CA1302258C - Pharmaceutical compositions comprising microcapsules - Google Patents

Abstract

A B S T R A C T

Pharmaceutical formulations comprise:
(i) microcapsules which consist essentially of a biocompatible polymeric wall material encapsulating a drug, and (ii) a lipid-soluble surfactant which is mixed with the microcapsules or is incorporated within or coats the wall material of the microcapsules.
Such formulations may be presented as an aerosol or dry powder for inhalation. Microcapsules with surfactant incorporated in the wall material may be suspended in a pharmaceutically acceptable water-immiscible oil and the resulting suspension emulsified in an aqueous medium to obtain a formulation for oral administration.

Description

~3~)~2S13 This invention relates to controlling the release of drugs from pharmaceutical formulations.
Currently available treatments for asthma and bronchitis, although generall~ effective, are limited by the necessity for frequent drug administration and/or the possibility of unpleasant or debilitating side effects. It has long been established that direct application o~
bronchodilating drugs to the lungs by inhalation provides rapid relief for asthmatic and bronchitic symptoms.
~owever r the very rapid systemic absorption of drugs when administered by this route results in a relatively short duration of the desired clinical effect. Consequently this route of administration has not been as acceptable for the prophylatic administration of bronchodilating drugs in an attempt to prevent acute asthmatic attacks. Certain oral dosage forms are available for this latter purpose.
However, they are not administered directly to the site of actionO The dosages required are therefore very much higher and the incidence of unpleasant side effects is much greater.
The respiratory tract may also be used as a means of drug administration in circumstances where other routes are inappropriate or inconvenient. Certainly anaesthetic agents are administered by this route for their systemic activity, and there is evidence in the literature that peptides such as insulin can be absorbed systematically from the lungs.
The process of microencapsulation of drugs in various polymeric materials is a well known means of producing controlled release drug delivery systems.
Factors controlling the release of drugs from these microcapsules have been well described in the literature.
In summary the critical factors are:
lo the method of encapsulation and therefore the physical nature of the microcapsule;
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2. the sp~ci~ic polym~ aterial chosen to form ~h~ walls o~ ~he microcapsule~

3, the phy~ical state o~ tha polyme~ic ~aterial in the micro~a~s~le, i.e. the ~egree of c~ystallinit~; and 4. the solubility and difusion characteristics of th~ ~alt ~orn~ of the dru~ chos~n.
Children and the elderly have di~iculty in swallowing convention~l t~blet~ ana capsules. Unfor~una~ely the~:e hav~ ~en many technical difficutties in p~o2~cir.g controlled r~le~e drug ~liv~ry sys~ems which could be adminis~er~d in syrup or liquid form. Th2 greatest technical dl~icultie~ ar~, on the one ha~d, o~ keepin~ the aetive in~cedient largely out o~ a~ueou~ sol~stio~ dur ing sto~age, whLle at the s~me time ~llo~ing this a~ive ~ngredient to dissol~e ~lowly once the pro~uct has been admLni~tered to a pat ient, We have now prod~ced microencapsulated drug par ~icles typLcally Ln sizes r~ngi~ in excess Q~ 1 um. The drugs emp~oyed have been incorporated in ~ariaus polymeric wall ~orming rnaterial~. It ~qas ~o~nd that ~hen these microcapsules ~er~ exposed ~o lipid-soluble sur~actan. or when such a suractant was incvrpora~ed in the wa~l ma~erial o the microca~sule, the rele~se of drug ~rom ~he microcap~ s wa~ retarded. The r~te o~ ~el~ase ~ the ~ru~
co~ld be controll~ with sespect to time.
Ac ordingly, th~ ~es~nt inventlon provides pharm~ce~tical formulations 6ui~able for inhala~i~n, compsiein~:
~ i) microcapsules having an ave~aga di~et~r of from O~l ~o lO um which con~ist e~senti~lly o~ ~ bi~ccmpatible biodeg~adable polymeric wall material encaps~la~ing a d;u~, and (iil a lipid-~oluble sur~a~tan~ which is ~ixe~ wi~h the ~icrocapsules or iR incorpo~ate~ within or coat~ the w~ll mater ial o~ the microcap~les.

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~1 .3();~2~;8 The invention ~urther provid~s ph~rmace~tical com~o~itions ~uit~ble for ingestion, comptising:
( i' ) n~icrocapsules having an average ~l~me~er of from 0~1 ~o ~0 um, whi~h con~l~t es~entially o~ ~ biocom~tible p~lyme~ wall ~ats~ ial encap~ulating a drug, and a ~ d-solu~l~ surfactant~ which is mix~ with the mie~o~ap~lles or i5 incorporated ~athin or ~:o~s the wa~l ma~erlal o~ the mlcrocaps~le~, Such formulation~ oan be ~imple m~ res og mi~cocapsule~ c~psulating a drug ~nd s~l~factant.
Alternatively or a~iti~nally, ~ic~o~apsules encapsulating dru~ may have been expo~ o sur ~aa~ant so ~hat ~he ~urEactant o~ms a coating ~ the wal~ material o~ the microcapsulea, Mi~oc~psule~ havin~ surfactant incorpo~a~ed in th~ir w~lls may ~l$o bg pr~pared by dissolYin~ ~he polymeric material fo~ the walls in a ~ol~tent, dispersing ~u~ctant and drug in the polymer solu~ion, ev~porating of ~
th~ solvent and o~aining the particles thus $o~m~ with the de~ired a~era~e diamet~ ph~maceuti~all~ acce~ta~le carrier or diluent may be pro~ided in the formulation~
~ h~ for~ulation m~y b~ pre~ented in a form ~ta~le for inhalation. For ~his ~u~pose, it may take the focm of an aero~ol in w~ich ~he miceocapsul~s a~e s~spended in ~he propallant ~or th~ ae~o6al or it m~y ~e in dry powder fo~m.
~se of the present 8y5tem fo~ local appli~atlon of drugs to the lungs exeends beyond broncho~ Ln~ ~gents. Othe~
drugs important ~n the trsatm~n~ of a~thma ~ay ba ad~inistsre~ in ~his way including ~oc~icosteroids~ di~odium cromo~l~cate antihistamine~ an~ leuko~riene a~tago~is~s.
~urtherm~e, low ~elease o~ antibiotic ~d an~iviral m~terial~, ch~mothe~apeutic agents ~ ancer t~eatment in th~ lung may be a~hieved.
~ lternatively, an orally administrablo p~epar~ion may be ~o~mulated, A pr~er~d sucn oral ~orm~lation is p r ep a r ed by s u spe nd l n g th} m ir ~ o c}p s ul e s I nco rp~: a ting ch }

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~ur~actant in their walls in a pharmacautically acceptable wate~immi cibl~ oil an~ emulsl~ying the oil suspension o micr~capsule~ in an aqueou~ medi~lm.
I~y ~I~ixi~g ~h~ lipid-~oluble s~l~factant with the mlcco~apsules or incorpordtin~ the su~ ~ac~nt in the walls o~ 'che micr~capsules, the ~el2ase o~ ~ug fro~ the rnlcraeap~ule~ can he cont~olled. ~n its ~rrl, this controls the dPgree ~nd duration o~ ~he pha~nacological ~ffect obtained, A~ ~ar a~ the pYe~rred liquid oral doæage ~ m i~ conc~rned, ~ ~rug ~ele~s~ del ivety ~ystem can be p~o~uced with 1~ ~table in the ~q~le~u~ ~orm b~lt ~1 `? ~t_ '- I

-` 1.3~ 58 which releases drug in vi~o at rates similar to that produced by various conventional long acting formulations.
Further, the system is easier to administer to children and older patients. Protection of drugs by way of microencapsulation in the system can improve their stability in aqueous media. The flavour and palatability of liquid formulations may be improved.
The drug encapsulated in the microcapsules may be any agent which exhibits a pharmacological effect. The drug may be selected from antibiotics such as ampicillin or penicillin Vr cardiovascular drugs such as betablockers, calcium antagonists or nitrates such as isosorbide dinitrate or isosorbide mononitrate, a drug for cough and cold preparations such as dextromethorphan or diphenhydramine, peptide drugs such as insulin or human growth hormone, other naturally occurring agents and derivatives such as prostaglandins, anti-viral agents and anti-convulsants such as phenytoin and sodium valproate.
Preferably, the drug is a bronchodilating agent.
Suitable bronchodilator compounds include beta-receptor agonists and, more particularly, beta-adrenergic agonist agents such as salbutamol (2-tert.butylamino-1-(4-hydroxy-3-hydroxymethyl phenyl)ethanol, normally presented as its sulphate) and terbutaline (2-tert.butylamino-1-(3,5-dihydroxyphenyl~ethanol, normally presented as its sulphate). Other bronchodilating agents which may be employed are xanthines such as theophylline, anti-cholinergic agents such as ipatropium bromide and the like, calciu~ antagonists such as nifedipine and biological agents such as leukotrienes and derivatives thereof.
The amount of drug incorporated in the microparticles usually ranges from less than 1% to as high as 95% by weight, preferably from 1 to 80% by weight. Two or more drugs may be encapsulated in the microcapsules. In such an event, the drugs must be inert with respect to each other.

~3~Z5i3 The polymeric wall material of the microcapsules must ~e biocompatible. A biocompatible polymeric material is a polymeric material which is not toxic to the human body, is not carcinogenic and should not induce inflammation in body tissues. Preferably, the wall material is biodegradable in the sense that it should degrade by bodily processes to products readily disposable by the body and should not accumulate in the body. For microcapsules for inhalation, therefore, the wall material should be biodegradable. Suitable examples of polymeric materials include poly(glycolic acid), poly-d,l-lactic acid copolymers thereof, copolyoxalates, polycaprolactone, poly(lactic acid-caprolactone), and the like. For oral preparations, cellulose derivatives such as ethyl cellulose may be employed.
The molecular weight of the poly eric material for the walls of the microcapsules should be high enough so that it forms satisfactory polymer coatings. Usually a satisfactory molecular weight is greater than 10,000 daltons. The molecular weight of a polymer is also important from the point of view that molecular weight influences the biodegradation rate of the polymer. By an appropriate selection of polymeric materials a formulation can be made such that the resulting microcapsules remain intact until all of the drug is released and then degrade.
The microcapsules may be prepared in any suitable fashion. ~hey may be prepared by spray-drying. In this technique, the polymeric material for the walls of the microcapsules is dissolved in a solvent such as methylene chloride. An appropriate amount of surfactant, if desired, and drug, depending on the desired core load of the microcapsules, is dispersed in the polymer solution. This dispersion is then spray-dried. An inert gas such as nitrogen is typically forced through the nozzle of the spray-dryer with the dispersion to cause an aerosol of microcapsules to be formed initially. The microcapsules '~'" '" ~
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~.3i~2258 are then collected. Alternatively, the microcapsules may be prepared by:
~ a) di6solving o~ diapersing A ~ru~ in a solven~, typ~c~lly me~hylene çhlor~de, and di~ol~ing a ~locompatible and biodegra~able wall go~min~ material in the aolve~t:
~ b) ~p~rsi~g th~ solvent conta~ning the d~uq and orming material in a continuou~ pha~e p~4¢essing medium s~ch ~Q a 1 ~o 10~ by weight polyvinyl aleohol in water mixture:
(c) av~porating a ~ortion of ~he ~olvent ~rom the d~sparsion ~f st~p ~b), thezeby formln~ microcapsul~s containing the d~ug in sus~ensi~n; a~d ~ d) ext~act~ng ths remainder of ~he 50ivent ~rom the mic~oc~p~ul~s.
~ he miç~op~rtlcl~ product is usually mode ~ of part~Gles o~ a spherieAl ~hape altho~gh ~o~etimes the mlccocapsules ~ay be ir~egularly ~haped. Microcapsules for inbalation have an a~erage diameter o~ 0.1 to 10 um, pre~erably 1 to 5 u~ . Microoapsules foc ingestion have ~
aver~ge ~iamete~ o~ ~rom 0.1 ta 20 llm, preIerably S~om 1 to ~0 ~m.
The microcapsul~ incorporate a lipid-soluble s~r~actant as ~ druq releas~ cont~olling agent. The 3urfa~tant is typicall~ in liq~id for~. It is ~refera~ly a sorbitan f~tty aald ester ~uch a~ orbitan triol~te, ~orbitan monolaurate, so~bitan monoolea~, sorbitan monopalmit~te and so~ 7.n-mo~ostearate. ~lternatively, ~ e surfactant may ~e ~ polyox~mer or a sur~ace a~tive ~tty acld ~ h as ole~c a~id.
Where ~he fo~mulation is a ~imple mixtu~e o~
~cxooapsules a~d sura~tant, ~h~ su~actant i5 typically p~esent ~n an ~ount up to twic~ th~ weight, p~eferab~y up to the weigh~, o micro~ap~ules/ ~oweve~, in ~h~ case o~ an ~erosol the amount o~ surfac~ant i3 generally rathe~ less than this, 5urfactant can be inco~porated in the , ., I
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~3~2:~S13 walls of the microcapsules in an amount of up to 25% by weight of the microcapsules. Preferably, the amount is at least l~ by weight. Where moee than 10% by weigh~ is used, little useful additional effect is achieved. When microcapsules are exposed to surfactant to enable the surfactant to become coated on the microcapsule walls, typically the amount of surfactant to which the microcapsules are exposed is up to ten times, for example up to twice or more, the weight, preferably up to the weight, of the microcapsules.
Formulations according to the invention may be presented in a form suitable for inhalation. For this purpose, the formulations are generally loaded in an aerosol canister or, in dry powder form, in an inhaler. In an aerosol, the microcapsules are suspended in the propellant for the aerosol. In a ~ry powder inhaler, the microcapsules may be mixed with a diluent such as lactose.
Typically, such microcapsules have had surfactant incorporated in their walls during the encapsulation procedure. In both ways, a fine suspension of microcapsules may be taken into the lungs by a patient.
Typicall~, the aerosol canister or inhaler allows a metered dose of a drug such as a bronchodilating agent to be inhaled. This is generally achieved by the provision of a valve which meters the amount of formulation, fluid in the case of an aerosol, discharged with each actuation.
The microcapsules may be contacted with the surfactant prior to loading in an aerosol. Preferably, however, the surfactant is provided with the microcapsules and the propellant for the aerosol in the aerosol cannister. In such an instance, the surfactant may be provided in an amount ranging down to 10% of the weight of the microcapsules. The concentration of surfactant in the mixture in the aerosol cannister is typically no more than 5% by weight, preferably from 0.01 to l~ by weight. In the case of microcapsules for a dry powder inhaler, the ~31~58 surfactant is contacted with the microcapsule walls prior to loading the inhaler with the microcapsules.
Formulations according to the invention may alternatively be ingested orally. The microcapsules are exposed to surfactant and suspended in a pharmaceutically acceptable water-immiscible oil. The oil is typically liquid, a fixed oil such as a fatty acid ester of glycerol.
For example, the oil may be cotton seed oil or ethyl oleate. This suspension is then emulsified in an aqueous medium. By altering the drug loading in the microcapsules and by varying the relative concentrations of suefactants and oil, it is possible to alter the amoun~ of drug immediately available in the aqueous phase of the mixture as well as control the rate of release of drug from the mixture into systems which mimic oral absorption.
The formulations are administered to a patient by inhalation or orally. A therapeutically effective amount is taken by a patient. Dosages depend upon the condition being treated, the stage the condition has reached, the patient under treatment and the drug being administered.
Typically, however, one or two doses per day of a formulation of the invention may be given to a patient.
In a preferred embodiment where a bronchodilating agent is encapsulated for inhalation, asthma, bronchitis and other diseases of the respiratory system may be treated. The amount of formulation administered depends on the particular disease or disorder being treated and the type of bronchodilating agent being administered.
Generally, however, the formulations may be inhaled only once or twice during a day. Thus, a formulation may be inhaled on two occasions per day, with an eight to twelve hour gap before the second inhalation, in an amount sufficient to deliver from 50 ug to 2 mg, more preferably 100 to 500 ug, of bronchodilating agent to the lungs per occasion. The dosage for salbutamol, for example, may be two inhalations of 100 ug each. This contrasts with the .

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recommended dose for conventional salbutamol aerosol inhalations of 1 to 2 inhalations, each of lO0 ug, e~ery three to four hours up to a maximum of eight per twenty hours (Martindale, The Extra Pharmacopoeia, 28th edition, 1982). ~h~ ~osage for te~but~I~ne ~ay ~e ewo inhalations each o~ ~50 ~g.
~ he fo~lowin~ ~xam~les 1 to 6 illu~zs~ th~
in~sn~$on. ~n the accompanylnq F~guxe~;
~i~u~e 1 ~hows thc rss~lt~ o~ th~ a~s~ys of the superna~an~
far te~butaline sulphate ~n Exampl~ 2; ~nd Figurs ~ how~ the re~ults of the dissolution test in ~xample 2~
~5~
~ rbu~aline ~ulph~te mic~oo3psules w~e p;ep~red u~ing ~ ~uchi 130 Mini s~ray-d~ye~ equipped with ~ 0.7-~m spra~ no~21e ~rinkmann Ins~ru~ents ~o, wes~bu;y, N.Y.).
The ~pray-drying proc~dure was conducted as ~ollows:
A 1.25 wt ~ polyla~tide-glycolid~ cop41~m~r ~DL-P~G~ solutlon was prep~E~d u~in~ methyl~ne ch10~ide as the solv~nt. A~t~r ~om~lete dis~olution of ~he polymer, tarbutalln~ ~ulphat~ was added to the ~oly~er solution in an a~ount Qqu~lling ~he w~ight of D~-P~G. The terbuta~in~
6ulph3t~ particlR~ were then euspended by homogenization using A ~rinkma~n Polytro~ ho~ogenizeE (B~in~ann I~st~m~nts 50, Westbury N.~ ediately ~fter th~
homog~n~zativn w~ complEt~d, ~he d~u~/poly~ ixture w~
p~p~d into th~ nozzle of the ~ay dryer ~t a low rate o~
approxlmst~ly 1 ml~mln. T~ ~f~ect aerosoliz~ion, nltrogen wa~ al ~o dlr~cted through the no221e . ~h~ ~itro~n pre~s~r~ w~s maintairl~d ~t about 103 KPa ~5 lbs/i~2 )~ Th~
tempe~a~u~ oS th~ spray-d~ye~ ~hamber was kept at a~pro~ciFat~ly 70 C. A~t~r all o~ the dFu~/poly~eF T~lixture was proc~s~d, the ~pray dry~ w~s allow~d to gr~dually cool to room ~emper~tu~ and th~ m~crocapsule produot was coll~k~d~
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S~lutionc o~ sorbit~n triol~ate ~Sp~n 85) were prepared as follow~. Into ~ 113g (4 oz) glas~ ja~, 150 to 1~0~ o~ on ~as add~d via ~ ga~ cylinde~. Ne~t. an -1a ~
~ Registered ~rademarX

302Z~iZ3 appr~priate amount o~ ~pan ~5 wa~ added to each jar. T~
prepare 1~ Span B5 irl F~eon, approximataly 1.~ ~ of Span 85 was w~iqhed into a we~gh ~oat and poured into ~he ja~
con~cainln~ the F~on. To prep~ more dilu~e surfac.ant solutiQns it wa n~c~ssa~y to add the Sp~n 85 sur~actant via ~ plpet~e. ~t w~s da~er~i~ed that 10 drops o~ Span 8S
w~ighed app~oxim~ely 150 mg. The~efo~e 1 drop weighs a~pcoxl~a~ely 15 m~
r~on w~
1~; Span 85 -1/ 5 g 1~6 . 4 g ~, 25~ 25 drops l~û . O g 0,10% ~0 drops 16i,2 g O~Oi3 1 d~p 1~0.7 ~
A~ter th~ su~factant was added, th~ jaF~ were capped with Te~lots*lin~d screw caps and ~haken. The iars were ~tored at -'10~C.
Mic~ocapsul~s we~e weighed into pla~tic ~intillation vials and diff~rent s~lractant sol~ons were a~ded tO ~ach vial individually. The v~ls were labelled aecaedingly, and ~ ~tir bar w~s ~dded to each vlal. Th~
sample was allow~d /co sti~ un~evered for apprcximat~y 4 hours at room te~perature~ The samp~ es we~ the;L pl~ced undQ~ a hood and exp~sed to contin~20~ air ~low for 30 min to remcve all tr~ces of the Freosl, The microc~psulefspan 8~ mlx~u~e WAS then sc~aped ~ro~ the vial.
~ n a~ount of microcap~ule~ which con~ained ~pp~x~m~tely 15 mg of t~rbut~line ~llphate was weighed out in tr1plicate ar~d p~.aced ilnts sm~11 nylon ~ouche~ hes~
pouche~ oon~isted o~ 5 um, nylon mesh ( Small ~a~t~ lnc ., Miami, Flor~da), ~n~ we~e 3.81 cm x 3.~1 ~m (1.5 ln x l.S
~n). ~h~ pouches wer~ formed by heat sealins th~ edge~

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* ~egi~red ~rademark _ 1 l ~
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with a hot spatula blade. The microcapsules were sealed within the pouch by this method as well.
A nylon pouch containing the microcapsules was then placed in a 227 g (8 oz) glass jar, and 200 ml of deionized water was then added. Next, the glass jar was placed in a shakerbath maintained at 37C and oscillating at a rate of about 120 cycles/min. Aliquots were then~
removed periodically from the receiving fluid and assayed spectrophotometrically at 227 nm to determine their terbutaline s~lphate concentrations. The amounts of terbutaline sulphate released was then calculated by using the highest recorded absorbance to determine 100% release of drug from the microcapsules. After the maximum or 100%
release was obtained, the % release was determined proportionally. To illustrate, the following data were obtained for Micrccapsule Batch D743-021 after exposure to 0.10% Span 85 in Freon.
Time Abs = 227 nm C~nc (ug/mL) % Released 5 min 1.443 74.0 83.5 15 min 1.650 85.4 96.4 30 min 1.693 87.6 98.9 l h 1.711 88.6 lO0.0 Thus the maximum absorbance as determined spectrophotometrically at 227 nm was 88.6 ug/mL. This was determined via a standard curve which was done previously.
After determining the maximum release at l h of 88.6 ug/mL, the percent release at the earlier times was calculated proportionally. For example, the release at S min was calculated as follows:
74.0 ug/mL x 100% = 83.5 88.6 ug/mL
The results are shown in Table l below.

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`~` ~L3~2S8 xa~pl~ 2: t.iqu~
Microcapsule~ o~ ~erbutaline s~lphate we~e prod~eed by ~pray d~yin~ accorting to the i~e~erence ~x~mpl~ ~ The p~ticle siees o~ the mic~capsules were f rom 1 ~o 10 u~n. The ~ic~ocaps~ e mi~ced wieh ~c~r~it~n triolcats suractan~; thon mixed with the oil, ~chyl ol~at~ d finally emul~lfi~d in wate~ by ~ir~t ~dding ~che no~-io;~e ~u~ ctas~t Crer~opho~ ~ to ~he oil arld ocap~uls ~nix~ure and then ~ddi~g quantitie~ o~ wat~
with vi~crou~ mxin~t Th~ woight ratio ~f ter~ut~lin~
micro~apsule~ itan t~loleate wa~ ~bo~ 5. The ~ollDwing ~antit~tive ~cr~ula was emplDyed:
T~rbutalin~ rdicr~capsules 174 mg Soebitan ~r1ole~te1 ~1 ethyl ole~te 5 ml Cr~mophor ~L 5 ~1 Water ~S 100 ~nl ~ he aqueou6 supernat~nt was assayed ~o~
terb~talir.e content on tlle l~t, 5th an~ 14th day af~er production. ~ur~hermo~e a~ter the 14th day ~ 20ml s~pl~
o th~ s n~ixt~lre was expo6ed to th~ st3,nda~ USP dt ssolution 'c~ un in ~N 6.8 bu~er at 37C and a stirring ~equency o~ 50 cyc1e~/miz~. The r~su1'c~ ~e ~hown in Fisures i ~nd .
Sn ~i~ure 1, ~he data f ro~n the assays Oa ~up~xs~a'cant when th~ mixture waa s'cored for 14 days ~re 2re~nt~d. It is ~1ear ~om this ~iqure that the con~entra~ion o~ terbutalinY æulphate ~n the as~us phase ~n ~h~ 1 t ~y ~t,er producti~n waa 8.9~ Pf ~he total ter~u~1inc ~oncerl'cr~ti~n and at l 4 ~3y5 the ~oncen~ratio~
i wa~ the ~an~e. By con~r~st the ~esult~ in Fi~u~ 2 pre~ent data fo~ l:ho ln vitro d~ eso1ution o~ thi~ s~ire liquid ~or~u1at~on. Thi~ pharmacopoei~ test i~ ~he ~ne ~s th~
r~co~nended ~r many tabl~t ~nd çapsule lon~ acti~g $ormula~ion~. ~n Fig~ 2 it is quite apparer~t that wh~n ~ ~e~istered Trade~nark i, I ~

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the mixture was exposed to this USP test, drug dissolved slowly but completely in the aqueous media over a 2 hour period.
Example 3: Preparation of Aerosols containing Microcapsules Experimental aerosols were prepared by adding an appropriate quantity of microcapsules of terbutaline sulphate to an empty aluminium canister. The microcapsules were produced by spray-drying according to the Reference Example. They were designated batch D743-055-1. Their core loading of terbutaline sulphate was 26.6~ by weight.
The amount of terbutaline sulphate released from the microcapsules, in the absence of sur~actant, was measured ln vitro by the procedure described in Example 1. The percentages by weight of terbutaline sulphate released after 5, 10 and 30 mins were 84.5%, 98.6% and 98.8~, respectively.
The remaining ingredients for the aerosol, suitably cooled, were added. A metered valve capable of delivering 25 ul of the mixture was crimped to the canister to provide a seal. The following aerosols were prepared:
Aerosol No~ 1 Microcapsule batch D743-055-1 200 mg Sorbitan Trioleate 140 mg Trichlorofluoromethane 3.44 g (Propellant 11 BP 80) Dichlorotetrafluoroethane 3.44 g (Propellant 114 BP 80) Dichlorodifluoromethane 6.88 g (Propellant 12 BP 80) Aerosol No. 2 Microcapsule batch D743-055-1 200 mg Trichlorofl~oromethane 3.44 g (Propellant 11 BP 80) ~3C~2~58 Dichlorotetrafluoroethane 3.44 g (Propellant 114 BP 80) Dichlorodifluoromethane 6.88 g (Propellant 12 ~P 80) Example 4: In vivo studies involving terbutaline microcapsules Aerosols prepared as described in Example 3 were tested in human volunteers. In one experiment, Aerosol No.
1 was employed. The physiological effects produced by this aerosol were compared to similar effects producted in the volunteer by a commercially available terbutaline aerosol.
The human volunteer inhaled 4 puffs from the commercially available terbutaline inhaler (total inhaled dose approximately 1 mg terbutaline sulphate) and, on another occasion, inhaled 8 puffs from Aerosol No. 1 (inhaled dose approximately l mg terbutaline sulp~,ate). Airway resistance was measured at regular intervals following inhalation of the drug substance, utilising a constant volume body plethysmograph and expressed as specific airway conductance (sGaw). This method has been described by others, for instance see J E Harvey and A E Tattersfield Thorax 1982; 37:280-287. The results of this experiment are given in Table 2 below. Time here and in Table 3 is in minutes.

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~)2~i8 Table 2: ~ Change in sGaw Tim_Commercial AerosolAerosol No. l ~20 o 22 A second experiment was carried out using another human volunteer. Aerosol No. 2 of Example 3 was compared against a standard terbutaline aerosol. In this case the volunteer inhaled 4 puffs of the experimental formulation and 2 puffs from the standard inhalerl SGaw was again measured at regular intervals as described above. The results from this experiment are given in Table 3 below.
Table 3: ~ Change in sGAw TimeCommercial AerosolAerosol No. 2 47 lO

The data presented in ~ables 2 and 3 clearly indicates that Aerosols Nos. 1 and 2, containing microencapsulated terbutaline, were capable of prolonging the effect of the drug on s~aw. Comparing the results from the first and second experiments indicates that the sorbitan trioleate component of the aerosol mixture also had a significant influence on the results. It is clear that the initial response to terbutaline from Aerosol No. l ~as substantially depressed and that the response was constant for up to six hours. By comparison, the maximum pharmacological effect for Aerosol No 2 was delayed by approximately one hour as a result of the microencapsulation of the drug. The response was not '` , "

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~L3/~2:;~58 constant and was in steep decline by the time of four hours. These data clearly indicate that the surfactant prolongs the effect of the inhaled microcapsule formulation.
Example 5: Preparation of Microcapsules incorporating Surfactant in their wall material Salbutamol suphate microcapsules containing Span 85 were prepared using a suchi l90 Mini spray-dryer equipped with a 0.7 mm spra~ nozæle (srinkmann Instruments Co, Westbury, NY). The spray-drying procedure was conducted as ~ollowsO
A DL-PLG solution (~.~0 wt ~) was prepared using methylene chloride as the solvent. After complete dissolution of the polymer the Span 85 was added. An am-unt o Span ~5 was added such as to obtain a core loading of surfactant of 10~ by weight. After the Span 85 was dispersed throughout the solution, the salbutamol sulphate was added. An amount of salbutamol sulphate was added such as to obtain a core loading of drug desired of 20.1% by weight. The salbutamol sulphate particles were then suspended by homogenisation using a Brinkmann Polytron homogeniser (Brinkmann Instruments Co, Westbury, ~Y). To perform this homogenisation procedure, the probe of the homogeniser was submerged in the polymer/drug mixture. The homogeniser was operated at a setting of approximately 6.
The mixture was homogenised ~or three 30 second bursts, allowing 30 seconds between each burst.
Immediately after the homogenisation procedure, the polymer/dru~ mixture was placed on a stir plate and stirred vigorously to ensure that the salbutamol sulphate particles remained in suspension. A Gilson Minipulse 2 pump (Gilson Medical Electronics Inc, Middleton, WI) was then used to pump the mixture into the nozzle of the spray-dryer. A flow rate o~ approximately l ml/min was attained using size-14 Viton tubing (Cole-Parmer Instrument and Equipment Co, Chicago, IL). A small piece of aluminium ; .

, .

:~L3(~

foil was wrapped securely around the tubing and the mouth of the solvent jar to prevent loss of methylene chloride through evaporation.
To effect aerosolisation, nitrogen was directed through the nozzle of the spray-dryer. The nitrogen pressure ~as maintained at about 103 KPa (15 lb/in2) , as determined by the regulator on the nitrogen tank. The temperature of the spray-dryer's inlet chamber was maintained at about 50C, while the collection chamber was kept at approximately 40C. After all of the mixture was processed, the spray-dryer was allowed to gradually cool to room temperature and the microcapsule product was collected.
Example 6: Measurement of In Vitro Release Rate from .
Microcapsules incorporating Surfactant in their ~
__ material In order to simulate release of drug in the lungs, a simple dissolution/diffusion apparatus was utilised. In this system, accurately weighed amounts of salbutamol-containing microcapsules prepared according to Example 5, of salbutamol-containing microcapsules prepared according to Example 5 but without Span 85 or pure salbutamol were placed inside a sealed piece of dialysis tubing. The pieces of tubing were then suspended in beakers containing 150 ml of p~ 7.4 buffer. The buffer was stirred at a constant rate. Small samples were taken from the fluid in the beakers at regular intervals and assayed for active drug using the following procedure:
Samples of the buffer were injected directly on an HPLC fitted with a 2-Module with Novopak column and Guardpak pre-column, and a fluorescence detector set at 230 nm excitation with no emission filter. The solvent employed was a 4:96 acetonitrile/water with TEA adjusted to pH3 with orthophosphroic acid, and the flow rate was 2.5 ml per minute.

~L3~22~8 The release of salbutamol from the two different batches of microcapsules, one with and ~he other without surfactant, is demonstrated in Table 4 below. Clearly, the presence of the Span surfactant within the microcapsulses substantially delayed the release of the drug.
Example 7 Salbutamol microcapsules were prepared using the reference method and an in vitro release study was carried out as described in Example 1 except that oleic acid was used as the surfactant instead of sorbitan trioleate. The results obtained are shown in Table 5 below.

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Claims (17)

1. A pharmaceutical formulation suitable for inhalation, comprising:
(i) microcapsules having an average diameter of from 0.1 to 10 µm which consist essentially of a biocompatible biodegradable polymeric wall material encapsulating a drug, and (ii) a lipid-soluble surfactant which is mixed with the microcapsules or is incorporated within or coats the wall material of the microcapsules.

2. A formulation according to claim 1, which is in the form of an aerosol for inhalation.

3. A formulation according to claim 2, wherein the concentration of surfactant in the aerosol cannister is from 0.01 to 1% by weight.

4. A formulation according to claim 1, which is in the form of a dry powder for inhalation and wherein from 1 to 10% by weight of surfactant is incorporated in the walls of the microcapsules.

5. A pharmaceutical formulation suitable for ingestion, comprising:
(i) microcapsules having an average diameter of from 0.1 to 20 µm which consist essentially of a biocompatible polymer wall material encapsulating a drug, and (ii) a lipid-soluble surfactant which is mixed with the microcapsules or is incorporated within or coats the wall material of the microcapsules.

6. A formulation according to claim 5, which is in the form of a composition suitable for oral administration wherein the microcapsules, which are coated with surfactant, are suspended in a pharmaceutically acceptable water-immiscible oil which is in turn emulsified in an aqueous medium.

7. A formulation according to 1 or 5, wherein the surfactant is a sorbitan fatty acid ester.

8. A formulation according to claim 1 or 5, wherein the surfactant is sorbitan trioleate.

9. A formulation according to claim 1 or 5, wherein the drug is an antibiotic, cardiovascular drug, a drug for a cough or cold preparation, a peptide drug, any other naturally occurring agent to a derivative thereof, an anti-vital agent, an anti-convulsant or chemotherapeutic agent for cancer treatment.

10. A formulation according to claim 1 or 5, wherein the drug is a bronchodilating agent or other anti-asthma drug selected from corticosteroids, disodium cromolglycate and antihistamines.

11. A formulation according to claim 1 or 5, wherein the drug is a bronchodilating agent selected from a beta-adrenergic agonist, a xanthine, an anti-cholinargic agent, a calcium antagonist and a leukotriene or derivative thereof.

12., A formula according to claim 1 or 5, wherein the drug is salbutamol or terbutaline.

13. A formulation according to claim 1 or 5, wherein microcapsules encapsulating a bronchodilating agent are mixed with sorbitan fatty acid ester which is present in an amount up to the weight of the microcapsules.

14. A process for the preparation of a pharmaceutical formulation as defined in claim 1 or 5, which process comprises mixing the microcapsules with the surfactant.

15. A process for the preparation of a pharmaceutical formulation as defined in claim 1 or 5, which process comprises exposing the microcapsules encapsulating drug to surfactant so that the surfactant coats the wall material of the microcapsules.

16. A process for the preparation of a pharmaceutical formulation as defined in claim 1 or 5, in which the surfactant is incorporated in the wall material of the microcapsules, which process comprises dissolving the polymeric material for the walls in a solvent, dispersing surfactant and drug in the polymer solution, evaporating off the solvent and obtaining the microcapsules thus formed with an average diameter from 0.1 to 10 µm.

17. A process for the preparation of a pharmaceutical formulation as defined in claim 5 in which the surfactant is incorporated in the wall material of the microcapsules, which process comprises dissolving the polymeric material for the walls in a solvent, dispersing surfactant and drug in the polymer solution, evaporating off the solvent, obtaining the microcapsules thus formed with an average diameter of from 0.1 to 10 µm and suspending the microcapsules which have been exposed to surfactant in a pharmaceutically acceptable water-immiscible oil and emulsifying the resulting suspension in an aqueous medium.