CA2206803A1 - Powder formulations containing melezitose as a diluent - Google Patents
Powder formulations containing melezitose as a diluentInfo
- Publication number
- CA2206803A1 CA2206803A1 CA002206803A CA2206803A CA2206803A1 CA 2206803 A1 CA2206803 A1 CA 2206803A1 CA 002206803 A CA002206803 A CA 002206803A CA 2206803 A CA2206803 A CA 2206803A CA 2206803 A1 CA2206803 A1 CA 2206803A1
- Authority
- CA
- Canada
- Prior art keywords
- powder formulation
- powder
- melezitose
- polypeptide
- enhancer
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Abandoned
Links
Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/0012—Galenical forms characterised by the site of application
- A61K9/007—Pulmonary tract; Aromatherapy
- A61K9/0073—Sprays or powders for inhalation; Aerolised or nebulised preparations generated by other means than thermal energy
- A61K9/0075—Sprays or powders for inhalation; Aerolised or nebulised preparations generated by other means than thermal energy for inhalation via a dry powder inhaler [DPI], e.g. comprising micronized drug mixed with lactose carrier particles
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/56—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids
- A61K31/575—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids substituted in position 17 beta by a chain of three or more carbon atoms, e.g. cholane, cholestane, ergosterol, sitosterol
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K38/00—Medicinal preparations containing peptides
- A61K38/16—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
- A61K38/17—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
- A61K38/22—Hormones
- A61K38/28—Insulins
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K38/00—Medicinal preparations containing peptides
- A61K38/16—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
- A61K38/43—Enzymes; Proenzymes; Derivatives thereof
- A61K38/46—Hydrolases (3)
- A61K38/465—Hydrolases (3) acting on ester bonds (3.1), e.g. lipases, ribonucleases
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
- A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
- A61K47/26—Carbohydrates, e.g. sugar alcohols, amino sugars, nucleic acids, mono-, di- or oligo-saccharides; Derivatives thereof, e.g. polysorbates, sorbitan fatty acid esters or glycyrrhizin
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/0012—Galenical forms characterised by the site of application
- A61K9/007—Pulmonary tract; Aromatherapy
- A61K9/0073—Sprays or powders for inhalation; Aerolised or nebulised preparations generated by other means than thermal energy
- A61K9/008—Sprays or powders for inhalation; Aerolised or nebulised preparations generated by other means than thermal energy comprising drug dissolved or suspended in liquid propellant for inhalation via a pressurized metered dose inhaler [MDI]
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P39/00—General protective or antinoxious agents
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P5/00—Drugs for disorders of the endocrine system
- A61P5/48—Drugs for disorders of the endocrine system of the pancreatic hormones
- A61P5/50—Drugs for disorders of the endocrine system of the pancreatic hormones for increasing or potentiating the activity of insulin
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
- A61K9/141—Intimate drug-carrier mixtures characterised by the carrier, e.g. ordered mixtures, adsorbates, solid solutions, eutectica, co-dried, co-solubilised, co-kneaded, co-milled, co-ground products, co-precipitates, co-evaporates, co-extrudates, co-melts; Drug nanoparticles with adsorbed surface modifiers
- A61K9/145—Intimate drug-carrier mixtures characterised by the carrier, e.g. ordered mixtures, adsorbates, solid solutions, eutectica, co-dried, co-solubilised, co-kneaded, co-milled, co-ground products, co-precipitates, co-evaporates, co-extrudates, co-melts; Drug nanoparticles with adsorbed surface modifiers with organic compounds
Abstract
A powder formulation for the administration of medically useful polypeptides, comprising a medically useful polypeptide with melezitose as diluent.
Description
r Powder formulations containing melezitose as a diluent Field of the invention The present invention relates to powder formulations cont~ining mPrlir~lly useful s polypeptides.
Technic~l back~round Polypeptide powders Cont~ining m~Aic~lly useful polypeptides and ph~rrn~reutic~lly acceptable carriers or ~liluentc may be prepared for ~rlmini.~tration by inhalation or o otherwise. Inhalable polypeptide powder preparations have been described in WO95/00127 and W095/00128.
Diluents are cornmonplace in ph~ ceutit~l p~ tions, especi~lly in formulations for inh~l~tion. They are used to stabilise various drugs during m~n-.r~ .t and storage and to adjust the a-m--ount of powder m~kin~ up unit doses - in general, powder inh~lP~ are capable of delivering a drug ~ubsL~ce with good dose accuracy only for certain dose sizes, while dirre~c.1t drugs have different potencies and must therefore be delivered in dirre~ t amounts. As these amounts are often too small for proper dose accuracy to be ensured, diluents are added to give the desired dose size.
Previously, reducing sugars such as lactose and glucose have been used as ~ çn~ in polypeptide powder formulations. These however have a tendency to react with polypeptides and are therefore llnc~ti~factory.
~5 It is suggested in W095/00127 and W095/00128, relating to polypeptide powders for inh~ tion, that non-reducing sugars such as raffinose, melezitose, lactitol, maltitol, trehalose, sucrose, m~nnitol and starch may be preferred additives for the polypeptide powders.
It has now been found that melezitose is an exceptionally good diluent colllp~cd with other possible non-reducing sugar diluents for polypeptide powder formulations, giving an unexpectedly high respirable fraction of powder when inhaled.
Surnrnarv of the invention Accordingly, the present invention provides a powder formulation for the a~lmini~tration of m~rli~lly useful polypeptides, compricin~ a m~ lly useful polypeptide with mç1ezitQse as diluent.
~-lmini~tratjon is preferably by inhalation.
The .-~k~ Qse may comprise for exarnple D~ .7;~0~ x-D-mPle7.itose), ~-~
gluco~y~ osi-l~, ~a-D- gluco~ldnosyl-l,3-~-D-fructofuranosyl (~-D-m~1e7.i~ose) or 15 i~ol~ .;lusc. The mel~z.itose may be for exarnple in the fonn of the mono~d~ or dihydrate.
The powder forrnulation of the present invention has b~en found to be very effective upon oral inhalation, giving a superior fraction of respirable particles compared u ith powder 20 formulations with other diluents, as is described herein. As a result, a higher fraction of the inhaled powder will reach the lungs and a higher fraction of the polypeptide is nti1i~e~1 The powder formulation of the present invention is also suitable for use in nasal inhalation.
25 The powder formulation of the present invention is suitable for both systerruc and local treatment. When local action is desired in the respiratory tract, no other ingredient is necesS~ry in the powder formulation. When systemic action is required, an enh~ncer, i.e. a substance which enhances the absorption of the polypeptide in the respiratory tract, should generally be included in the formulation. Such substances are included in W095/00127 30 and W095/00l28, incorporated herein by reference. In certain cases, small polypeptides are absorbed in the respiratory tract without the aid of an enhancer. In these cases an W O 96/19207 PCT/SE9S/OlS41 enh~ncer may be excluded from the formulations of mele7itose and the medically useful polypephde. In different embotlimPrlt~ therefore the present invention provides a powder comprising a medically useful polypeptide and melezitose; a powder comprising a m.o-liç~lly useful polypeptide and melezitose and specifically including an er h~n~er; and a s powder comprising a medically useful polypeptide and melezitose, specifically excluding an ~nh~nrer. The powder according to the present invention excluding an enh~ncer~ is most useful (a) when local action of the polypeptide is desired; or (b) when systemic action of smaller polypeptides which are absorbed in the re~.~hd~o,y tract without the aid of an enhancer is desired. Polypeptides which are absorbed in the le;~ aloly tract without the aid o of an enh~ncer may be identified using conventional cell or, preferably, animal models, in the latter case by co-~lp~ g plasma polypeptide levels following ~Aministration7 for example by means of a Wright Dust Feed a~aldLus, of powders with and without çnh~n~r. The ~wd~r spe~ifi~ ~lly incl~ in~ an çnh~n~çr acc~ g to the present invention, is most useful when systemic action of polypeptides which are not abso,l,cd in the l~s~ tol~ tract without the aid of an Pnh~nrPr, is desired.
Preferred enh~n~ ers include C8 l6 fatty acids and salts thereof, bile salts, phospholipids and aLkyl sacch~ri~les Of the fatty acids and salts thereof, Cg-CI6 fatty acids salts are preferred. Examples of preferred fatty acid salts are sodium, potassium and Iysine salts of caprylate (Cg), caprate (C10), laurate (C~2) and myristate (Cl4). As the nature of the counterion is not of special signifi~nce, any of the salts of the fatty acids are potentially useful. A particularly ~-~fel.cd fatty acid salt is sodium caprate.
~5 ~ Suitable bile salts may be for example salts of cholic acid, chenodeoxycholic acid, glycocholic acid, taurocholic acid, glycochenodeoxycholic acid, taurochenodeoxycholic acid, deoxycholic acid, glycodeoxycholic acid, taurodeoxycholic acid, lithocholic acid, and ursodeoxycholic acid.
Of the bile salts, trihydroxy bile salts are preferred. More preferred are the salts of cholic, glycocholic and taurocholic acids, especially the sodium and potassium salts thereof. The most preferred bile salt is sodium taurocholate.
s Suitable phospholipids may be for example single-chain phospholipids, for example lysophosphatidylchc-linPc, lysophosph~ti~lylglycerols, lysophosphatidyleth~nt~l~min~c, lysophosphatidylinositols and lysophosphatidylserines or double-chain phospholipids, for example diacylphosphatidylcholines, diacylphosphatidylglycerols, diacylphosphatidylethanol~minPs, diacylphosphatidylinositols and o diacylphosphatidylserines.
Of the phospholipids, diacylphosphatidylglycerols and diacylphosphatidylcholines are d, for example dioctan~lphosphaLidylglycerol and dioctanoylphosph~ti-lylcholine.
IS Suitable aLkyl s~qcc-h~ri(les may be for e~mple aLkyl glucosides or alkyl m~ltosi~les, such as decyl glllcoci~le and dodecyl m~lt~ e, The most preferred enhancers are bile salts.
The polypeptide may be any medically or diagnostically useful peptide or protein of small to mPtlillm size, i.e. up to about 40 kD molecular weight (MW). It is expected that polypeptides having a molecular weight of up to 30 kD will be most useful in the present invention, such as polypeptides having a molecular weight of up to 25 kD or up to 20 kD, and especially up to 15 kD, up to lOkD, or up to 5 kD.
The polypeptide is preferably a peptide hormone such as insulin, glucagon, C-peptide of insulin, vasopressin, desmopressin, corticotropin (ACTH), corticotropin releasing hormone (CRH), gonadotropin releasing horrnone (GnRH), gonadotropin releasing hormone agonists and antagonists, gonadotrophin (luteinizing hormone, or LHRH), calcitonin, parathyroid hormone (PTH)~ bioactive fragments of PTH such as PTH(34) and PTH(38), growth hormone (GH) (for example human growth hormone (hGH)), growth s hormone rele~cin~ horrnone (GHRH), somatostatin, oxytocin, atrial natriuretic factor (ANF), Ihylot,o~ releasing hormone (TRH), deoxyribonuclease (DNase), prolactin, and follicle stim~ ting hormone (FSH), and analogues of any of the above.
Other possible polypeptides include growth factors, interleukin~, polypeptide vaccines, enzymes, endorphins, glycoproteins, liL)~pl-)teins, and polypeptides involved in the blood coagulation c~cc~le.
The preferred polypeptide is insulin.
In the powder form~ tion of the present invention melezitose may be present in an amount of up to almost 100% by weight of the total powder. For example the mele7.itQse may be present in an arnount bet~. _cn 20% and almost 100%, for e~cample ~L.. ~n 30% and almost 100% or be~ 40% and almost 100%, or '~l-.~n 50% and almost 100%, e.g lS between 60% and almost 100%, or between 65% and alrnost 100%, such as l~l~. ~n 65%
and 99% or bet~ around 70% and around 99% such as bel~ 80% and 98% by weight of the total weight of powder.
As with all pharmaceutical preparations, certain additives, for exarnple for pH regulation, for example organic or inorganic salts, to give taste, or to increase stability, for example preservatives, carbohydrates, amino acids, peptides and proteins, may also be included in the formulation.
When the powder ~ pa.~lion of the present invention is inten-lçd for oral inhalation the 2s polypeptide should consist of (a) primary particles having a ~ m~-ter of less than about 10 microns, for exarnple between 0.01 and 10 rnicrons and preferably between 0.1 and 6 microns, for example between 0.01 and 5 micons, or (b) agglomerates of said particles.
Preferably at least 50% of the polypeptide consists of particles witnin the desired size range. For example at least 60%, preferably at least 70%, more preferably at least 80% and ~ 30 most preferably at least 90% of the polypeptide consists of particles within the desired size range, when oral inhalation is desired.
W 096/19207 PCT/SE9S/OlS41 The melezitose in the form~ tion for oral inhalation may largely consist of particles having a mPtPr of less than about 10 microns so that the resultant powder as a whole consists of optionally agglom~ratPA primary particles having a ~ mPter of less than about 10 microns;
s ~l~ern~tively the mPlç7itose may largely consist of much bigger particles ("coarse particles"), so that an "ordered mL~ture" may be formed b~l~..~n the active compounds and them~l~7itose. In the ordered mixture, ~ltçr.-~tively known as an interactive or adhesive mixture, the polypeptide particles will be fairly evenly distributed over the surf~ of the coarse ...clo~i~ose Preferably in such case the active compounds are not in the form of agglomerates ~o prior to formation of the ordered ~ lu~G. The coarse particles may have a ~ mPter of over 20 microns, such as over 60 microns. Above these lower limits, the ~ mPtçr of the coarse particles is not of critical im~ol ~nce so various coarse particle sizes may be used, if desired accol~ling to the practical ~G~Uil~ S of the particular fonnlll_tion There is no l~UilG~.lt for the coarse particles in the ordered mixture to be of the same size, but the coarse particles IS may advantageously be of similar size within the ordered ll~L~ Gfc.~ly, the coarse particles have a ~ ,. .t~ .l of 60 - 800 c~s.
The particle size is less important in nasal inhalation although small par~icles are desirable.
An ordered mixture would not normally be employed in nasal inhalation.
A useful mP~h~-nicm for delivery of the powder into the respiratory tract of a patient is through a portable inhaler device suitable for dry powder inhalation. Many such devices, typically designed to deliver ~nti~cthm~tic or ~ntiinfl~mmi tory agents into the l~;tlJllal~lly system, are on the market.
2s The described powder preparation can be m~nl-f~rtured in several ways, using con~entional techniques. Particles in a required size range may be obtained by any known method, for example by freeze-drying or by controlled crystallisation methods, for example crystallisation using supercritical fluids; or by rnicronisation methods. For example, one can dry rnix the polypeptide and melezitose (and optional e~h~ncer) powders, and then micronise the substances together; alternatively, the substances can be micronised separately, and then W Og6/19Z07 PCT/S~9S/01541 mixed. Where the colllpounds to be rnixed have dirrel~,nt physical properties such as - hardness and brittlen~ss, recict~n~e to microrlisation varies and they may require ~lirrel~ent pressures to be broken down to suitable particle sizes. When microrused together, therefore, the obtained particle size of one of the col~ or.ents may be llnc~ticf~rtory. In such case it s would be advantageous to micronise the di~erent co~ ents separately and then rnix them.
It is also possible, where an ordered llli~lul~ is not int~nlleA, first to dissolve the components in a suitable solvent, e.g. water, to obtain mixing on the molecular level. This procedure also makes it possible to adjust the pH-value to a desired level. To obtain a powder, the solvent o must be removed by a process which retains the polypeptide's biological activity. Suitadble drying methods include vacuum concentration, open drying, spray drying, and freeze drying.
Telll~dLllres over 40~C for more than a few minutes should generally be avoided, as some degradation of the polypeptide may occur. Following the dIying step, the solid m~t~.ri~l can, if n~cs~ry~ be ground to obtain a coarse ~w~el~ then, if ~ cs~- ~, rnicronised IS
If desired, the powder can be ~ C~ to imE~rove the flow ~JlU~.Lies, e.g., by drygranulation to form sph~rir~1 ~gglo.~ S with superior h~nrlling ~ CI~' ;CI irc, before it is incorporated into thè int~n~le-l inhaler device. In such a case, the device would be configured to ensure that the agglomerates are subst~nfi~lly deagglomerated prior to exiting the device, SO that the particles çnt~ring the respiratory tract of the patient are largely within the desired slze range.
Where an ordered mixture is desired, the active compound may be processed, for example by micronisation, in order to obtain, if desired, particles within a particular size range. The melezitose may also be processed, for exarnple to obtain a desired size and desirable surface pro~eLLies, such as a particular surface to weight ratio, or a certain nlgg~rlnçs~, and to ensure optimal adhesion forces in the ordered mixture. Such physical requirements of an ordered mixture are well known, as are the various means of obtaining an ordered rnixture which fulfills the said requirements, and may be determined easily by the skilled person accoldillg to the particular circumct~nl~es.
W O 96/19207 PCTtSE9S/OlS41 The powders of the present invention are useful for the local or systemic tre~tm~nt of ~licç~cec and may be ~mini.~tered for example via the upper and lower respiratory tract, including by the nasal route. As such the present invention also provides said powder for use in therapy;
the use of the powder in the m~nnfartl-re of a medicarnent for the tre~tmP~t of dice~ces via the respiratory tract; and a method for the treatm~nt of a patient in need of therapy, comprising ~tlminictçrin~ to said patient a therapeutir~lly effective amount of the powder of the present invention.
The tlice~ces which may be treated with the powder of the present invention are any of lO those which may be treated with the particular polypeptide in each case; for example powders cont~ining insulin according to the present invention may be used for example in the treatment of diabetes; powders cont~ining corticotropin may be used for example in the of infl~mm~tory ~l;c~es; powders cont~inin~ GnRH ~ay be useful for ~x~r~
in the [~ P.nt of male infertility. The in-lic~tiQns for all of the m~ntion~d polypeptides 15 are well known. The powders of the present invention may also be used in prophylactic Although the powders of the present invention are particularly directed to polypeptide powders for inhalation from dry powder inhaler devices, the polypeptide powders may also 20 be included in compositions for other forms of ~tlmini~tration, for example in injection solutions and aerosol form~ tions.
The respirable fraction upon oral inhalation of the powders of the present invention may be determinecl by the method described in the Examples herein.
Certain embo lim.~.r~tc of the invention are illustrated in the following Examples, which are not to be considered limitin~:
Example 1 30 Insulin (O.~ig) was dissolved in distilled water (50 ml). Diluent ( 14.4g) was added and dissolved and the pH was adjusted to 7.4. The obtained solid cake was crushed, sieved, and W O 96/19207 PCTISE9S/OlS41 rnicronised in a jet rnill. The rnicronised powders were agglomerated and filled into a Turbuhaler ~ dry powder inhaler and the dose was released at an air flow rate of 60 I~min, under varying conditions.
s The released dose was collected using a multi-stage impinger; the content of insulin in each stage of the impinger was det~minto-d using liquid chromatography with detection at 235 nm. The results were as follows.
fraction of 30%RH, 75%RH, 30%RH, particles of size 60 L/min 60 Ilmin 60 L~rnin, less than 6.8 llm, open moisture % provocation**
Diluent myo-ino~itol 52 18 3 m~ltitol 66 1O 8 m~nnitol 65 17 9 trehalose 58 22 17 raffinose 40 17 p~l~tinite 30 18 15 stachyose 52 5 mlole7itQse 73 3 32 o ** the preparation had been moisture provocated for three days in open plates.
It is clearly seen that melezitose gave the highest fraction of respirable particles in all cases.
Moreover the respirable fraction is not as dependent on external factors when melezitose is the diluent.
Example 2 Insulin (12 parts) was dissolved in .li~till~l water. Sodium taurocholate (enhancer, 4 parts) was added. Various diluents (84 parts) were added and dissolved and the pH was adjusted to 7.4. The solution was concentrated by evaporation of the water. The obtained solid s cake was crushed, sieved, and micronised in a jet mill.. The micronised powder was agglomerated and filled into a Turbuhaler ~ dry powder inhaler and the dose was released at an air flow rate of 60 I~rnin, under varying conditions.
The released dose was collected using a multi-stage impinger; the content of insulin in each o stage of the impinger was (ieterrnin~d using liquid chromatography with detection at 235 nrn. The results were as follows.
Fraction of particles of 30% RH 90% RH
size less than 6.8 ~m, % 60 L/min 60 Ilmin ,llrl~7;l~se 65.0 21.7 trehalose 60.5 6.3 myo-inositol 71.6 10.9 mannitol 79.4 4.4 maltitol 44.7 0.1 These results show that the fnnnul~tion with melezitose is much less affected by high hllmi~ity in the air.
Example 3 Micronised formulations containing DNase, surfactant (sodium taurocholate or dioctanoylphosphatidylglcerol), and melezitose (ratio DNase: surfactant: melezitose 1:
0.33: 98.67, total weight 50 mg), were added to propellant 134a or propellant 227 (approximately 10 ml) in a plastic coated glass bottle. The formulations were mixed with an ultra turrax for approximately 10 minutes.
Identical formulations were prepared to which 5% of ethanol prior to the mixing with an ultraturrax apparatus for approximately 10 minutes.
s The quality of the sl-cpencions forrned were ~csçcsed imm~ t~ly and after 20 hours. In all cases good suspensions were observed.
This shows that the m~le~itose-cont~inin~ forrnulations of the present invention are suitable for use in for-m--ulations other than for dry-powder inhalation, in this case in aerosol o formulations.
Technic~l back~round Polypeptide powders Cont~ining m~Aic~lly useful polypeptides and ph~rrn~reutic~lly acceptable carriers or ~liluentc may be prepared for ~rlmini.~tration by inhalation or o otherwise. Inhalable polypeptide powder preparations have been described in WO95/00127 and W095/00128.
Diluents are cornmonplace in ph~ ceutit~l p~ tions, especi~lly in formulations for inh~l~tion. They are used to stabilise various drugs during m~n-.r~ .t and storage and to adjust the a-m--ount of powder m~kin~ up unit doses - in general, powder inh~lP~ are capable of delivering a drug ~ubsL~ce with good dose accuracy only for certain dose sizes, while dirre~c.1t drugs have different potencies and must therefore be delivered in dirre~ t amounts. As these amounts are often too small for proper dose accuracy to be ensured, diluents are added to give the desired dose size.
Previously, reducing sugars such as lactose and glucose have been used as ~ çn~ in polypeptide powder formulations. These however have a tendency to react with polypeptides and are therefore llnc~ti~factory.
~5 It is suggested in W095/00127 and W095/00128, relating to polypeptide powders for inh~ tion, that non-reducing sugars such as raffinose, melezitose, lactitol, maltitol, trehalose, sucrose, m~nnitol and starch may be preferred additives for the polypeptide powders.
It has now been found that melezitose is an exceptionally good diluent colllp~cd with other possible non-reducing sugar diluents for polypeptide powder formulations, giving an unexpectedly high respirable fraction of powder when inhaled.
Surnrnarv of the invention Accordingly, the present invention provides a powder formulation for the a~lmini~tration of m~rli~lly useful polypeptides, compricin~ a m~ lly useful polypeptide with mç1ezitQse as diluent.
~-lmini~tratjon is preferably by inhalation.
The .-~k~ Qse may comprise for exarnple D~ .7;~0~ x-D-mPle7.itose), ~-~
gluco~y~ osi-l~, ~a-D- gluco~ldnosyl-l,3-~-D-fructofuranosyl (~-D-m~1e7.i~ose) or 15 i~ol~ .;lusc. The mel~z.itose may be for exarnple in the fonn of the mono~d~ or dihydrate.
The powder forrnulation of the present invention has b~en found to be very effective upon oral inhalation, giving a superior fraction of respirable particles compared u ith powder 20 formulations with other diluents, as is described herein. As a result, a higher fraction of the inhaled powder will reach the lungs and a higher fraction of the polypeptide is nti1i~e~1 The powder formulation of the present invention is also suitable for use in nasal inhalation.
25 The powder formulation of the present invention is suitable for both systerruc and local treatment. When local action is desired in the respiratory tract, no other ingredient is necesS~ry in the powder formulation. When systemic action is required, an enh~ncer, i.e. a substance which enhances the absorption of the polypeptide in the respiratory tract, should generally be included in the formulation. Such substances are included in W095/00127 30 and W095/00l28, incorporated herein by reference. In certain cases, small polypeptides are absorbed in the respiratory tract without the aid of an enhancer. In these cases an W O 96/19207 PCT/SE9S/OlS41 enh~ncer may be excluded from the formulations of mele7itose and the medically useful polypephde. In different embotlimPrlt~ therefore the present invention provides a powder comprising a medically useful polypeptide and melezitose; a powder comprising a m.o-liç~lly useful polypeptide and melezitose and specifically including an er h~n~er; and a s powder comprising a medically useful polypeptide and melezitose, specifically excluding an ~nh~nrer. The powder according to the present invention excluding an enh~ncer~ is most useful (a) when local action of the polypeptide is desired; or (b) when systemic action of smaller polypeptides which are absorbed in the re~.~hd~o,y tract without the aid of an enhancer is desired. Polypeptides which are absorbed in the le;~ aloly tract without the aid o of an enh~ncer may be identified using conventional cell or, preferably, animal models, in the latter case by co-~lp~ g plasma polypeptide levels following ~Aministration7 for example by means of a Wright Dust Feed a~aldLus, of powders with and without çnh~n~r. The ~wd~r spe~ifi~ ~lly incl~ in~ an çnh~n~çr acc~ g to the present invention, is most useful when systemic action of polypeptides which are not abso,l,cd in the l~s~ tol~ tract without the aid of an Pnh~nrPr, is desired.
Preferred enh~n~ ers include C8 l6 fatty acids and salts thereof, bile salts, phospholipids and aLkyl sacch~ri~les Of the fatty acids and salts thereof, Cg-CI6 fatty acids salts are preferred. Examples of preferred fatty acid salts are sodium, potassium and Iysine salts of caprylate (Cg), caprate (C10), laurate (C~2) and myristate (Cl4). As the nature of the counterion is not of special signifi~nce, any of the salts of the fatty acids are potentially useful. A particularly ~-~fel.cd fatty acid salt is sodium caprate.
~5 ~ Suitable bile salts may be for example salts of cholic acid, chenodeoxycholic acid, glycocholic acid, taurocholic acid, glycochenodeoxycholic acid, taurochenodeoxycholic acid, deoxycholic acid, glycodeoxycholic acid, taurodeoxycholic acid, lithocholic acid, and ursodeoxycholic acid.
Of the bile salts, trihydroxy bile salts are preferred. More preferred are the salts of cholic, glycocholic and taurocholic acids, especially the sodium and potassium salts thereof. The most preferred bile salt is sodium taurocholate.
s Suitable phospholipids may be for example single-chain phospholipids, for example lysophosphatidylchc-linPc, lysophosph~ti~lylglycerols, lysophosphatidyleth~nt~l~min~c, lysophosphatidylinositols and lysophosphatidylserines or double-chain phospholipids, for example diacylphosphatidylcholines, diacylphosphatidylglycerols, diacylphosphatidylethanol~minPs, diacylphosphatidylinositols and o diacylphosphatidylserines.
Of the phospholipids, diacylphosphatidylglycerols and diacylphosphatidylcholines are d, for example dioctan~lphosphaLidylglycerol and dioctanoylphosph~ti-lylcholine.
IS Suitable aLkyl s~qcc-h~ri(les may be for e~mple aLkyl glucosides or alkyl m~ltosi~les, such as decyl glllcoci~le and dodecyl m~lt~ e, The most preferred enhancers are bile salts.
The polypeptide may be any medically or diagnostically useful peptide or protein of small to mPtlillm size, i.e. up to about 40 kD molecular weight (MW). It is expected that polypeptides having a molecular weight of up to 30 kD will be most useful in the present invention, such as polypeptides having a molecular weight of up to 25 kD or up to 20 kD, and especially up to 15 kD, up to lOkD, or up to 5 kD.
The polypeptide is preferably a peptide hormone such as insulin, glucagon, C-peptide of insulin, vasopressin, desmopressin, corticotropin (ACTH), corticotropin releasing hormone (CRH), gonadotropin releasing horrnone (GnRH), gonadotropin releasing hormone agonists and antagonists, gonadotrophin (luteinizing hormone, or LHRH), calcitonin, parathyroid hormone (PTH)~ bioactive fragments of PTH such as PTH(34) and PTH(38), growth hormone (GH) (for example human growth hormone (hGH)), growth s hormone rele~cin~ horrnone (GHRH), somatostatin, oxytocin, atrial natriuretic factor (ANF), Ihylot,o~ releasing hormone (TRH), deoxyribonuclease (DNase), prolactin, and follicle stim~ ting hormone (FSH), and analogues of any of the above.
Other possible polypeptides include growth factors, interleukin~, polypeptide vaccines, enzymes, endorphins, glycoproteins, liL)~pl-)teins, and polypeptides involved in the blood coagulation c~cc~le.
The preferred polypeptide is insulin.
In the powder form~ tion of the present invention melezitose may be present in an amount of up to almost 100% by weight of the total powder. For example the mele7.itQse may be present in an arnount bet~. _cn 20% and almost 100%, for e~cample ~L.. ~n 30% and almost 100% or be~ 40% and almost 100%, or '~l-.~n 50% and almost 100%, e.g lS between 60% and almost 100%, or between 65% and alrnost 100%, such as l~l~. ~n 65%
and 99% or bet~ around 70% and around 99% such as bel~ 80% and 98% by weight of the total weight of powder.
As with all pharmaceutical preparations, certain additives, for exarnple for pH regulation, for example organic or inorganic salts, to give taste, or to increase stability, for example preservatives, carbohydrates, amino acids, peptides and proteins, may also be included in the formulation.
When the powder ~ pa.~lion of the present invention is inten-lçd for oral inhalation the 2s polypeptide should consist of (a) primary particles having a ~ m~-ter of less than about 10 microns, for exarnple between 0.01 and 10 rnicrons and preferably between 0.1 and 6 microns, for example between 0.01 and 5 micons, or (b) agglomerates of said particles.
Preferably at least 50% of the polypeptide consists of particles witnin the desired size range. For example at least 60%, preferably at least 70%, more preferably at least 80% and ~ 30 most preferably at least 90% of the polypeptide consists of particles within the desired size range, when oral inhalation is desired.
W 096/19207 PCT/SE9S/OlS41 The melezitose in the form~ tion for oral inhalation may largely consist of particles having a mPtPr of less than about 10 microns so that the resultant powder as a whole consists of optionally agglom~ratPA primary particles having a ~ mPter of less than about 10 microns;
s ~l~ern~tively the mPlç7itose may largely consist of much bigger particles ("coarse particles"), so that an "ordered mL~ture" may be formed b~l~..~n the active compounds and them~l~7itose. In the ordered mixture, ~ltçr.-~tively known as an interactive or adhesive mixture, the polypeptide particles will be fairly evenly distributed over the surf~ of the coarse ...clo~i~ose Preferably in such case the active compounds are not in the form of agglomerates ~o prior to formation of the ordered ~ lu~G. The coarse particles may have a ~ mPter of over 20 microns, such as over 60 microns. Above these lower limits, the ~ mPtçr of the coarse particles is not of critical im~ol ~nce so various coarse particle sizes may be used, if desired accol~ling to the practical ~G~Uil~ S of the particular fonnlll_tion There is no l~UilG~.lt for the coarse particles in the ordered mixture to be of the same size, but the coarse particles IS may advantageously be of similar size within the ordered ll~L~ Gfc.~ly, the coarse particles have a ~ ,. .t~ .l of 60 - 800 c~s.
The particle size is less important in nasal inhalation although small par~icles are desirable.
An ordered mixture would not normally be employed in nasal inhalation.
A useful mP~h~-nicm for delivery of the powder into the respiratory tract of a patient is through a portable inhaler device suitable for dry powder inhalation. Many such devices, typically designed to deliver ~nti~cthm~tic or ~ntiinfl~mmi tory agents into the l~;tlJllal~lly system, are on the market.
2s The described powder preparation can be m~nl-f~rtured in several ways, using con~entional techniques. Particles in a required size range may be obtained by any known method, for example by freeze-drying or by controlled crystallisation methods, for example crystallisation using supercritical fluids; or by rnicronisation methods. For example, one can dry rnix the polypeptide and melezitose (and optional e~h~ncer) powders, and then micronise the substances together; alternatively, the substances can be micronised separately, and then W Og6/19Z07 PCT/S~9S/01541 mixed. Where the colllpounds to be rnixed have dirrel~,nt physical properties such as - hardness and brittlen~ss, recict~n~e to microrlisation varies and they may require ~lirrel~ent pressures to be broken down to suitable particle sizes. When microrused together, therefore, the obtained particle size of one of the col~ or.ents may be llnc~ticf~rtory. In such case it s would be advantageous to micronise the di~erent co~ ents separately and then rnix them.
It is also possible, where an ordered llli~lul~ is not int~nlleA, first to dissolve the components in a suitable solvent, e.g. water, to obtain mixing on the molecular level. This procedure also makes it possible to adjust the pH-value to a desired level. To obtain a powder, the solvent o must be removed by a process which retains the polypeptide's biological activity. Suitadble drying methods include vacuum concentration, open drying, spray drying, and freeze drying.
Telll~dLllres over 40~C for more than a few minutes should generally be avoided, as some degradation of the polypeptide may occur. Following the dIying step, the solid m~t~.ri~l can, if n~cs~ry~ be ground to obtain a coarse ~w~el~ then, if ~ cs~- ~, rnicronised IS
If desired, the powder can be ~ C~ to imE~rove the flow ~JlU~.Lies, e.g., by drygranulation to form sph~rir~1 ~gglo.~ S with superior h~nrlling ~ CI~' ;CI irc, before it is incorporated into thè int~n~le-l inhaler device. In such a case, the device would be configured to ensure that the agglomerates are subst~nfi~lly deagglomerated prior to exiting the device, SO that the particles çnt~ring the respiratory tract of the patient are largely within the desired slze range.
Where an ordered mixture is desired, the active compound may be processed, for example by micronisation, in order to obtain, if desired, particles within a particular size range. The melezitose may also be processed, for exarnple to obtain a desired size and desirable surface pro~eLLies, such as a particular surface to weight ratio, or a certain nlgg~rlnçs~, and to ensure optimal adhesion forces in the ordered mixture. Such physical requirements of an ordered mixture are well known, as are the various means of obtaining an ordered rnixture which fulfills the said requirements, and may be determined easily by the skilled person accoldillg to the particular circumct~nl~es.
W O 96/19207 PCTtSE9S/OlS41 The powders of the present invention are useful for the local or systemic tre~tm~nt of ~licç~cec and may be ~mini.~tered for example via the upper and lower respiratory tract, including by the nasal route. As such the present invention also provides said powder for use in therapy;
the use of the powder in the m~nnfartl-re of a medicarnent for the tre~tmP~t of dice~ces via the respiratory tract; and a method for the treatm~nt of a patient in need of therapy, comprising ~tlminictçrin~ to said patient a therapeutir~lly effective amount of the powder of the present invention.
The tlice~ces which may be treated with the powder of the present invention are any of lO those which may be treated with the particular polypeptide in each case; for example powders cont~ining insulin according to the present invention may be used for example in the treatment of diabetes; powders cont~ining corticotropin may be used for example in the of infl~mm~tory ~l;c~es; powders cont~inin~ GnRH ~ay be useful for ~x~r~
in the [~ P.nt of male infertility. The in-lic~tiQns for all of the m~ntion~d polypeptides 15 are well known. The powders of the present invention may also be used in prophylactic Although the powders of the present invention are particularly directed to polypeptide powders for inhalation from dry powder inhaler devices, the polypeptide powders may also 20 be included in compositions for other forms of ~tlmini~tration, for example in injection solutions and aerosol form~ tions.
The respirable fraction upon oral inhalation of the powders of the present invention may be determinecl by the method described in the Examples herein.
Certain embo lim.~.r~tc of the invention are illustrated in the following Examples, which are not to be considered limitin~:
Example 1 30 Insulin (O.~ig) was dissolved in distilled water (50 ml). Diluent ( 14.4g) was added and dissolved and the pH was adjusted to 7.4. The obtained solid cake was crushed, sieved, and W O 96/19207 PCTISE9S/OlS41 rnicronised in a jet rnill. The rnicronised powders were agglomerated and filled into a Turbuhaler ~ dry powder inhaler and the dose was released at an air flow rate of 60 I~min, under varying conditions.
s The released dose was collected using a multi-stage impinger; the content of insulin in each stage of the impinger was det~minto-d using liquid chromatography with detection at 235 nm. The results were as follows.
fraction of 30%RH, 75%RH, 30%RH, particles of size 60 L/min 60 Ilmin 60 L~rnin, less than 6.8 llm, open moisture % provocation**
Diluent myo-ino~itol 52 18 3 m~ltitol 66 1O 8 m~nnitol 65 17 9 trehalose 58 22 17 raffinose 40 17 p~l~tinite 30 18 15 stachyose 52 5 mlole7itQse 73 3 32 o ** the preparation had been moisture provocated for three days in open plates.
It is clearly seen that melezitose gave the highest fraction of respirable particles in all cases.
Moreover the respirable fraction is not as dependent on external factors when melezitose is the diluent.
Example 2 Insulin (12 parts) was dissolved in .li~till~l water. Sodium taurocholate (enhancer, 4 parts) was added. Various diluents (84 parts) were added and dissolved and the pH was adjusted to 7.4. The solution was concentrated by evaporation of the water. The obtained solid s cake was crushed, sieved, and micronised in a jet mill.. The micronised powder was agglomerated and filled into a Turbuhaler ~ dry powder inhaler and the dose was released at an air flow rate of 60 I~rnin, under varying conditions.
The released dose was collected using a multi-stage impinger; the content of insulin in each o stage of the impinger was (ieterrnin~d using liquid chromatography with detection at 235 nrn. The results were as follows.
Fraction of particles of 30% RH 90% RH
size less than 6.8 ~m, % 60 L/min 60 Ilmin ,llrl~7;l~se 65.0 21.7 trehalose 60.5 6.3 myo-inositol 71.6 10.9 mannitol 79.4 4.4 maltitol 44.7 0.1 These results show that the fnnnul~tion with melezitose is much less affected by high hllmi~ity in the air.
Example 3 Micronised formulations containing DNase, surfactant (sodium taurocholate or dioctanoylphosphatidylglcerol), and melezitose (ratio DNase: surfactant: melezitose 1:
0.33: 98.67, total weight 50 mg), were added to propellant 134a or propellant 227 (approximately 10 ml) in a plastic coated glass bottle. The formulations were mixed with an ultra turrax for approximately 10 minutes.
Identical formulations were prepared to which 5% of ethanol prior to the mixing with an ultraturrax apparatus for approximately 10 minutes.
s The quality of the sl-cpencions forrned were ~csçcsed imm~ t~ly and after 20 hours. In all cases good suspensions were observed.
This shows that the m~le~itose-cont~inin~ forrnulations of the present invention are suitable for use in for-m--ulations other than for dry-powder inhalation, in this case in aerosol o formulations.
Claims (53)
1. A powder formulation for the administration of medically useful polypeptides,comprising a medically useful polypeptide with melezitose as diluent.
2. A powder formulation as claimed in claim 1, wherein the melezitose comprises D-melezitose (.alpha.-D-melezitose), .beta.-D-glucopyranoside, O-.alpha.-D- glucopyranosyl-1,3-.beta.-D-fructofuranosyl (.beta.-D-melezitose) or isomelezitose.
3. A powder formulation as claimed in claim 1 or claim 2, wherein the melezitose is in the form of the monohydrate or dihydrate.
4. A powder formulation as claimed in any of claims 1-3, wherein the formulationincludes an enhancer which enhances the absorption of the medically useful polypeptide in the lower respiratory tract.
5. A powder formulation as claimed in claim 4, wherein the enhancer is selected from C8-16 fatty acids and salts thereof, bile salts, phospholipids and alkyl saccharides.
6. A powder formulation as claimed in claim 4, wherein the enhancer is selected from the sodium, potassium and lysine salts of caprylate (C8), caprate (C10), laurate (C12) and myristate (C14).
7. A powder formulation as claimed in claim 4, wherein the enhancer is selected from bile salts selected from salts of cholic acid, chenodeoxycholic acid, glycocholic acid, taurocholic acid, glycochenodeoxycholic acid, taurochenodeoxycholic acid, deoxycholic acid, glycodeoxycholic acid, taurodeoxycholic acid, lithocholic acid, and ursodeoxycholic acid.
8. A powder formulation as claimed in claim 4, wherein the enhancer is selected from trihydroxy bile salts.
9. A powder formulation as claimed in claim 4, wherein the enhancer is selected from the salts of cholic, glycocholic and taurocholic acids.
10. A powder formulation as claimed in claim 4, wherein the enhancer is selected from the sodium and potassium salts of cholic, glycocholic and taurocholic acids.
11. A powder formulation as claimed in claim 4, wherein the enhancer is sodium taurocholate.
12. A powder formulation as claimed in claim 4, wherein the enhancer is selected from single-chain phospholipids.
13. A powder formulation as claimed in claim 4, wherein the enhancer is selected from lysophosphatidylcholines, lysophoshatidylglycerols, lysophosphatidylethanolamines, lysophosphatidylinositols and lysophosphatidylserines.
14. A powder formulation as claimed in claim 4, wherein the enhancer is selected from double-chain phospholipids.
15. A powder formulation as claimed in claim 4, wherein the enhancer is selected from diacylphosphatidylcholines, diacylphosphatidylglycerols, diacylphosphatidylethanolamines, diacylphosphatidylinositols and diacylphosphatidylserines.
16. A powder formulation as claimed in claim 4, wherein the enhancer is selected from dioctanoylphosphatidylglycerol and dioctanoylphosphatidylcholine.
17. A powder formulation as claimed in claim 4, wherein the enhancer is selected from alkyl glucosides or alkyl maltosides, such as decyl glucoside and dodecyl maltoside.
18. A powder formulation as claimed in any of claims 1-17, wherein the polypeptide is selected from insulin, glucagon, C-peptide of insulin, vasopressin, desmopressin, corticotropin (ACTH), corticotropin releasing hormone (CRH), gonadotropin releasing hormone (GnRH), gonadotropin releasing hormone agonists and antagonists, gonadotrophin (luteinizing hormone, or LHRH), calcitonin, parathyroid hormone (PTH), bioactive fragments of PTH such as PTH(34) and PTH(38), growth hormone (GH) (forexample human growth hormone (hGH)), growth hormone releasing hormone (GHRH), somatostatin, oxytocin, atrial natriuretic factor (ANF), thyrotropin releasing hormone (TRH), deoxyribonuclease (DNase), prolactin, and follicle stimulating hormone (FSH), and analogues thereof.
19. A powder formulation as claimed in any of claims 1-18, wherein the polypeptide is of molecular weight (MW) up to about 40 kD.
20. A powder formulation as claimed in claim 19, wherein the polypeptide has a molecular weight of up to 30 kD.
21. A powder formulation as claimed in claim 19, wherein the polypeptide has a molecular weight of up to 25kD.
22. A powder formulation as claimed in claim 19, wherein the polypeptide has a molecular weight of up to 20 kD.
23. A powder formulation as claimed in claim 19, wherein the polypeptide has a molecular weight of up to 15 kD.
24. A powder formulation as claimed in claim 19, wherein the polypeptide has a molecular weight of up to 10 kD.
25. A powder formulation as claimed in claim 19, wherein the polypeptide has a molecular weight of up to 5 kD.
26. A powder formulation as claimed in claim 18, wherein the polypeptide is insulin.
27. A powder formulation as claimed in any preceding claim, wherein the melezitose is present in an amount of between 20% and almost 100% by weight of the powder.
28. A powder formulation as claimed in any claim 27, wherein the melezitose is present in an amount of between 30% and almost 100% by weight of the powder.
29. A powder formulation as claimed in claim 28, wherein the melezitose is present in an amount of between 40% and almost 100% by weight of the powder.
30. A power formulation as claimed in claim 29, wherein melezitose is present in an amount of between 50% and almost 100% by weight of the powder.
31. A powder formulation as claimed in claim 30, wherein the melezitose is present in an amount of between 60% and almost 100% by weight of the powder.
32. A powder formulation as claimed in claim 31, wherein the melezitose is present in an amount of between 65% and almost 100% by weight of the powder.
33. A powder formulation as claimed in claim 32, wherein the melezitose is present in an amount of between 65% and 99% by weight of the powder.
34. A powder formulation as claimed in claim 33, wherein the melezitose is present in an amount of between 70% and 99% by weight of the powder.
35. A powder formulation as claimed in claim 34, wherein the melezitose is present in an amount of between 80% and 98% by weight of the powder.
36. A powder formulation as claimed in any preceding claim, wherein the polypeptide comprises (a) primary particles having a diameter of between 0.01 and 10 microns, or (b) agglomerates of said particles.
37. A powder formulation as claimed in any preceding claim, wherein the polypeptide comprises (a) primary particles having a diameter of between 1 and 6 microns, or (b) agglomerates of said particles.
38. A powder formulation as claimed in claim 35 or 36, wherein at least 50% of the polypeptide consists of particles within the desired size range.
39. A powder formulation as claimed in claim 38, wherein at least 60% of the polypeptide consist of particles within the desired size range.
40. A powder formulation as claimed in claim 39, wherein at least 70% of the polypeptide consists of particles within the desired size range.
41. A powder formulation as claimed in claim 40, wherein at least 80% of the polypeptide consists of particles within the desired size range.
42. A powder formulation as claimed in claim 41, wherein at least 90% of the polypeptide consists of particles within the desired size range.
43. A powder formulation as claimed in any preceding claim, wherein the melezitose consists of particles having a diameter of less than about 10 microns.
44. A powder formulation as claimed in any of claims 1-43, wherein the melezitose consists of coarse particles of diameter over 20 microns.
45. A powder formulation as claimed in claim 44, wherein the melezitose consists of coarse particles having a diameter of 60 - 800 microns.
46. A powder formulation as claimed in any of claims 1 - 45, wherein an enhancer is excluded from the formulation.
47. A method for the manufacture of a powder formulation as claimed in any of claims 1-43 and 46, comprising the steps of: dry mixing of the polypeptide and melezitose, and optional enhancer powders; and micronising the substances together.
48. A method for the manufacture of a powder formulation as claimed in any of claims 1-43 and 46, comprising the steps of: micronising the polypeptide and micronising and melezitose, and optional enhancer powders separately; and mixing the micronised powders.
49. A method for the manufacture of a powder formulation as claimed in any of claims 1-43 and 46 comprising the steps of: dissolving the components in a solvent; optionally adjusting the pH-value to a desired level; removing the solvent; drying; and optional micronising of the obtained solid.
50. A method for the manufacture of a powder formulation as claimed in claim 44 or 45, comprising dry mixing melezitose and micronised polypeptide powders.
51. A powder as claimed in any of claims 1-50, for use in therapy.
52. The use of a powder as claimed in any of claims 1-50 in the manufacture of amedicament for the treatment of diseases via the respiratory tract.
53. A method for the treatment of a patient in need of therapy, comprising administering to said patient a therapeutically effective amount of a powder as claimed in any of claims 1-50.
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| SE9404468-2 | 1994-12-22 | ||
| SE9404468A SE9404468D0 (en) | 1994-12-22 | 1994-12-22 | Powder formulations |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CA2206803A1 true CA2206803A1 (en) | 1996-06-27 |
Family
ID=20396435
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CA002206803A Abandoned CA2206803A1 (en) | 1994-12-22 | 1995-12-19 | Powder formulations containing melezitose as a diluent |
Country Status (34)
| Country | Link |
|---|---|
| US (1) | US6004574A (en) |
| EP (2) | EP0799030B1 (en) |
| JP (1) | JPH10510828A (en) |
| KR (1) | KR100391873B1 (en) |
| CN (1) | CN1080114C (en) |
| AR (1) | AR002261A1 (en) |
| AT (2) | ATE220900T1 (en) |
| AU (1) | AU702898B2 (en) |
| BR (1) | BR9510422A (en) |
| CA (1) | CA2206803A1 (en) |
| CZ (1) | CZ288487B6 (en) |
| DE (2) | DE69533294T2 (en) |
| DK (2) | DK1224929T3 (en) |
| EE (1) | EE03381B1 (en) |
| ES (2) | ES2222306T3 (en) |
| FI (1) | FI972654A0 (en) |
| HK (1) | HK1003619A1 (en) |
| HU (1) | HU217975B (en) |
| IL (1) | IL116459A (en) |
| IS (1) | IS1848B (en) |
| MY (1) | MY114211A (en) |
| NO (1) | NO315966B1 (en) |
| NZ (1) | NZ298168A (en) |
| PL (1) | PL183944B1 (en) |
| PT (2) | PT799030E (en) |
| RU (1) | RU2144819C1 (en) |
| SA (1) | SA95160484B1 (en) |
| SE (1) | SE9404468D0 (en) |
| SK (1) | SK283147B6 (en) |
| TR (1) | TR199501632A1 (en) |
| TW (1) | TW474823B (en) |
| UA (1) | UA44757C2 (en) |
| WO (1) | WO1996019207A1 (en) |
| ZA (1) | ZA9510753B (en) |
Families Citing this family (42)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| TW402506B (en) * | 1993-06-24 | 2000-08-21 | Astra Ab | Therapeutic preparation for inhalation |
| US5830853A (en) | 1994-06-23 | 1998-11-03 | Astra Aktiebolag | Systemic administration of a therapeutic preparation |
| US6794357B1 (en) * | 1993-06-24 | 2004-09-21 | Astrazeneca Ab | Compositions for inhalation |
| US6632456B1 (en) * | 1993-06-24 | 2003-10-14 | Astrazeneca Ab | Compositions for inhalation |
| JP4155594B2 (en) * | 1994-12-22 | 2008-09-24 | アストラゼネカ・アクチエボラーグ | Aerosol formulation |
| US6524557B1 (en) * | 1994-12-22 | 2003-02-25 | Astrazeneca Ab | Aerosol formulations of peptides and proteins |
| US5898028A (en) * | 1997-03-20 | 1999-04-27 | Novo Nordisk A/S | Method for producing powder formulation comprising an insulin |
| US6043214A (en) * | 1997-03-20 | 2000-03-28 | Novo Nordisk A/S | Method for producing powder formulation comprising an insulin |
| JP2001518916A (en) * | 1997-03-20 | 2001-10-16 | ノボ ノルディスク アクティーゼルスカブ | Therapeutic powder formulation for pulmonary administration containing crystalline insulin |
| WO2000061178A1 (en) * | 1999-04-13 | 2000-10-19 | Inhale Therapeutics Systems, Inc. | Pulmonary administration of dry powder formulations for treating infertility |
| AU779869B2 (en) * | 1999-04-13 | 2005-02-17 | Nektar Therapeutics | Pulmonary administration of dry powder formulations for treating infertility |
| GB0011807D0 (en) * | 2000-05-16 | 2000-07-05 | Quadrant Holdings Cambridge | Formulation for inhalation |
| JP2004515467A (en) * | 2000-08-07 | 2004-05-27 | ネクター セラピューティックス | Inhalable, spray-dried, 4-helix bundle protein powder with minimal aggregates |
| US6835802B2 (en) | 2001-06-04 | 2004-12-28 | Nobex Corporation | Methods of synthesizing substantially monodispersed mixtures of polymers having polyethylene glycol moieties |
| US6713452B2 (en) | 2001-06-04 | 2004-03-30 | Nobex Corporation | Mixtures of calcitonin drug-oligomer conjugates comprising polyalkylene glycol, uses thereof, and methods of making same |
| US6828305B2 (en) | 2001-06-04 | 2004-12-07 | Nobex Corporation | Mixtures of growth hormone drug-oligomer conjugates comprising polyalkylene glycol, uses thereof, and methods of making same |
| US7713932B2 (en) | 2001-06-04 | 2010-05-11 | Biocon Limited | Calcitonin drug-oligomer conjugates, and uses thereof |
| US6828297B2 (en) | 2001-06-04 | 2004-12-07 | Nobex Corporation | Mixtures of insulin drug-oligomer conjugates comprising polyalkylene glycol, uses thereof, and methods of making same |
| US6770625B2 (en) | 2001-09-07 | 2004-08-03 | Nobex Corporation | Pharmaceutical compositions of calcitonin drug-oligomer conjugates and methods of treating diseases therewith |
| US7030082B2 (en) * | 2001-09-07 | 2006-04-18 | Nobex Corporation | Pharmaceutical compositions of drug-oligomer conjugates and methods of treating disease therewith |
| MXPA04004730A (en) | 2001-11-19 | 2004-07-30 | Becton Dickinson Co | Pharmaceutical compositions in particulate form. |
| SE0200657D0 (en) * | 2002-03-04 | 2002-03-04 | Astrazeneca Ab | Novel Formulation |
| US7875700B2 (en) | 2004-07-19 | 2011-01-25 | Biocon Limited | Cation complexes of insulin compound conjugates, formulation and uses thereof |
| US20140162965A1 (en) | 2004-08-25 | 2014-06-12 | Aegis Therapeutics, Inc. | Compositions for oral drug administration |
| EP2457580A1 (en) * | 2004-08-25 | 2012-05-30 | The UAB Research Foundation | Absorption enhancers for drug administration |
| US8268791B2 (en) * | 2004-08-25 | 2012-09-18 | Aegis Therapeutics, Llc. | Alkylglycoside compositions for drug administration |
| US9895444B2 (en) | 2004-08-25 | 2018-02-20 | Aegis Therapeutics, Llc | Compositions for drug administration |
| US20060046962A1 (en) | 2004-08-25 | 2006-03-02 | Aegis Therapeutics Llc | Absorption enhancers for drug administration |
| US20090047347A1 (en) * | 2005-07-29 | 2009-02-19 | Aegis Therapeutics, Inc. | Compositions for Drug Administration |
| US8226949B2 (en) | 2006-06-23 | 2012-07-24 | Aegis Therapeutics Llc | Stabilizing alkylglycoside compositions and methods thereof |
| MX2010003979A (en) | 2007-10-16 | 2010-06-02 | Biocon Ltd | An orally administerable solid pharmaceutical composition and a process thereof. |
| ES2586032T3 (en) | 2008-03-28 | 2016-10-11 | Hale Biopharma Ventures, Llc | Administration of benzodiazepine compositions |
| CN101618023B (en) * | 2008-06-30 | 2011-11-30 | 江苏先声药物研究有限公司 | Method for preparing micronized protein |
| US8440631B2 (en) | 2008-12-22 | 2013-05-14 | Aegis Therapeutics, Llc | Compositions for drug administration |
| EP3269805A1 (en) | 2010-04-20 | 2018-01-17 | Octapharma AG | New stabilizing agent for pharmaceutical proteins |
| PT3415139T (en) | 2011-06-14 | 2022-06-20 | Neurelis Inc | Administration of benzodiazepine |
| US9480966B2 (en) * | 2012-04-30 | 2016-11-01 | General Electric Company | Substrates and methods for collection, stabilization and elution of biomolecules |
| JP6533777B2 (en) * | 2014-03-25 | 2019-06-19 | 国立大学法人 香川大学 | Inhibitor of malaria transmission containing rare sugars as active ingredient and inhibitor of malaria parasite |
| WO2016003889A1 (en) * | 2014-06-30 | 2016-01-07 | Tate & Lyle Ingredients Americas Llc | Coating compositions for consumable articles |
| DK3212212T3 (en) | 2014-10-31 | 2020-12-21 | Univ Monash | POWDER FORMULATION |
| GB2578075B (en) | 2015-09-09 | 2020-08-26 | Drawbridge Health Inc | Systems, methods, and devices for sample collection, stabilization and preservation |
| WO2019157099A1 (en) | 2018-02-06 | 2019-08-15 | Aegis Therapeutics, Llc | Intranasal epinephrine formulations and methods for the treatment of disease |
Family Cites Families (25)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| BE556587A (en) * | 1957-01-31 | 1957-04-11 | ||
| GB1144905A (en) * | 1965-03-25 | 1969-03-12 | Fisons Pharmaceuticals Ltd | Substituted bis-(2-carboxy-chromonyl-oxy) derivatives and preparation and pharmaceutical compositions thereof |
| DE2750090A1 (en) * | 1976-11-19 | 1978-06-01 | Sandoz Ag | NEW FORMS OF ADMINISTRATION FOR ORGANIC COMPOUNDS |
| SE7812207L (en) * | 1977-12-01 | 1979-06-02 | Welsh Nat School Med | APPARATUS, PROCEDURE AND MANUFACTURED PRODUCTS FOR USE IN THE ADMINISTRATION OF ANTIHISTAMINES |
| JPS6034925B2 (en) * | 1979-07-31 | 1985-08-12 | 帝人株式会社 | Long-acting nasal preparation and its manufacturing method |
| JPS59163313A (en) * | 1983-03-09 | 1984-09-14 | Teijin Ltd | Peptide hormone composition for nasal administration |
| DE3326089A1 (en) * | 1983-07-20 | 1985-02-07 | Gödecke AG, 1000 Berlin | INHALATION-INTENDED PHARMACEUTICAL FORM OF CALCIUM ANTAGONISTS |
| JPS61267528A (en) * | 1984-11-26 | 1986-11-27 | Yamanouchi Pharmaceut Co Ltd | Transnasal calcitonin agent containing absorbefacient |
| JPS63500175A (en) * | 1985-05-22 | 1988-01-21 | リポソ−ム テクノロジ−，インコ−ポレイテツド | Liposome inhalation method and inhalation system |
| IT1204826B (en) * | 1986-03-04 | 1989-03-10 | Chiesi Farma Spa | INHALATION PHARMACEUTICAL COMPOSITIONS |
| NZ222907A (en) * | 1986-12-16 | 1990-08-28 | Novo Industri As | Preparation for intranasal administration containing a phospholipid absorption enhancing system |
| US5179079A (en) * | 1986-12-16 | 1993-01-12 | Novo Nordisk A/S | Nasal formulation and intranasal administration therewith |
| EP0360340A1 (en) * | 1988-09-19 | 1990-03-28 | Akzo N.V. | Composition for nasal administration containing a peptide |
| JPH02104531A (en) * | 1988-10-14 | 1990-04-17 | Toyo Jozo Co Ltd | Physiologically active peptide composition for nasal application |
| US5011678A (en) * | 1989-02-01 | 1991-04-30 | California Biotechnology Inc. | Composition and method for administration of pharmaceutically active substances |
| US5176132A (en) * | 1989-05-31 | 1993-01-05 | Fisons Plc | Medicament inhalation device and formulation |
| JP2642486B2 (en) * | 1989-08-04 | 1997-08-20 | 田辺製薬株式会社 | Ultrafine particle method for poorly soluble drugs |
| JPH05963A (en) * | 1990-04-13 | 1993-01-08 | Toray Ind Inc | Polypeptide composition |
| GB9010742D0 (en) * | 1990-05-14 | 1990-07-04 | Quadrant Bioresources Ltd | Stabilization of biological macromolecular substances |
| CA2082951C (en) * | 1991-03-15 | 1999-12-21 | Robert M. Platz | Pulmonary administration of granulocyte colony stimulating factor |
| ATE146359T1 (en) * | 1992-01-21 | 1997-01-15 | Stanford Res Inst Int | IMPROVED METHOD FOR PRODUCING MICRONIZED POLYPEPTIDE DRUGS |
| JP3717925B2 (en) * | 1992-09-29 | 2005-11-16 | ネクター セラピューティクス | Pulmonary introduction of active fragments of parathyroid hormone |
| TW402506B (en) * | 1993-06-24 | 2000-08-21 | Astra Ab | Therapeutic preparation for inhalation |
| US5506203C1 (en) * | 1993-06-24 | 2001-02-06 | Astra Ab | Systemic administration of a therapeutic preparation |
| IS1796B (en) * | 1993-06-24 | 2001-12-31 | Ab Astra | Inhaled polypeptide formulation composition which also contains an enhancer compound |
-
1994
- 1994-12-22 SE SE9404468A patent/SE9404468D0/en unknown
-
1995
- 1995-12-18 ZA ZA9510753A patent/ZA9510753B/en unknown
- 1995-12-19 AT AT95942342T patent/ATE220900T1/en not_active IP Right Cessation
- 1995-12-19 AT AT01130870T patent/ATE271382T1/en not_active IP Right Cessation
- 1995-12-19 RU RU97112496A patent/RU2144819C1/en not_active IP Right Cessation
- 1995-12-19 TW TW084113557A patent/TW474823B/en not_active IP Right Cessation
- 1995-12-19 NZ NZ298168A patent/NZ298168A/en unknown
- 1995-12-19 EE EE9700135A patent/EE03381B1/en not_active IP Right Cessation
- 1995-12-19 EP EP95942342A patent/EP0799030B1/en not_active Expired - Lifetime
- 1995-12-19 WO PCT/SE1995/001541 patent/WO1996019207A1/en active IP Right Grant
- 1995-12-19 ES ES01130870T patent/ES2222306T3/en not_active Expired - Lifetime
- 1995-12-19 DE DE69533294T patent/DE69533294T2/en not_active Expired - Fee Related
- 1995-12-19 AU AU43592/96A patent/AU702898B2/en not_active Ceased
- 1995-12-19 UA UA97073876A patent/UA44757C2/en unknown
- 1995-12-19 DK DK01130870T patent/DK1224929T3/en active
- 1995-12-19 US US08/617,753 patent/US6004574A/en not_active Expired - Fee Related
- 1995-12-19 SK SK812-97A patent/SK283147B6/en unknown
- 1995-12-19 CZ CZ19971946A patent/CZ288487B6/en not_active IP Right Cessation
- 1995-12-19 ES ES95942342T patent/ES2177674T3/en not_active Expired - Lifetime
- 1995-12-19 IL IL11645995A patent/IL116459A/en not_active IP Right Cessation
- 1995-12-19 PT PT95942342T patent/PT799030E/en unknown
- 1995-12-19 CA CA002206803A patent/CA2206803A1/en not_active Abandoned
- 1995-12-19 MY MYPI95003942A patent/MY114211A/en unknown
- 1995-12-19 EP EP01130870A patent/EP1224929B1/en not_active Expired - Lifetime
- 1995-12-19 PT PT01130870T patent/PT1224929E/en unknown
- 1995-12-19 DK DK95942342T patent/DK0799030T3/en active
- 1995-12-19 PL PL95320751A patent/PL183944B1/en not_active IP Right Cessation
- 1995-12-19 CN CN95196965A patent/CN1080114C/en not_active Expired - Fee Related
- 1995-12-19 BR BR9510422A patent/BR9510422A/en not_active Application Discontinuation
- 1995-12-19 DE DE69527542T patent/DE69527542T2/en not_active Expired - Fee Related
- 1995-12-19 HU HU9800493A patent/HU217975B/en not_active IP Right Cessation
- 1995-12-19 JP JP8519731A patent/JPH10510828A/en active Pending
- 1995-12-19 KR KR1019970704254A patent/KR100391873B1/en not_active IP Right Cessation
- 1995-12-21 AR ARP950100706A patent/AR002261A1/en active IP Right Grant
- 1995-12-21 TR TR95/01632A patent/TR199501632A1/en unknown
- 1995-12-30 SA SA95160484A patent/SA95160484B1/en unknown
-
1997
- 1997-06-03 IS IS4495A patent/IS1848B/en unknown
- 1997-06-10 NO NO19972660A patent/NO315966B1/en unknown
- 1997-06-19 FI FI972654A patent/FI972654A0/en unknown
-
1998
- 1998-04-02 HK HK98102788A patent/HK1003619A1/en not_active IP Right Cessation
Also Published As
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| CA2206803A1 (en) | Powder formulations containing melezitose as a diluent | |
| US5747445A (en) | Therapeutic preparation for inhalation | |
| US5830853A (en) | Systemic administration of a therapeutic preparation | |
| EP0797431B1 (en) | Aerosol formulations of peptides and proteins | |
| US5506203A (en) | Systemic administration of a therapeutic preparation | |
| US5518998A (en) | Therapeutic preparation for inhalation | |
| US6165976A (en) | Therapeutic preparation for inhalation | |
| US20010003739A1 (en) | Systemic administration of a therapeutic preparation | |
| MXPA97004551A (en) | Formulations in powder containing melecitose as a diluye | |
| US20010025037A1 (en) | Systemic administration of a therapeutic preparation |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| EEER | Examination request | ||
| FZDE | Discontinued |