcitonin having the ~ollowing structures:

(a) H-Cys-Ser-Asn-Leu-Ser-Thr-Cys-Val-Leu-Gly-Lys-Leu-Ser-Gln-Glu-Leu-His-Lys-Leu-Gln-Tyr-Tyr-Pro-Arg-Thr-Asn Thr-Gly-Ser-Gly-Thr-Pro-NH2 (Salmon); and (b~ H-Cys-Ser-Asn-Leu-Ser-Thr-Cys-Val-Lcu--' .: . , :. .: . : .. .. ,. . ~ ... ~, WO ~/09781 PCT~US90/0~928 3~ -22-Gly-Lys-Leu-Ser-Gln-Glu-Leu-His-Lys-Leu-Gln-Tyr-Tyr-Pro-Arg-Thr-Asp-Val-Gly-Ala-Gly-Thr-Pro-N~2 (Eel).

24. D-Arginine24 Calcitonin having the following structures:

(a) H-Cys-Ser-Asn-Leu-Ser-Thr-Cys-Val-Leu-Gly-Lys-Leu-Ser-Gln-Glu-Leu-His-Lys-Leu-Gln-Thr-Tyr-Pro-D-Arg-Thr-Asn-Thr-Gly-Ser-Gly-Thr-Pro-NH2 (Salmon); and (b) H-Cys-Ser-Asn-Leu-Ser-Thr-Cys-Val-Leu-Gly-Lys-Leu-S~r-Gln-Glu-Leu-His-Lys-Leu-Gln-Thr-Tyr-Pro-D-Arg-Thr-Asp-Val-Gly-Ala-Gly-Thr-Pro-NH2 (Eel).

25. Amides Analogues o~ Cal~itonin having the ~ollowing structures:

WO ~/097BI PCT/US90/00928 2 ~ 3 ~

:::

(a) Y-Cys-Ser-Asn-Leu-Ser-Thr-Cys-Val-Leu-Gly-l 2 3 4 5 6 7 8 9 10 x X
Lys-Leu-Ser-Gln-Glu-Leu-His-Lys-Leu-Gln-Thr-X

Tyr-Pro-Arg-Thr-Asn-Thr-Gly-Ser-Gly-Thr-Pro-NH2 22 23 2~ 25 26 27 28 29 30 31 32 wherein Y is Nta) decanoyl and X is N(e) decanoyl. ~:~

26. [N-alpha, 1,7~Di-Alanine, Des-l9~Leucine] Cal~itonin having the following structures: ~:

(a) [N-alpha-X, 1, 7 Di-Alanine (8-Y) Des-19-Leucine]
calci~onin, wherein X is H, ~ree amino or acyl-amino wherein acyl is derived ~rom a carboxylic acid having 1-10 carbon atoms, ~-lactic acid ~r hal~
amide o~ malonic, succinic, glutaric, or adlpic acid~; Y i5 ~-valine, glycinQ~ ~-methionine, g-alanine, ~-leucine or ~-isoleucine; and (b) [N-alpha-X, 1, 7-Di-Alanine, Des-l9-Leucine]
calcitonin, wherein X is an acyl derived ~rom carboxylic acid having 1-5 carbon atoms.

WOgO/0~781 PCT/US90/00928 ~ 5 -24-27. 1,7-Di-Alanine, 8-Glycine, D~s-l9-Leucine Calcitonin `~
having the following structure:

H2N-Ala-Ser-Asn-Leu-Ser-Thr-Ala-Gly-Leu-GIy-Lys-l 5 lo Leu-Ser-Gln-Glu-Leu-~is-Lys-Gln-Thr-Tyr-Pro-Arg-Thr-Asn-Thr-Gly-Ser-Gly-Thr-Pro-(C=0)-NH2.

28. N~-Propionyl, 1,7-D$-Alanlne, Des-l~-~eucine Calcitonin having the following structure:

CH3-CH2-(C=O)-Hn-Ala-Ser-Asn-Leu-Ser-Thr-Ala-Val-Leu-Gly-Lys-Leu-Ser-Gln-Glu-Leu-His-Lys-Gln-Thr-Tyr-Pro-Arg-Thr-Asn-Thr-Gly-Ser-Gly-Thr-Pro-(C~0)-N~lz.

.

: `

~ .... . ~ .. , " .. . . . . . . . .

WO ~/os781 PCT/VS90/00928 ~ 25 ~3~9~ `

PreParation o~ the Formulations In accordance with the present invention, the active drug and the extender, both being in a solid form, are dissolved in water by means of mechanical mixing, followed by lyophilization and comminution to the desired particle size, using well-known technlque employed in the prior art. The drug/extender complex, at least 90% o~ which possess an effective particle diameter of about 2 to 10 ~ is combined with a solvent or surfactant by means of blending and metered into a suitable aerosol container. Lastly, the desired amount of the 90/10 dichlorodifluoromethane/
dichlorotetra~luoroethane is charged into the container to complete the process in making the sel~-propelled ~ormulation.

Preparative examples and typical ~ormulatlons are set forth below, however, it is ko be understood that these examples are given by way o~ illustration only and are not to be construed as limiting the invention either in spirit or in scope as many modifications will be apparent to those skilled in the art.

' ' ~ ' ' ' ' ` '; , . . ; ; ! "

WO90/09781 P~T/US~0/0092~

99.25 grams of DL-Methionine and 0.75 grams of salmon calcitonin (4848 MRC unit/mg) were dissolved in 5.5 liters of deionized water. The resultant solution was lyophilized, and the powder was micronized. An analysis of the micronized powder showed the presenae of 0.74~ w/w calcitonin and 101.15%
w/w DL-Methionine.

~ he micronized calcitonin/DL-Methione complex was then combined with oleic acid and a 90/10 blend of Dymel 12/Dymel 114 in a suitable container. The so prepared formulation was found to contain:

0.250 grams of calcitonin/DL-MethioninQ;
0.095 grams of oleic acid; and 16.023 grams of 90/10 D~mel 12/Dymel 11~.

Dose delivery was found to contain an average of 7.32~g of calcitonin and 1063~g DL-Methionine per actuation, while content uniformity was found to be an average of 1.795~g/unit of calcitonin and 259.2~g/unit DL-Methionine. Particle size measurement showed an M50 of 4.4~ and an M90 of 13.5~.

,. . . - . .. . .

WO90/n9781 PCT/US~OtO0928 2 ~

95.S grams of DL Methionine and 4.5 grams of salmon calcitonin were dissolved in 5.5 liters of deionized water.
The solution was lyophilized and the so obtained powder was micronized. The calcitonin/DL-Methionine complex was then processed as in Example 1. Dose delivery measurement showed 45 mg of calcitonin and 955 mg DL-Methionine per actuation.

A calcitonin/DL-Methionine complex was prepared and processed as in Example 1. The final formulation contained 0.125 grams o~ calcitonin/DL-Methionine, 0.095 grams of oleic acid and 16.1~8 grams of 90/10 mixture o~ Dymel 12/D~mel 11~.

Dose delivery was found to be 22.5~g o~ calcltonin and ~77.5~g of DL-Methionine per ac~uation.

16.0 grams of DL-Methionine and 4.0 grams o~ salmon calcitonin (having calcitonin activity of 4000 MRC unit/mg) WO9Vt0978l PCT/~S90/00928 were dissolved in one liter of deionized water. The resultant solution was lyophilized and the powder was micronizedO A
slurry was prepared consisting of 20.0 grams of DL-Methionine/SCT, 40.0 grams of absolute ethanol, and 40.0 grams of oleic acid. 250 ml of the slurry was then combined with 9.75 ml of 90/10 of Dymel 12/Dymel 114 propellant blend to produce the following self-propelled aerosol suspensionO

Inqredients Volume (ml) DL-Methionine 0.050 Ethanol, absolute O.lOO
Oleic acid O.lO0 90/lO Dymel 12/Dymel 114 9.750 Total 10.000 1'he formulation provides 200 IU/50~lL per actuat~on~

5.62 grams of triamcinolone acetonide (a steroidal hormone/anti-inflammiatory agent) and 23.0 grams of L-alanine were dissolved in 1.5 liters of deionized water. The resultant solution was lyophilized and the powder micronized , . ~ . . . . . .

WOgO/09781 PCT/US90/~0~28 ~ 3 ~ 9 ~3 --2~--and sifted to meet particle size requirem~nts. A slurry was then prepared using the micronized powder, 15 grams of SPAN 85 and 120 grams of ethanol. The slurry was then combined with a propellant mixture containing 3,000 grams of Dymel 114 and 12,000 ~rams of Dymel 12. The formulation had the following composition:

Composition in Inqredients % w/w Triamcinolone acetonide 0.037 L-alanin 0.152 SPAN 85 o.ogg Ethanol, absolute 0.792 Dymel 12 79.151 Dymel 114 19.769 Total100.000 Lung absorption studies conducted on Sprague-Dawley rats using calcitonin ~ormulations o~ the present invention showed . `
highly signi~icant hypocalcemic responses over that of the placebo. , While only certain embodiments of our invention have been W~90~09781 PCT/US9~/~0~'~8 9~

described in specific detail, it will be apparent to those skilled in the ar~ that many other specific embodiments may be practiced and many changes may be made all within the spirit of the invention and the scope of the appended claimsO

Claims

WHAT WE CLAIM IS:

1. A self-propelled therapeutic aerosol suspension for inhalation comprising: from about 0.01 to about 5.0% w/w of a water soluble, propellant insoluble solid homogeneous complex in micronized form of at least one active drug and a pharmaceutically acceptable extender, wherein said active drug comprises from about 0.1 to about 25.0% w/w of said homogeneous drug/extender complex;

from about 0.1 to about 3.0% w/w of a solvent and/or surfactant; and from about 92.0 to about 99.89% w/w of a pharmaceutically acceptable propellant mixture.

2. The self-propelled therapeutic aerosol suspension of claim 1 for oral application.

3. The self-propelled therapeutic aerosol suspension of claim 1 for intranasal application.

4. The self-propelled therapeutic aerosol suspension of claim 1 wherein at least 90% of said homogeneous complex in micronized form has an effective particle diameter of about 2 to about 10µ.

5. The self-propelled therapeutic aerosol suspension of claim 1 wherein said propellant mixture essentially consists of about 90% w/w dichlorodifluoromethane and about 10% w/w dichlorotetrafluorethane, or about 90% w/w dichlorodi-fluoromethane and about 10% w/w tichlorofluoromethane.

6. The self-propelled therapeutic aerosol suspension of claim 1 wherein said propellant mixture has a density of about 1.33 to about 1.40 gm/cc.

7. The self-propelled therapeutic aerosol suspension of claim 1 wherein said extender is selected from the group consisting of amino acids, monosaccharides, disaccharides, polysaccharides, peptides and proteins.

8. The self-propelled therapeutic aerosol suspension of claim 1 wherein said extender is DL-Methionine.

9. The self-propelled therapeutic aerosol suspension of claim 1 wherein said solvent is ethanol.

10. The self-propelled therapeutic aerosol suspension of claim 1 wherein said surfactant is oleic acid.

11. The self-propelled therapeutic aerosol suspension of claim 1 wherein said active drug is selected from the group consisting of bronchodilators, cardiovascular drugs, hormones and enzymes.

12. The self-propelled therapeutic aerosol suspension of claim 1 wherein said active drug is a polypeptide.

13. The self-propelled therapeutic aerosol suspension of claim 12 wherein said polypeptide is selected from the group consisting of eel, bovine, porcine, ovine, rat, chicken and human calcitonin.

14. The self-propelled therapeutic aerosol suspension of claim 12 wherein said polypeptide is salmon calcitonin.

15. The self-propelled therapeutic aerosol suspension of claim 12 wherein said polypeptide is obtained from natural sources.

16. The self-propelled therapeutic aerosol suspension of claim 12 wherein said polypeptide is obtained by a AMENDED CLAIMS
[ received BY the International Bureau on 20 August 1990 (20.08.90);
original claims 20-28,30,31,33,35-44 amended;other claims unchanged (9 pages)]
synthetic route.

17. The self-propelled therapeutic aerosol suspension of claim 12 wherein said polypeptide has a potency of from about 100 to about 10,000 international units per mg of polypeptide.

18. The self-propelled therapeutic aerosol suspension of claim 12 wherein said polypeptide is [N-alpha-X, 1,7 Di-Alanine (8-Y) Des-19-Leucine] calcitonin, wherein X is H, free amino or acyl-amino wherein acyl is derived from a carboxylic acid having 1-10 carbon atoms, L-lactic acid or half amide of malonic, succinic, glutaric, or adipic acids; and Y is L-valine, glycine, L-methionine, L-alanine, L-leucine or L-isoleucine.

19. The self-propelled therapeutic aerosol suspension of claim 12 wherein said polypeptide is [-alpha-X, 1,7-Di-Alanine, Des-19-Leucine] calcitonin, wherein X is an acyl derived from carboxylic acid having 1-5 carbon atoms.

20. The self-propelled therapeutic aerosol suspension of claim 12 wherein said polypeptide is:

21. The self-propelled therapeutic aerosol suspension of claim 12 wherein said polypeptide is:

22. The self-propelled therapeutic aerosol suspension of claim 12 wherein said polypeptide is:

23. The self-propelled therapeutic aerosol suspension of claim 12 wherein said polypeptide is;

24. The self-propelled therapeutic aerosol suspension of claim 12 wherein said polypeptide is:

(Salmon).

25. The self-propelled therapeutic aerosol suspension of claim 12 wherein said polypeptide is:

26. The self-propelled therapeutic aerosol suspension of claim 12 wherein said polypeptide is:

27. The self-propelled therapeutic aerosol suspension of claim 12 wherein said polypeptide is:

28. The self-propelled therapeutic aerosol suspension of claim 12 wherein said polypeptide is:

29. The self-propelled therapeutic aerosol suspension of claim 12 wherein said polypeptide is:

30. The self-propelled therapeutic aerosol suspension of claim 12 wherein said polypeptide is:

31. The self-propelled therapeutic aerosol suspension of claim 12 wherein said polypeptide is:

32. The self-propelled therapeutic aerosol suspension of claim 12 wherein said polypeptide is:

; where R1 is S-n-alkyl, Cys or H and R2 is S-n-alkyl or H, R1 being S-n-alkyl, Cys or H when R2 is H and R2 being S-n-alkyl or H when R1 is H.

33. The self-propelled therapeutic aerosol suspension of claim 12 wherein said polypeptide is:

34. The self propelled therapeutic aerosol suspension of claim 12 wherein said polypeptide is:

35. The self-propelled therapeutic aerosol suspension of claim 12 wherein said polypeptide is:

36. The self-propelled therapeutic aerosol suspension of claim 12 wherein said polypeptide is:

37. The self-propelled therapeutic aerosol suspension of claim 12 wherein said polypeptide is:

38. The self-propelled therapeutic aerosol suspension of claim 12 wherein said polypeptide is:

39. The self-propelled therapeutic aerosol suspension of claim 12 wherein said polypeptide is:

40. The self-propelled therapeutic aerosol suspension of claim 12 wherein said polypeptide is:

41. The self-propelled therapeutic aerosol suspension of claim 12 wherein said polypeptide is:

42. The self-propelled therapeutic aerosol suspension of claim 12 wherein said polypeptide is:

43. The self-propelled therapeutic aerosol suspension of claim 12 wherein said polypeptide is:

44. The self-propelled therapeutic aerosol suspension of claim 12 wherein said polypeptide is:

wherein Y is N(a) decanoyl and X is N(e) decanoyl.

45. The self-propelled therapeutic aerosol suspension of claim 12 wherein said polypeptide is:

46. The self-propelled therapeutic aerosol suspension of claim 12 wherein said polypeptide is:

47. A method for the treatment of a patient suffering from diseases of hyperparathyroidism, idiopathic hypercalcemia of infancy, Paget's disease, vitamin D intoxication, or osteolytic bone metastases, said diseases characterized by hypercalcemia and high phosphate concentrations in the blood of said patient comprising: administering to said patient in need of such treatment to effect control of at least one of said diseases an effective amount of the composition of claim 12.

48. A method of making a self-propelled aerosol suspension for inhalation comprising the steps of:

dissolving a solid active drug and a solid pharmaceutically acceptable extender in an aqueous solution;
lyophilizing said solution to form a solid, homogeneous complex of said drug and said extender in the form of a powder;

comminuting said powder to obtain a particle size of which at least 90% has an effective diameter of about 2 to about 10µ;

combining said particles with a small amount of a solvent and/or surfactant: and adding an aerosol propellant mixture thereto consisting of 90% w/w dichlorodifluoromethane and 10% w/w dichlorotetrafluoroethane, or 90% w/w dichloro-difluoromethane and 10% w/w trichlorofluoromethane.