CA2231050A1 - System for rendering substantially non-dissoluble bio-affecting agents bio-available - Google Patents
System for rendering substantially non-dissoluble bio-affecting agents bio-available Download PDFInfo
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- CA2231050A1 CA2231050A1 CA 2231050 CA2231050A CA2231050A1 CA 2231050 A1 CA2231050 A1 CA 2231050A1 CA 2231050 CA2231050 CA 2231050 CA 2231050 A CA2231050 A CA 2231050A CA 2231050 A1 CA2231050 A1 CA 2231050A1
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- soluble polymer
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Classifications
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- 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
- A61K9/146—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 macromolecular compounds
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- A—HUMAN NECESSITIES
- A01—AGRICULTURE; FORESTRY; ANIMAL HUSBANDRY; HUNTING; TRAPPING; FISHING
- A01N—PRESERVATION OF BODIES OF HUMANS OR ANIMALS OR PLANTS OR PARTS THEREOF; BIOCIDES, e.g. AS DISINFECTANTS, AS PESTICIDES OR AS HERBICIDES; PEST REPELLANTS OR ATTRACTANTS; PLANT GROWTH REGULATORS
- A01N25/00—Biocides, pest repellants or attractants, or plant growth regulators, characterised by their forms, or by their non-active ingredients or by their methods of application, e.g. seed treatment or sequential application; Substances for reducing the noxious effect of the active ingredients to organisms other than pests
- A01N25/08—Biocides, pest repellants or attractants, or plant growth regulators, characterised by their forms, or by their non-active ingredients or by their methods of application, e.g. seed treatment or sequential application; Substances for reducing the noxious effect of the active ingredients to organisms other than pests containing solids as carriers or diluents
- A01N25/10—Macromolecular compounds
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- 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
- A61K9/70—Web, sheet or filament bases ; Films; Fibres of the matrix type containing drug
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- B—PERFORMING OPERATIONS; TRANSPORTING
- B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
- B01J—CHEMICAL OR PHYSICAL PROCESSES, e.g. CATALYSIS OR COLLOID CHEMISTRY; THEIR RELEVANT APPARATUS
- B01J13/00—Colloid chemistry, e.g. the production of colloidal materials or their solutions, not otherwise provided for; Making microcapsules or microballoons
- B01J13/02—Making microcapsules or microballoons
- B01J13/04—Making microcapsules or microballoons by physical processes, e.g. drying, spraying
Abstract
The present invention is a method of preparing a system for delivering a bio-affecting agent and the composition prepared thereby. The invention includes forming a solid dispersion of the bio-affecting agent in an increased energy state in a water-soluble polymer which is compatible with the bio-affecting agent. As a consequence of transforming the bio-affecting agent to an increased-energy condition and freezing it in such condition in a water-soluble polymer, the bio-affecting agent is made available ("bio-available") to a bio-system upon dissolution of the polymer. This method and composition has been found extremely effective for delivery of otherwise substantially non-soluble drugs and other bio-affecting ingredients.
Description
CA 022310~0 1998-03-03 WO 97/08950 PCTAJS96/14qS7 S~sTF~l~ FOR RENl)l~l~TNG SUBSl['ANTTA~,T,Y NON-D~[SSOLUBLE
RIo-AFFE~cTING AGI~NTS BIO-AVArl,~Bl,F, This application is a continuation-in-part of copending application Serial No.
08/524,531, filed on September 7, 1995, the entire disclosure of which is incorporated herein by reference.
BACKGROUND OF TEIE INVI~ N
The present invention relates to the art of ~-lminicter~ng bio-affecting agents to bio-systems, and, in particular, for rendering agents, which a.re ~ub~ lially non-dissoluble in an aqueous environment, available for interaction with a host bio-system, e.g., a human or animal.
lBio-systems, such as hllm~nc, plants, insects, fish, birds, and m~-nm~lc, are primarily aqueous systems. In order to effectively ~(1minictçr an bio-affecting agent to such bio-systems, it is necess~ry to make the agent available for interaction with physiological activity in the bio-system. This is referred to herein as "bio-availability." ]n the case of bio-affecting agents which are non-dissoluble in an aqueous environment, as welll as in the case of those which are only poorly water-soluble, effective ~minictration ofthe bio-affecting agent can be difficult due to inadequate bio-availability of the agent and consequent low pharmacological activity.
These solubility problems affect many parameters of adll~ Lion, such as the method of ?~dmini.ctration, the rate of a(lmini.ctration, the concentration of ~dmini~ration, etc.
It is known that rate of dissolution of drug particulates can be increased by increasing the surface area ofthe solid, i.e., decreasing the particle size. Consequently, methods of making finely divided drugs have been studied and efforts have been made to control the size and size range of drug particles in pharmaceutical compositions. For example, dry milling techniques have been used to reduce particle size and thereby infl~l~nce drug absorption.
However, in conventional dry milling, as discussed by T .?l~hm~n et al., The Theory and Pracfice of Industrial Pharmacy, Chapter 2, "Milling", p. 4~5 (1986), the limit of fin~nçcc is reached in the region of about 100 ,um (= 100,000 nm), where the milled material begins to cake onto the surfaces of the milling chamber. Lachman et al. note that wet grinding is beneficial in further reducing particle size, but that flocculation restricts the lower particle size CA 022310~0 1998-03-03 I;mit to applox;~ çly 10,um (= 10,000 nm). There tends to be a bias in the pharm~cel/t art against wet milling due to concerns associated with co~ AI;on. Co""l~elcial airjet milling techniques have provided particles ranging in average particle size from as low as about 1,um to 50 ~m (= 1,000 nm to 50,000 nm).
Other techniques for p,epa,illg pharm~ce~ltical compositions with enhanced aqueous solubility pl op~l lies include loading drugs into liposomes or polymers, e.g., during emulsion poly",e, i~alion. However, such techniques have problems and limitations. For example, a lipid-soluble drug is often required in plepali..g suitable liposomes. Further, unacceptably large amounts of the liposome or polymer are often required to prepare unit drug doses.
10 Further still, techniques for pl~ lillg such pharm~.;e~tical compositions tend to be co--l~ ,x.
A principal technical difficulty encountered with emulsion polymerization is the removal of CO..~ i"~ , such as unreacted monomer or h.i~id~or (which can be toxic) at the end ofthe m~mlf~ct-lring process.
U.S. Patent No. 4,540,602 (Motoyama et al.) discloses a solid drug pulverized in an 15 aqueous solution of a water-soluble high molecular weight substance using a wet grinding m~chine. However, Motoyama et al. teach that, as a result of such wet grinding, the drug is formed into finely divided particles ranging from 0.5 ~m (500 nm) to less than 5 ,um (5,000 nm) in diameter.
EPO 275,796 describes the production of colloidally dispersible systems comprising a 20 substance in the form of spherical particles smaller than 500 nm. However, the method involves a precipitation effected by mixing a solution of the substance and a miscible non-solvent for the substance, and results in the formation of non-crystalline nanoparticles.
Furthermore, precipitation techniques for pl~ .-hlg particles tend to provide particles co..~ ed with solvents. Such solvents are often toxic and can be very difficult, if not 25 impossible, to adequately remove to pharmaceutically acceptable levels. Accordingly pl e.;i~ lion methods are usually impractical.
U.S. Patent No. 4,107,288 describes particles in the size range from 10 to 1,000 nm co..~ a biologically or pharmacodynamically active material. However, the particles comprise a crosslinked matrix of macromolecules having the active material supported on or 30 incol~,o,~ted into the matrix.
CA 022310~0 1998-03-03 W O 97/OX950 PCTrUS96/14~57 U.S. Patent No. 5,145,684 describes a method for providing drug particles having an effective average particle size of less than about 400 nm. Th,e method includçs wet milling the drug in the presence of a grinding medium in conjunction with a surface modifier. As in previous methods, the '684 protocol requires grinding or milling to produce size reduction.
5 The method further requires the use of an additive in the forrrl of a surface modifier.
Moreover, drugs pl ~al c;d by milling, even wet milling such as that described in the '684 disclosure, are subject to degradation resulting from hea.t as well as physical and chemical trauma associated with fracture. Grinding also creates "hot spots," i.e., volumes of localized higher telll~)el ~LIlres which can exceed the melting point or degradation of the drug. The 10 process is also lengthy, requiring attrition exposure over several days. This type of process effectively exposes the drug to a long "heat history", wherein exposure to elevated temperatures has been significant, and the purity and potency ofthe drug is rl;",;".~ d to a significant extent. Furthermore, particles reduced by milling ~re often co..~ ed by the residue of the grinding operations, especially when ball milling is used and the grinding balls 15 are worn down by abrasion.
It has also been known in the art of drug delivery to improve bio-availability by aggregating substantially non-dissoluble active ingredients on the surface of soluble sub~ es, such as water-soluble beads. The active ingredient can be deposited on such substrates by spraying a solution of the active ingredient over a fl~ ed bed while "flashing off" the solvent 20 used for the active ingredient. This method is highly inefficient in that it requires several hours to deposit a sufficient amount of active ingredient to prepare a useable delivery system.
Furthermore, an additional ingredient which is unnecessary to the system must be used, i.e., the solvent required to dissolve the active ingredient. As previously mentioned, the solvent must be flashed offduring agglegation. Thus, this system is a long and cumbersome process 25 and does not provide efficiency of dosage delivery.
Solubilization techniques for drugs which have low aqueous solubility require the use of organic solvents for processing in a solution state. This requires the use of expensive recove~y systems for solvent h~ntlling capability. When general melt processing techniques are used to form dispersions, bulk melting and mixing steps often expose the drug to a prolonged 30 heat history.
CA 022310~0 1998-03-03 It is desirable to provide stable dispersible drug particles in the sub-micrometer size range which can be readily p~ epal ed in the absence of size reduction by grinding or milling.
Moreover, it ~,vould be highly desirable to provide pharm~ceutical compositions having Pnh~nced bio-availability.
It is, Il-el erol e, an object of the present invention to overcome the disadvantages associated with methods for pl epa- ;ng delivery systems for bio-~ g ingredients, especially those which are subsl~Lially non-dissoluble. As a consequence of o~el co",ing the drawbacks known in the art, it has been found that other and further objects which enh~nçe the art of delivery systems have been realized as a result of the present invention.
SUMM~RY OF T~ INVFl~TION
The invention is a composition for delivery of a bio-arr~ g agent to a bio-system, and a methods of making and using a delivery system which in~ludçs a bio-affecting agent.
The composition and method include the use of:
a solid dispersion of the bio-affecting agent in an increased-energy state in a water-soluble (or water-dispersible) polymer which is eo-"~alible with the agent and which has a glass transition te"")e~ re (Tg) in the range of from about 0~C to about 200~C, whereby the agent is rendered bio-available in an aqueous envholu~w~l.
Preferably, the water-soluble polymer is any polymer which has a glass transition temperature in the range offrom about 25~C to about 150~C, and more preferably in the range offrom about 40~C to about 100~C.
Pl ere, l ed water-soluble polymers include polymethacrylic acid polymers. Preferably, the polymeth~crylic acid polymers have the structure:
----C--CH2--C--CH2--C--CH2--(~--CH2---Cl=O IC=O ~=0 ~=0 (1) CA 022310~0 1998-03-03 W O 97/0~950 PCTAUS96/14457 wLere;n: Rl, R2, R3, R4 are any substituents provided that the polymer has a glass transition temperature in desired range. Accordingly, Rl, R2, R3, R4 preferably are independently hydrogen ~IH) or any alkyl, airyl, alkaryl, aralkyl, alrninoalkyl, a.lkyl-substituted aiminoalkyl, ~..l"onioalkyl, or alkyl-substituted ammonioalkyl group. Still more plere.~bly, R', R2, R3, R4 5 in Structure (1) are independently H, Cl-C6 alkyl, ~mino~likyl, methyl- or dirnethyl-aminoallyl, or methyl-, di nethyl-, or trimethyl-ammonioalkyl. Yet more ~ f~l~bly, in Structure (1):
Rl is H, CH3;
R2 is H, CH3, C2H5, CH2CH2N(CH3)2;
R3 is H, CH3; and R4 is CH3, C2H5, C3H" C~Hg, CH2CH2N(CH3)3+X-, wherein X~ is any monovalent anion.
A highly prere" ed water-soluble polymer is a terpolymer of butyl methP~c.rylate, (2-dimethyl aminoethyl) methacrylate, and methyl methacrylate in relative proportions 1:2:1.
Preferably, the water-soluble polymer is a polymer having pH-ser.sitive solubility in 15 aqueous media. The water-soluble polyirners pl e~ Lially have solubility in aqueous media having a pH of from about 1 to about 11. More p~c;rel~bly, the water-soluble polymer has solubi1ity in acidic aqueous media, i.e., having a pH of about 7 or less.
The bio-affecting agent can be any agent known to have an effect in a biologicalsystem. Plerelably, the bio-affechng agent is substantially non-dissoluble in an aqueous 20 envholll"~ L. More preferably, the bio-affecting agent has a solubility which is defined as practically insoluble or insoluble according to the USP. The bio-affecting agent is preferably selected from the group consisting of antifungals, anti-infl,.mm~tories, anti-hypertensives, antimicrobials, steroidal drugs, hormones, prost~gl~n-1in~, interferons, and mixtures thereof.
Moreover, the composition comprising the bio-affect;ng agent and the water-soluble 25 polymer preferably mee$s or exceeds USP dissolution standards for the agent.
The composition of this embodiment can include a solid dispersion provided by flash-flow processing a feedstock including the bio-affecting agent and the polymer. The flash-flow processing can be flash heat processing or flash shear processing. The flash heat processing method is particularly pl erel ~ ~d when processing bio-affecting agents which are 30 heat-sensitive. Alternatively, the solid dispersion can be provided by extrusion mixing for a time sufficient to form the solid dispersion. Preferably, the t;me of extrusion mixing is less s CA 022310~0 1998-03-03 W O 97/08950 PCT~US96/14457 than about 2 minllt~s, more preferably, less than about 30 seconds. When the solid dispersion is provided by extrusion mixing, it is highly pl crel I cd that the bio-affecting agent is an ~ntifimg~l, anti-;.,ll;t~ oly, or anti-hypertensive agent.
The composition of the invention incllld~s the bio-affecting agent in an at least 5 s~L~,lially uniform or amorphous solid dispersion. Preferably, the bio-~rc.;lil~g agent is present in the form of nanoparticles distributed throughout the solid dispersion. More plcrel~bly, the nano~al licles have an average particle size of less than about 1000 nm. Still more p~ crcl ~bly, the average particle size of the nanoparticles is less than about 400 nm. The bio-affecting agent can be dispersed in the water-soluble polymer at the molecular level.
The composition can be prepared as a controlled-release particulate by mççh~nically red~lcing the solid dispersion. Preferably, the particulate is part of a dosage unit, which is plcrcl~ly selected from the group consisting of ç~psllle~J tablets, and rapid-dissolve tablets.
Alternatively, the solid dispersion is sized and shaped for fixation in an intravascular (or other ,(JalCnlCI ~1) delivery apl)al~lus. Moreover, the solid dispersion can be provided in the form of a slow dissolving structures such as a suppository or a lozenge or the like.
The method inr,llldçs .~imlllt~neously l~nsrol.l,ing the bio-~rrcclillg agent to an increased-energy state and fixing the agent in that state. The method can include ~imlllt~neously ~ n~rull"h~g and fixing by flash-flow processing. This method inr,ludçs use of flash heat processing or flash shear processing. Heat-sensitive agents are beneficially processed by flash heat processing. Alternatively, the ~iml~lt~neous L,~n~ro,."i"g and fixing can be effected by extrusion mixing for a time sufficient to form the solid dispersion, plercl~bly for a time of less than about 2 minllte~, more preferably less than about 30 seconds.
In the latter approach, the bio-affecting agent is most prcre,~,bly an ~ntifilng~
anti-;..... ....n~ tory, or anti-hypertensive agent.
The method of tran~rol Illhlg the bio-affecting agent into the increased-energy state can include redllc.ing in the absence of mechanical attrition, the bio-affecting agent to dispersed nanoparticles having an average particle size of less than about 1000 nm. More preferably, the mer.h~nical re~ucing yields an average particle size of the nanoparticles of less than about 400 nm. Alternatively, the method can be used to disperse the bio-affecting agent at a molecular level to provide a solid solution.
CA 022310~0 1998-03-03 W O 97/08950 PCTrUS96/14457 The method can further include mechanically re~u~ing the solid dispersion to particulates. Thus, the rnethod can further include incorpora!ting the particulates in a dosage unit, such as a capsule or a rapid-dissolve tablet. Alternativc:ly, the method can further include sizing and shaping the solid dispersion for fixation in an intra.venous (or other l)a~ tel~l) fluid 5 delivery device. Lozenges, suppositories, and other slow release delivery structures can also be employed to deliver the bio-affecting agent.
The invention filrther inrl~ldçs method and composition for delivery of a bio-affecting agent. The composition produced by the method includes:
a) a carrier comprising a water-soluble polymer having a glass transition temperature 10 in the range offrom about 0~C to about 200~C; and b) a bio-affecting agent microscopically disl,e. ~ed in said water-soluble polymer.
Plt;rel~bly, the water-soluble polymer has pH-sensitive solubility in aqueous media. In particular, it is pl~rel I ed that the water-soluble polymer be substantially indissoluble in saliva but soluble in gastric fluid.
The invention is also a method for delivering a composition of a bio-affecting agent, as described, to a bio-system. The method includes ~ rlmini~tering to the bio-system a solid dispersion cOIlllplisillg the bio-affecting agent fixed in an increased-energy state in a water-soluble polymer having a glass transition temperature in the range offrom about 0~C to about 200~C, wherein the solid dispersion 20 renders the bio-affecting agent bio-available to the bio-systern.
The method and composition of the invention possess numerous advantages over theprior art. For example, the method of processing a bio-affecting agent with a water-soluble polymer to form a solid dispersion according to the invention avoids use of solvents or mech~nic~l attrition or co.. ~ tion~ which methods have various disadvantages detailed 25 hereinabove. Moreover, the method substantially decreases the heat history of the bio-a~eling agent, with the advantage that the agent remains substantially less degraded or decomposed throughout the processing. The method and composition of the invention also dr~m~tic~lly enhance the bio-availability of bio-affecting agents which are otherwise substantially non-dissoluble in aqueous environments, thereby enabling delivery of such agents 30 to bio-systems with greater ease and simplicity and through more routes than has heretofore been possible.
CA 022310',0 1998-03-03 These and further advantages will be appreciated by those skilled in the art in view of the following detailed description of the invention and the drawings as set forth below, and the scope of the invention will be pointed out in the appended claims.
RRTF,F DF.~CI~TPTION OF T~ DR~WINGS
Figure 1 is a graph which shows the effectiveness of the present invention by depicting the profile of the dissolution characteristics of a solid dispersion prepared by flash heat procç~ing according to the present invention.
Figure 2 is a graph showing the dissolution profile of bulk niredi~ .c which has not been prepared for çnh~nced dissolution.
Figure 3 is a graph which shows the effectiveness ofthe present invention by depicting the profile of the dissolution characteristics of a solid dispersion of niredipine pl epal ed by extrusion processing according to the present invention.
Figure 4 is a graph which shows the effectiveness of the present invention by depicting the dissolution profile for solid dispersions of an ~ntifilng~l drug pl~palt;d according to the present invention as contrasted against the dissolution profile of a known delivery system for the ~ntifilng~l agent and the dissolution profile ofthe bulk antifilng~l agent which has not been plepaled for çnh~ncecl dissolution.
Dli'T~n,li'D DF.~C~TPTION OF T~F INV~NTION
The present invention is a composition and method of pl epaling a composition for delivering a bio-affecting agent and rendering the bio-affecting agent bio-available in an aqueous environment. The composition of the present invention can be referred to as a solid dispersion of the bio-affecting agent in a water-soluble polymer.
The present invention is both a composition and method for delivery of a bio-affecting agent to a s--bslallLially aqueous bio-envilonlllel.l. The present invention renders the bio-affecting agent more bio-available in the aqueous environment. The method for plepa-i--g the unique composition of the present invention inçl~ldeo, 1 ) ll ansrc l l-lh~g the bio-affecting agent to an "increased-energy" state, and 2) fixing the bio-affecting agent in the "increased-energy" state in a water-soluble polymer. The terrns "increased-energy" or "higher energy" state refer to the stable dispersion of a bio-affecting agent or drug in a solid matrix, CA 022310~0 1998-03-03 such that the bio-affecting agent is either dispersed at a molecular level or is dispersed in microscopic particulate domains having an average particle size of less than 1000 nm, and p,t;~.~bly less than about 400 nm. The increased energy state is achieved by modifying particle formation rather than by size reduction through grinding or attrition. Generally, the 5 invention l~ ~n~r" ~s the bio-affecting agent into solution form or n~op&~ licle form which has a higher surface energy or free energy than, for example, native crystals which can have an average size of over 10 ,um.
The composition of the present invention is described herein as a solid dispersion of the bio-affecting agent in the water-soluble polymer. Upon dissolution of the polymer in the 10 bio-system, the bio-affecting agent is rendered bio-available to the host. "Bio-availability" as used herein means that the bio-affecting agent is taken up by the host bio-system for interaction with the bio affecting agent. The me~ ", for being "taken up" in~ludes, but is not limited to, absorption, adsorption, tran~Çe,~l~ce, cohesion, adhesion, chemical, biological, and biochemical reactions, etc.
The invention inrlproves the bio-availability of bio-affecting agents, especially those whose activity is otherwise limited or çlimin~ted because of their relative inability to be dissolved into aqueous media. The term "substantially non-dissoluble" is applied to materials which are either substantially insoluble in water or are not w;ater-soluble to any appreciable degree. Thus, substantially non-dissoluble bio-affecting agellts include those bio-affecting agents which are either non-soluble or only sparingly soluble in biological fluids, such as blood, Iymph, gastrointçstin~l fluids, cerebrospinal fluid, plant saps, and the likê. The bio-affecting agents typically are not enterosoluble as defined hereinbelow.
A material may be said to be "substantially non-dissoluble" if it has a solubility of less than 10 mg/rnL in water (or other aqueous merlium) having a pH of from about I to about 8.
The solubility of any substance in an aqueous me~ m is a property which is readily determined by a skilled artisan. In fact, thê solubilities of many substances, including drugs, are known and published in compendia such as The Merck I~i~dex, 1 2th edition ( 1996). Most preferably, the bio-affecting agent has a solubility low enough to qualify the agent as "practically insoluble, or insoluble" as defined by the USP. According to this definition, the bio-affecting agent is substantially non-dissoluble if it has a solubility requiring at least 10,000 parts of solvent (aqueous medium) for I part of the solute (bio-affecting agent).
CA 022310~0 1998-03-03 W O 97/08950 PCT~US96/14457 It is believed that all bio-affecting agents can be used in the present invention, bu~ t~e invention is particularly directed to col"bining a subst~nti~lly non-dissoluble bio-affecting agent with a water-soluble polymer in a unique manner to render the non-dissoluble agent bio-available. Substances which would otherwise be capable of being bio-afIe~ g as defined S herein, but which qualify as substantially non-dissoluble, are pl erel I t;d for delivery accol .lillg to the invention. It is also contemplated that a subst~nti~lly non-dissoluble bio-affecting agent can be used in collll~illalion with other substances, incl~ ing other bio-a~eclillg agents, which are s~sla,llially more soluble in aqueous media.
The polymers which are useful as "water-soluble polyrners" in the present invention 10 include polymers, copolymers, terpolymers, interpolymers, polymeric ~m~lg~m.e, etc., having molecular weights which range from oligomers to high molecular weight polymeric substances and polymers having pH dependent solubility characteristics.
"Water-soluble," as used herein, applies to polymers which readily dissolve or disperse in water and other aqueous media at any or all pH values without the ~Csict~nce of a 15 dissolution-promoting substances such as surf~ct~nte, emulsifiers, etc. The fact that the polymer does not require an agent to mediate its dissolution in an aqueous envil un~ lll does not mean, however, that delivery systems pl epal ed in accordance with the present invention do not include such agents. In order to engineer the apl)l op, iate delivery system, any additional substances which are required to control, promote, mediate, or modulate the 20 bio-availability of the bio-affecting agent(s) can be used. These substances are referred to herein as "bio-availability promoters." Furthermore, col,lbillaLions of bio-availability promoters can be used in the present delivery systems.
By virtue of the present invention the bio-availability of a bio-affecting agent is çnh~n~ed by altering the physicochemical condition of the bio-affecting agent. This is 25 achieved by processing the bio-affecting agent with a water-soluble polymeric carrier to produce a solid dispersion of the bio-affecting agent in the polymer. By "solid dispersion" is meant an appal enlly homogeneous solid substance which consists of a microscopically heterogenous mixture of the bio-affecting agent and the water-soluble polymer (and other materials as otherwise defined herein). In conventional terminology, the bio-affecting agent 30 conctitutto.s the "dispersed phase", while the water-soluble polymer con.etitutçc the "dispersion medium" or"continuous phase."
CA 022310~0 1998-03-03 W O 97/08950 PCTrUS96/144~7 1[ he method(s) of the present invention can be used to make solidl dispersion col,.po~iLions which are either:
a) Solution systems where at least a portion, and pl ere. ~bly all of the bio-affecting agent is in solution phase with the polymer or dispersed at thle molecular level (i.e., "molecular dispersions"); or b) Heterogenous systems where the bio-affecting agent is present in more or lessdiscrete supramolecular domains (nanoparticles), which may be aggregates of molecules, ulllrul ~ y dispersed within the polymer. Furthermore, as a result of the q~lenchin~ of the water-soluble polymer in accordance with the present invention, the bio-a~i~in~ agent is prevented from forming macro-scale distinct phases or large domains in the final product.
As noted, the solid dispersion can include discrete domains of the bio-~ffec~ingsubstance distributed substantially homogeneously throughout the polymeric me~ m When present, these discrete domains are generally referred to herein as "nanoparticles." In the case of cryst~lli7~hle bio-affecting agents, the domains of the bio-affecting agent might be desi~n~ted "nanocrystals." These terms connote the extraordinarily small dimensionality of the dispersed phase of the solid dispersions of the invention. Specifically, the particles of dispersed phase in the solid dispersions are typically of the order of nanometers (~I x 10-9 m) to hundreds of nanometers (~100 x 10-9 m). Thus, the scale of such particles is conveniently referred to as "nanometer-scale" or "nanoscale." It is believed that this feature of the proceccin~ method of the invention significantly contributes to increasing the bio-availability of the bio-affecting agent.
Other solid dispersions according to the invention include the bio-affecting agent dispersed at the molecular level through the water-soluble polymer. These solid dispersions of the invention may be characterized as solid solutions, since they meet the criteria conventionally reserved for solutions. Typically, little or no supramolecular o~gani~alion is present in such solutions. However, it must be recognized that a solid dispersion according to the invention can include the bio-affecting agent in a range of physical states ranging from molecular dispersion to amorphous or pre-crystalline associat.ions of molecules to nanoparticulate domains.
The solid dispersions of the invention, therefore, refer to intim~te mixtures of two or more colllpollenLs which form a contin~n-m wherein substantially all domains of the CA 022310~0 1998-03-03 bio-* rr~.~ g agent have a higher entropy than the entropy of the agent in its native condition.
As a result of forming the solid dispersions of the present invention, the bio-affecting agent is fixed or frozen in the solid water-soluble polymer in an increased-energy state."Increased-energy state" as used herein means a physicochemical condition of the bio-affecting 5 agent which has a higher entropy than the bio-affecting agent would have in its native con-1ition For CA~ C~ the bio-a~e~;ling agent is, in a pl~;relled embodiment, converted to a s .l,sl~-lially amorphous form and dispersed throughout the water-soluble polymer in the melt condition such that, when the agent crystallizes (if, in fact, it does crystallize), the average clystal size will constitute particles of nanoscale dimension, i.e., nanop~ Licles. The 10 bio-~rrec~;.u agent is thereby captured in a highly randomized condition as co---,~a~ed to the bio-affecting agent in its native form. The increased energy state of the present invention is sufficient to render the drug more bio-available in an aqueous enviloll---e-". As previously cl~ssed herein, bio-available means a condition which permits the active ingredient to interact with, i.e., become available for use in, the target bio-system, i.e., the body of the host lS animal or human patient.
The composition of the present invention, referred to herein as a solid dispersion, can be formed by a number ofter.hniqlles In one plere..ed embodiment the solid dispersion is formed by subjecting a feedstock which includes both the agent and the polymer to flash-flow processing. Flash-flow processing is defined hereinbelow and incl~ldes both flash-heat processing and flash-shear processing. Alternatively, it has been found that the solid dispersion of the present invention can be provided by extrusion mixing the agent and the polymer for a time sufficient to l- ~n~ro~ ~-- and fix the agent during quenching. In a ~. ~re. . ed embodiment, the time required to extrusion mix the ingredients is less than about two minutes (2 min), and is preferably less than about thirty seconds (30 sec).
As a result of the present invention, the bio-affecting agent can be provided as a solid dosage form which has an ~.nh~nced dissolution rate which can often be ~imlll~ted by in vi~ro data. It is theorized that the increases in dissolution rate are achieved by a combination of effects, the most significant being the reduction of particle size to an extent not achieved by conventional comminution approaches. The smaller size particle (i.e., the nanoparticles of the invention) appalenlly imparts to the bio-affecting agent a higher surface energy or free energy than the agent has in its original or native state, providing for enhanced solubility in water, CA 022310~0 1998-03-03 W O 97/08950 PCTnUS96/14457 generally co~ onding to çnh~nced bio-availability in the bio-system. As previously mentioned, techniques known to date for producing dispersions in the prior art generally require either the solubilization or melting of a drug with a freely soluble carrier in a water-like (low viscosity) state, followed by further processing to p~ ecip~ le or congeal the material into 5 a solid forrn.
The technique and composition of the present invention has inherent advantages in the production of solid dispersions of bio-aa~ g agents. As a result of the present invention, the bio-~cl~ agent and the carrier polymer can be combined in a process which mixes, melts, forms, and solidifies in a continuous process, to provicle the bio-affecting agent in a 10 solid solution or dispersion and having an increased energy clondition as defined hel~i--ab~/e.
The resulting compositions are easily employed to make any of a variety of delivery systems, inc~ 1in~ tablets, etc., which would otherwise be incapable of effectively delivering the bio-affecting agent.
Another very important advantage of the invention is that the bio-affecting agent is 15 exposed to a lower heat history during the process of being rendered bio-available. The heat history required in the inventive process is very short co...pa.ed to conventional teçhniques used in the formation of congealed materials. Consequently, the process of the invention induces less degradation or decomposition of the bio-affecting agent, meaning that purity and potency are improved over prior art systems. This is particu]larly beneficial for those 20 bio-affecting agents which are heat-sensitive.
The systems of the present invention are implemented by the use of bio-affectingagents and water-soluble polymers which are "compatible" v~ith each other. The term "compatible" is used herein to mean that the polymer has physical characteristics which render it processable according to the invention. Specifically, the water-soluble polymer must be 25 capable of being processed at ternperatures at or above the melting point (Tm) of the bio-affecting agent but below the temperature of decomposition (Td) of the bio-affecting agent and the polyrner. Consequently, it is preferable to use a polymer which is flowable (generally, thermoplastic) at a temperature which is equal to or above the melting point of the bio-affecting agent, but below the decomposition temperature of either the agent or the 30 polymer itself.
CA 022310~0 1998-03-03 WO 97/08950 PCTrUS96/14457 Moreover, bio-affecting agents and polymers are said to be "con~paLible" if they ~re soluble or dispersible in each other in the flowable/non-decomposition stage. For example, if one were to visualize the bio-affecting agent/water-soluble polymer composition immediately after soli~ific~tion, in many cases it would appear substantially as a lran,l,a~enl or tr~nclllc~nt 5 glass, i.e., any inhomogeneities are of a scale such that one cannot visually di~tin~ h the solubilized bio-arrecLi,-g agent from the water-soluble polymer.
Co---palil,ility herein also means that the polymer and bio-affecting agent solidify such that the bio-affecting agent is captured in an "increased-energy" condition and held stably in that state following completion of solidification. The bio-a~.;li"g agents may later crystallize, 10 but any crystals which form are of the order of nal opa. Licles, i.e., the crystals will have a condition of considerably higher entropy than the native crystals of the agent, which have an average particle size generally in the range of from about 10 ~m to about 50 ,um. If the polymer and bio-affecting agent solidify at rates which permit the bio-affecting agent to form domains which es.~enti~lly return the bio-affecting agent to a lower entropy form, e.g., a crystal 15 size which appr xim~tes the agent in its native condition, then the combil-~lion is not considered col--palil)le as defined herein. More importantly, little or no improvement in bio-availability is obtained by such incol--palible co...l)inalions. Thus, compatibility further means that the polymer is capable of being quenched or formed into a solid along with the bio-affecting agent such that the bio-affecting agent is not permitted to return to a lower 20 energy state, or to a condition of particles having an average size of greater than about 1000 nm.
It is, of course, pl er~- l ed that the polymer have physical characteristics which promote the formation of solid dispersions described herein. Applicants have unexpecte-lly found that glass transition temperature (Tg) is a property of polymers which correlates well with the 25 ~ fillness of polymers in the method of the invention. In particular, Applicants have found it to be pl ere- ~ ed that the polymer has a Tg in the range of from about 0~C to about 200~C.
More preferably, the polymer has a Tg in the range offrom about 25~C to about 150~C. Still more preferably, the polymer has a Tg in the range offrom about 40~C to about 100~C.
Applicants have found that Tg is related to the flowability or processability of the 30 polymer, with a lower Tg generally correlating with a lower viscosity at a given temperature.
Polymers having a Tg outside of the temperature ranges set forth above are less desirable. On I
the one hand, if the T8 is too high, the polymer will tend to be too viscous, making the polymer difficult to process. On the other hand, if the T,~ is too low, the polymer may not be viscous enough to effectively capture or freeze the bio-affecting agent in the desired increased-energy state. Moreover, Applicants have found that the polymers ch~aracterized by the T8 ranges 5 given above tend to have solubilities in aqueous em/i~onlme"L j sufficient to render them effective for ~nh~n(ing the bio-availability of nor-dissoluble Ibio-a~e~ g agents.
The polymers useful according to the invention generally also meet other physicochemical characteristics. For example, the polymers useful in this invention generally have an average molecular weight of above 500 daltons (Da), and p, ert;l,lbly above 1500 Da.
Polymers having molecular weights of 100,000 Da or more mlay be p,~r~"ed for particular applications. Also, the water-soluble polymers of the presenl; invention preferably have an intrinsic viscosity of from about 1,000 centipoise (cP) to millions of cP, and a melt viscosity of from about 50 cP to about 100,000 cP. The viscosity ofthe polymer can be measured by a Brookfield Viscometer. It is also believed that polymers which do not crystallize are probably 15 preferable to those which do crystallize, but this property is not well understood.
Polymeth~crylic acid polymers (also I~Ç~lled to herein as "polymethacrylates") are among the water-soluble polymers p-er~ d for use accordimg to the invention. For example, p,erel-ed polymethacrylates have the general structure:
Rl R3 Rl R3 --CH2~--CH2~--CH2~ CH2---C=O ~=0 IC=O IC=~O (I) 1~ ~ 1~
20 wherein: R', R2, R3, R4 are independently hydrogen (H) or any alkyl, aryl, alkaryl, aralkyl, aminoalkyl, alkyl-substituted aminoalkyl, ammonioalkyl, or alkyl-substituted ammonioalkyl group.
Preferably, Rl, R2, R3, R4 are independently H, Cl-C6 alkyl, amino (Cl-C6)-alkyl, methyl- or dimethyl-aminoalkyl, or methyl-, dimethyl-, or trirnethyl-amrnonioalkyl.
CA 022310~0 1998-03-03 W O 97/08950 PCT~US96/14457 More preferably the polymethacrylates of Structure (1) have the following substit~l~nt~
Rl is H, CH3;
R2 is H, CH3, C2H5, CH2CH2N(CH3)2;
R3 is H, CH3; and R4 is CH3, C2H5, C3H" C4Hg~ CH2CH2N(CH3)3+X-. wherein X~ is any monovalent anion, preferably Cl~.
Exemplary polymethacrylic acid polymers are described in detail in A.J. Shukla, "Polymeth~rylates", pp. 362-366 in Handbook of Pharm~( et~fic~ ~cipients, 2d ed., Ainley Wade and Paul J. Weller, eds. (1994). A large number ofthese polymers are available as coating materials under the EUDRAGIT trade name from Rohm GmbH. One polymer found to be particularly effective is a methacrylic acid ester terpolymeric product of butyl mP.th~rylate, (2-dimethyl aminoethyl) methacrylate, and methyl methacrylate in proportions 1:2:1, sold as EUDRAGIT E.
It is ~l~;rel-ed that the water-soluble polymers be polymers whose solubility ispH-sensitive. Specifically, the polymer is said to be pH-sensitive if its solubility in an aqueous m~rlillm is affected by pH. Preferably, the water-soluble polymers used in the method and composition of the invention have higher solubility at pH 1 to pH 10, than at a pH outside this range. More pre~--ed polymers are those which are subst~nti~lly more soluble at acid pH
than at neutral or basic pH. Thus, the water-soluble polymer is desirably soluble below pH 7.
By sPlectin~ a water-soluble polymer havirig a pH-sensitive solubility, specifically an acid-sensitive solubility, solubility ofthe solid dispersions ofthe invention can be .~ d until the material are exposed to acid conditions. Thus, materials can be m~mlfs~ctllred which are subsla~lLially indissoluble in saliva but soluble in gastric fluid, thereby permitting selective control over the bio-availability of the bio-affecting agent. (In certain applications, namely delivering the bio-affecting agent to the intestine, the water-soluble polymer preferably has an alkali-sensitive solubility.) All such polymers are terrned ~'enterosoluble."
Plerell~d enterosoluble polymers can also be defined according to the comonomersfrom which they are prepared. For example, the copolyrners and terpolymers of methacrylic acid with methyl acrylate and/or methyl methacrylate are highly pler~ d, having solubilities in CA 022310~0 1998-03-03 W O 97/08950 PCTAUS96/14~57 the range offrom about pH 5.5 to about pH 7.2. Such polymers have been described for use as enteric coatings for tablet plepa,~ion. T ~çhm~nn et al., "New methacrylic acid copolyrners for improved coating technology," Presentation from AAPS Tenth Annual Meeting (1995), published by Huls America Inc.
S The EUDRAGIT polymers possess solubilities which are sensitive to pH, meAning that their solubilities may be higher at certain pHs and lower at otlhers. Depending upon pH, the solubility of these polymers can vary over an order of mAgnitlJIde or more. Certain of the polymetllAcryla~es have high aqueous solubility under acidic c,onditions, and have been used to promote rapid release of active agents in the gastric region of the ga~ e~ tract. The EUDRAGIT E product has such acid-sensitive solubility, being soluble in gastric fluid and weakly acidic buffer solutions (i.e., less that about pH ~). Others are p~erere,llially soluble in mild alkali (e.g., pH 6-7) and therefore are suitable for delivel ing bio-affecting substances to the i~.le~ e while bypassing the gastric region. However, thlese polymethacrylates have not been employed as solid solution carrier materials for bio-arre~,ling agents, a new application to which Applicants have unexpectedly found them to be very v~rell adapted.
Preferably, the bio-affecting agents suitable for use in the method and composition of the invention are drugs which are potentially bio-affecting to slnim~lc, incl~ltling humans and other m~mmA1e A non-limiting list ofthese bio-affecting agents in~ludçc, for example:
antitl-e~iives~ Antihi~tAmine~, deconge~L~Ls, alkaloids, mineral supplements, laxatives, vitamins, AntAritl~, ion f~Y~.h~nge resins, anti-cholesterolemics, anti-lipidl agents, anlia"l,~thrnics, antipyretics, analgesics, appetite sllpplessal-ls, expectorants, anti-anxiety agents, anti-ulcer agents, anti-inflAmmAtory substances, coronary dilators, cerebral dilators, peripheral vasodila~ors, anti-infectives, antifungals, antivirals, psychotropics, A.,l;...Al-ics, sfimulAnt~
gastroin~-estinAl agents, sedatives, antidiarrheal plepa,~Lions, anti-anginal drugs, vasodilators, 25 anti-hypertensive drugs, vasoconstrictors, migraine ll~inlll~ 7 antibiotics, tranquilizers, anti-psychotics, antitumor drugs, anticoA~ nt~i, antithrombotic drugs, hypnotics, anti-emetics, anti-nAnc~nt~, anti-convulsants, neuromll~clllAr drugs, hyper- and hypoglycemic agents, thyroid and anti-thyroid preparations, diuretics, antispasmodics, uterine relaxants, mineral and nutritional additives, anti-obesity drugs, anabolic drugs, erythropoietic drugs, 30 anti-A~thmAtics, cough supplessal-ls, mucolytics, anti-uricemic drugs, prostAElAndin~
il.Le,~el-ons, cytokines, steroidal and peptide hormones, ploteii,l-s, and mixtures thereof.
CA 022310~0 1998-03-03 W O 97/08950 PCT~US96/14457 Other bio-affecting agents for use in the present invention include antidiarrheals such as IMODIUM AD, ~ntihi~ es, ~ntitllssives, deconpe~ vitamins, and breath r,c;shelle, ~. Also contemplated for use herein are anxiolytics such as XANAX; antipsychotics such as CLOZARIL and HALDOL; non-steroidal anti-il.n~.. ~lories (NSAID's) such as S VOLTAREN and LODINE; antihi~ .;..Fs such as SELDANE, HISMANAL, RELAFEN, and TAVIST; antiemetics such as KYTRIL and ces~met; bronchodilators such as bentolin, PROVENTlL; antidel.ressa.,L~ such as PROZAC, ZOLOFT, and PAXIL; anti-migraines such as imigran; ACE-inhibitors such as VASOTEC, CAPOTEN and ZESTRIL; anti-Alzheimer's agents such as nicergoline; and CaH-antagonists such as PROCARDIA, ADALAT, and 10 CALAN.
The popular H2-antagonists which can be used include ~imetitlin~ r~niti~ine hydrochloride, famotidine, ni7~ti~ine, ebrotidine, mifentidine, rox~titline, pi~til1ine and ace~ l ;(1inP
The invention is especially useful for the following sul,~a"~ially non-dissoluble 15 compounds: vasodilators such as nicergoline; anti-infl~mm~tories, antipyretics, and ~n~lgPcics such as indometh~in; antiarthritics such as diacerin; progestogens, palliative lle~ P~-t compounds for breast and endometrial carcinoma, and estrus regulators such as megestrol;
sedatives and hypnotics such as barbitals; ~n~lgesics, anticonvulsants such as ca,ba...~7epine;
antihy~e, lensi~es such as niredi~ e; uricosurics such as probenecid; anti-~ngin~l~ such as 20 felodipine; ~nti~p~modics such as fenalamide; plant fungicides such as fenarimol; and anti-h~ l.ics such as ferldçn(l~7Qle.
In prere,.ed embodiments the bio-affecting agents include ~ntifi~ng~lc7 anti-;.. n;~.. ~ories, anti-hypertensives, antimicrobials, steroidal drugs, hormones, prost~gl~ndin~, interferons, and mixtures thereof.
In the case of one pl er~ d embodiment, it has been found that the substantiallynon-dissoluble bio-affecting agents ibuprofen and nifedipine are each coml,d~ible with the acid soluble polymer known as EUDRAGIT E, a copolymer based on dimethylaminoethyl mPth~crylate and other neutral methacrylic acid esters, and marketed by Rohm GmbH. This polymer is available in solvent free granules (EUDRAGIT E 100) and in a 12.5% solution in propan-2-ol/acetone (60:40) (EUDRAGIT E 12.5). EUDRAGIT E has high aqueous solubility especially under acidic conditions (below pH 5) and provides for rapid release of the CA 022310~0 1998-03-03 drug in the gastric region of the gastrointestin~l tract. Although the polymer is principally amorphous, microcrystalline domains of the polymer can be identified in the virgin polyrner.
Irl a p.ere,-ed embodiment, the process of the present invention can be implem~onted by flash-flow processing. Flash-flow processing is achieved by subjecting feedstock to S ~imlllt~neoll~ application of heat and shear sufficient to perrnit L~ rol.llaLion ofthe morphology of the feedstock. Flash-flow processing creates a. condition of internal flow which means that the feedstock material is enabled to move and separate at a sub-particle level. In this embodiment, the feedstock would include a water-soluble polymer and a sub~ ally non-dissolub1e bio-affecting agent.
Flash-flow processing can be effected by flash-heat processing or flash-shear processing. In a pl~r~ d embodiment, the present invention collle~ lates flash-flow processing by the flash-shear method which is described in con~ ol-ly known U.S. Patent No.
5,380,473 to lBogue et al., the contents of which is incorporat~d herein by reference. The process reported in the Bogue et al. '473 patent is characterized by increasing the temperature of a non-solubilized feedstock carrier to a point at which it undergoes internal-flow, followed by forcibly expelling or ejecting a stream of the feedstock and. subjecting the stream to disruptive fluid shear force which separates the stream into separate masses having tran~-.--ed morphology.
In an alternative embodiment to the flash-shear method, the components of the present invention can be mixed and processed in a mix extrusion method without the benefit of forming disrupted masses as in the flash-shear method. As a rnost pl ~re. . ~d mode of operation of this alternative embodiment, the feedstock materials e.g., a water-soluble polymer and a subst~nti~lly non-dissoluble bio-affecting agent (without solubilizing additives) are subjected to mix extrusion over a very short period of time, ~ erel ~bly not more than about two min~ltes7 and most preferably not more than about thirty seconds.
Another contemplated embodiment includes processing the co.llponents in a flash-heat process which creates conditions such as those found in cotton candy m~c.hines. In this process, the feedstock is introduced to a spinner head in which it is subject to heat and shear created by centrifugal force from the spinning head. Disclosures which relate to methods and appal~L~Is suitable for spinning substances include the following: U.S. Pa~ent No. 4,855,326;
CA 022310~0 1998-03-03 W O 97/08950 PCTrUS96/14457 U.S. Patent No. 4,873,08S; U.S. Patent No. 5,034,421; U.S. Patent No. 4,997,856; and U.S.
PatentNo. 5,028,632.
Examples in the U.S. patents listed above describe processing feedstock material by subjecting it to high speed spinning on spinning head in which the feedstock is also subjected 5 to heat provided by a heating element. The change of temperature is quite large, which is believed to be occasioned by the spinning head quickly and efficiently spreading the feedstock material against the heating element circu",~ere"Lially disposed around the perimeter of the spinning head. Thus, extensive surface contact of the feedstock against the heating element is provided. Nonetheless, the spinning procedure is sufflciently fast that the heat history of the 10 bio-a~-,ling agent is not significantly prolonged.
As previously ~1iccn~ed herein, carriers used in the systems ofthe present invention are water-soluble polymers which are compalil)le with the bio-affecting agents selected herein.
These carriers have sufficient heat stability for flash-flow processing and can range from low molecular weight crystalline or amorphous materials to high molecular weight thermoplastic 15 polymers. Thermoplastic polymers, while having no defined melting point, can be processed in a temperature region above its glass transition temperature, where the polymers elastomeric properties are sufficient to allow elongation and dissolution of the active ingredient therein.
The present invention includes the co-l-bi,-alion ofthe active ingredient with the coll")~ le polymer (and other excipients) in a melt form to enable the active ingredient to be 20 captured in an increased-energy condition upon qu~nc.hing Thus, the bio-affecting agent is solubilized in the substrate or polymer and does not separate into its own crystalline domains.
The drug may form very fine crystals (nanoparticles) in the carrier as a result of being qu~n~hed in the increased-energy condition, such crystals having significantly enhanced dissolution and/or dispersibility. In the present invention, the carriers themselves have good 25 aqueous solubility. As a result of the system described herein, the poorly soluble drug is liberated from the solid solution or dispersion as nanoparticles as the carrier is solubilized. It is the nanoparticulate dispersion which provides the enh~n~ed bio-availability in vivo.
It is further contemplated that the present invention can be used to provide products from the compositions resulting herein. Delivery systems can be çngineered to provide the 30 delivery profile which renders the bio-affecting agent available at the rate and intensity required to treat the host. For example, fibers which are obtained as a result of processing in CA 022310~0 1998-03-03 acco~ dallce with the present invention can be ground to proviide small particles of drug-bearing polyrner. (Note that it is not the grinding of the fibers which provides a sub~lall~ially homogeneous distribution of the bio-affecting agent in the carrier. Rather, unlike the prior art, the distribution of the bio-affecting agent has been effected in the ~ntecedent process in which the fibers were formed.) The drug-bearing particles can then be coated by tech~iques known in the art. For example, the particles can be coated by means of the method set forth in commonly-owned copending U.S. Application Serial No. 08t334,729 which was filed on November 4, 1994, entitled "Delivery of Controlled-Release Systems," tlle disclosure of which is incorporated herein by reference. The once-coated particles can be used as controlled-release particles for capsules.
Alternatively, the drug-bearing particles resulting frorn grinding product processed in accordance with the present invention can be used to make tablets, ~ bly rapidlydissolving tablets, according to known techniques. A 1)l ere, . ed tableting technique is the method set forth in commonly-owned copending U.S. Application Serial No. 08/259,496, filed June 14, 1994, and Application Serial No. PCT/US95/07194, filed June 6, 1995, both entitled "Process and Apparatus for Making Rapidly-Dissolving Dosage Units and Product Therefrom," the entire disclosures of which are incorporated herein by reference.
The present invention incl~lcles both the controlled-release particles resulting from grinding the fibers produced in accordance with the present invention and capsules and rapid dissolved tablets co~ g the controlled-released particles. With respect to these products, it should be noted that fragile fibers bearing the bio-affecting agent are easily disrupted by application of physical stress, implying that the bio-affecting ,agent is exposed to minim~l heat during grinding to produce reducéd particle size of drug bea~ing polymer. This is, indeed, a vast improvement over grinding raw active ingredients whichl generates significant heat usually encountered in forced attrition. The heat which is generated by conventional direct grinding of drugs can be sufficient to cause recryst~lli7~tion, which would work to increase the average particle size. Thus, using the fragile fibers resulting from the process of the present invention, the lowest average particle size of the bio-affecting agent can be attained for delivery to the bio-system, thereby maximi7.ing the bio-availability of the bio-affecting agent.Tablets produced in accordance with the present invention can be processed to provide yet further desired characteristics. For example, the tablets of the present invention can be CA 022310~0 1998-03-03 coated with a semi-permeable membrane to achieve controlled-release of the active.
Furthermore, the tablets of the present invention can be form~ ted to contain tablet çh~nnçlin~ agents or dissolution agents (bio-availability promoters) to increase or control breakdown of the tablet. Typical of such bio-availability promoters are cellulosics such as S h~droxyell,~yl cellulose, hydroxypropylmethyl cellulose, etc.
Moreover, in certain embo-limPnte, the compositions resulting from processing inaccol dance ~,vith the present invention can also be ground or pulverized and subjected to further procee.eing to make agglomerates which can be tableted. This is especially useful where additional excipients are required to be added before labl-ling or where the composition itself is not directly tabletable.
Yet other uses of the present invention include intravascular (e.g., intravenous, intra-arterial) delivery of drugs. It is known that substantially non-dissoluble agents must be reduced significantly in size before intravascular delivery. Indeed, some agents cannot be delivered intravascularly. As a result of the present invention, however, a mass of drug-bearing water-soluble polymer can be contacted with intravascularly fed fluid for delivery to the patient. The mass can be placed directly in the stream of flow of the fluid.
Alternatively, the mass can be housed in a compa, ~ ent by which the intravascular fluid passes in such a manner so that the drug is delivered by the fluid. In the embodiments in which the bio-affecting agents are used in intravascular applications, a colloid stabilizer is generally used to keep the particles of bio-affecting agents dispersed.
The composition and method of the present invention is a highly efficient system for providing a drug delivery system as a commercial product. The compositions of the invention can be used for intr~m~-~ec~ r injection, parenteral dosage, intranasal, in osmotic pumps, erodible systems which erode to release the bio-affecting agent, inh~l~nts transdermal patch systems, subcutaneous injection, vaginal pessary, suppositories, powders, intravenous (IV) ~rlminietration, lozenges or other oral delivery systems, and for topical applications.
Especially p, t;re, I ed uses are those wherein the composition is exposed to a body fluid such as pe, ~ ion or internal body fluids which solubilize the polymer and release the bio-affecting agent.
The present invention has been exemplified below in examples in which co-processed compositions of substantially non-dissoluble bio-affecting agents, e.g., ibuprofen or niredip-ne, CA 022310~0 1998-03-03 W O 97/08950 PCT~US96/14457 have been prepared in combination with a commercially obtained water-soluble polyrnP,th~crylate polymer. The dissolution rate of orally adnninistered drugs which have low aqueous solubility is quite slow. Low solubility is the result of a low rate of departure of drug molecules from the undispersed state. In accordance with the present invention, formulation 5 techniqu~ have been provided which produce solid dispersions (or solid solutions) of a bio-~ffe~in~ agent. The system formed by these forrn~ tionl techniques has been found to be valuable for making non-dissoluble agents bio-available to host bio-systems.
The examples set forth heteinbelow exemplify the pre sent composition, method, and duw~ ea-ll products resulting therefrom. The examples ha~e been set forth to satisfy 10 obligations under the statute, but are not in any way intçndecl to limit the scope of protection provided herein.
FX~MP~
l[buprofell is an excellent non-steroidal anti-infl~mm~lory drug. ~iretli,oh~e is a potent ~nti~ngin~l and antihypertensive drug. Both of these drugs are substantially insoluble in water 1~ and other aqueous media, as defined in the USP. These two compounds were, therefore, selected as model agents to demonstrate the capability of the present invention.It was discovered that a polymethacrylate aqueous p~lymer used in pharm~ceutical flm coating, EUDRAGIT E, was miscible with ibuprofen or nife~ipine under melt flow conditions.
The specific polymer used is a copolymer based on dimethylaminoethyl methacrylate and 20 methacrylic acid esters marketed by Rohm GmbH as EUDRAGIT E. This polymer has compendial status in the USP/NF.
FXAMPLE 1 - FLASH-EIEAT P]ROCESS
In this example, the polymethacrylate polymer EUDR AGIT E (EUDRAGIT E 100;
pellet form) obtained from Rohm GmbH, Darmstadt, Germany, was ground to a powder and 25 sized by passing the powder through a 60 mesh screen sieve. Ibuprofen (Product Code IBlD472, grade 25) obtained from BHC HBMC Advanced Materials Group, Bishop, Texas, was added to the resulting EUDRAGIT powder and blended together to form a blend in-.lu(ling 20 wt% ibuprofen in 80 wt% EUDRAGIT polyrner.
CA 022310~0 1998-03-03 The powder blend was processed in a 5" pharm~ceutiçRl spinning head with 36 heaters. The mRchine parameters included a spinning speed of 3,600 rpm, a power setting of 20.5%, and a m~im-lm temperature of 1 50~C. A fine, clear, and colorless floss was produced from the flash-heat process.
S Micloscopic ~ Al;on ofthe material in ~im~ ted gastric fluid (no pepsin) revealed the release of inmlmerable nanoparticles as the polymer solubilized. The size of the nanoparticles was not measurable by optical means, but was well below 1 ,um. It is believed that the size ofthe nanoparticles are ofthe order of 100 nm to 600 nm (i.e., 0.1 ,um to 0.6 ~4m).
One gram (1 g) ofthe ibuprofen-co.~ g solid dispersion (= 200 mg of ibuprofen) was added to 900 mL of 0.1 N HCI and stirred at 100 rpm for 0.5 h. Samples were taken and ibuprofen collc~llLl ~ion was measured by E~'LC UV. The solid dispersion gave an ibuprofen concentration of 0.066 ,ug/mL. This corresponds to an increase in solubility of over 100%
compared to the solubility of the raw drug as tested by the same analytical method (0.030 ~g/rnL).
~ E~AMPL~ 2 - EXTRUSION M~XING
The water-soluble polymer, EUDRAGIT E 100 was ground from pellet form to a fine powder and sized by passage through a 60 mesh sieve. The resulting sized powder was mixed with ibuprofen and blended to form a blend including 20 wt% ibuprofen in 80 wt%
EUDRAGIT polymer.
The resulting powder blend was processed in an APV-Baker MP2015 twin screw extruder with multiple heater zones and fitted with a 1 cm nozzle. The temperature of each of the four heating zones was set to 100~C, and the following temperatures were recorded: Zone 1 = 98 ~ C; Zone 2 = 102 ~ C; Zone 3 = 100 ~ C; Zone 4 = 105 ~ C . The speed of the twin screw was 120 rpm. The extruded product was a solid dispersion of ibuprofen in the polymethacrylate, having a continuous rod structure.
One gram (1 g) of the ibuprofen-contRining solid dispersion (= 200 mg of ibuprofen) was added to 900 mL of 0.1 N HCI and stirred at 100 rpm for 0.5 h. Samples were taken and il)u~ en concentration was measured by HPLC W. The solid dispersion gave an ibuprofen concentration of 0.067 ~g/mL. This corresponds to an increase in solubility of over 100%
co.,.l~al ed to the solubility of the raw drug as tested by the sarne analytical method (0.030 ~g/mL) I
~,X ~ M P~,F,3- Fl,~S~-~F,~T PR~O CF,~S
Once again, the water-soluble polymer, EUDRAGIT ]E, 100, was ground from pellet size to a fine powder and sized by passing the ground powdeî through a 60 mesh sieve.
Nifedipine (Product Code 15620, lot 55, Sanofi) obtained from InterChem Corp., Paramus, New Jersey, was added to the resulting EUDRAGIT powder ~nd blended together to form a b1end ins;l~ in~ 20 wt% ~.iredipi~.e in 80 wt% EUDRAGIT polyrner.
The powder blend was processed in a 5" pharm~c.e~ltical spinning head with 36 heaters. The m~chine parameters in~.indçd a spilllling speed a,:f 3,600 rpm, a power setting of 30%, and a maximum temperature of 183 ~C. The spun product was a solid dispersion of "iredipi~le in the polymethacrylate polymer, in the form of a ylellowish floss.
Dissolution testing of the rnaterial was pe, ~o"l,ed using a sim~ ted gastric fluid (no pepsin): 900 mL 0.1 N HCI, with 1% TWEEN 20., USP Method II. The sample was ~f,ri at 37~C, using 50 rpm for 30 min, and then using 200 rpm for 15 min. This solid dispersion was found to be 78% dissolved in 5 min, and 80% dissolved at 45 mLin. See Figure 1. This co",paled to a meager 1% dissolution at 5 min, and no more than 16% dissolution at 45 min, when the bulk (raw) drug was tested. See Figure 2.
F.X~nlp~,F,4- F~xTRuslo N-Ml~yIN G
The water-soluble polymer, EUDRAGIT E 100 was ground from pellet form to a fine powder and sized by passage through a 60 mesh sieve. The res-llting sized powder was mixed with nifedipine and blended to form a blend incl~l~ing 20 wt% nifedipine in 80 wt%
EUDRAGIT polymer.
The r~c--lting powder blend was processed in an APV-Baker MP2015 twin screw extruder with multiple heater zones and fitted with a 1 cm nozzle. The temperature of each of the four heating zones was set to 1 75~C, and the following temperatures were recorded: Zone 1 = 172~C; Zone 2 = 1 77~C; Zone 3 = 175 ~C; Zone 4 = 1 80~C. The speed of the twin screw was 120 rpm. The extruded product was a clear, yellow, solid dispersion of nifedipine in the polymeth~rylate~ having a discontinuous rod structure.
CA 022310~0 1998-03-03 WO 97/08950 PCTrUS96/14457 Dissolution testing of the extruded material was performed using a ~imnl~ted gastric fluid (no pepsin): 900 mL 0.1 N HCI, with 1% TWEEN 20, USP Method II. The sample was ~git~tell, at 37~C, using 50 rpm for 30 min, and then using 200 rpm for 15 min. This solid dispersion was found to be 76% dissolved in 5 min, and 81% dissolved at 45 min. See Figure 3. This co,.~palt;d to a meager 1% dissolution at 5 min, and no more than 16% dissolution at 45 min, when the bu1k (raw) drug was tested. See Figure 2.
~,X~MPI,F 5 - F~ ~SH-~F,~T PROC~ S
In this example, the polymer EUDRAGIT E 100 (in pellet form) was ground to a powder and sized by passing the powder through a 60 mesh screen sieve. An ~ntifilng~l agent was added to the r~ ting EUDR~GIT powder and blended together. The two ingredients were coml)il~ed on a 1: 1 ratio, i.e., the resulting blend had 50% antifungal agent and 50%
EUDRAGIT E polymer by weight.
The powder blend was processed in a spinning head operated at 60 Hz and 50% power cycling. Thus, the speed ofthe head was approximately 3,500-3,700 rpm and the t~---pe~ re at the perimeter of the head was m~int~ined at an average of approximately 218~C.
A fine clear floss was produced from the flash-heat process. Mic~oscopic e~ ;on of the material in sim~ ted gastric fluid (no pepsin) revealed the release of innnmerable nanoparticles as the polymer solubilized. The size of the nanoparticles was not measurable by optical means and was well below 1,um. It is believed that the size of the nanoparticles is of the order of 100 nm to 600 nm.
Dissolution testing ofthe material in sim-ll~ted gastric fluid (no pepsin) 900 mL and 1% TWEEN 20, USP Method II, 100 rpm, gave 88% dissolution in 10 min. This co-llpal~d to a meager 3.7% dissolution when the bulk drug substance was tested. See Figure 4.
F~AMpl .F 6 - FLASH-S~l~R PROCESS
Once again, the water-soluble polymer, EUDRAGIT E 100, was ground from pellet size to a fine powder and sized by passing the ground powder through a 60 mesh sieve. The resulting EUDRAGIT powder was mixed with the ~ntifi~ng~l agent and blended in a grinding mill. The powder blend was then processed in a flash-shear process using an extruder barrel CA 022310~0 1998-03-03 W O 97/08950 PCT~US96/144~7 temperature gradient from 164~C to a 185~CI which a nozzle temperature of 185~C~ and an ato,l,i~ion air pressure of 10 psi.
The Flash Shear nozzle at the exit end of extruder is of the type described in copending commonly-owned Application Serial No. 08/269,679, filed September 6, 1994, where the air was heated to 170~C and was at a pressure of 1.5 psi to 3 psi.
A thick fibrous rnaterial was produced by the process. Microscopic c,~ ion in .~im~ ted gastric fluid (no pepsin) revealed that a considerable number of nanoparticles were re1eased from the water-soluble polymer as the polymer became solubilized. The size of the nanoparticles was well below 1 ~m. It is believed that the si;z:e of the nallop~, licles produced as a result of the present process is in the range of about 100 nm to about 600 nm. The material disappeared completely, with a milky dispersion r~ ing thereafter.
Dissolution testing of the material in ~im-ll~ted gastric fluid (no pepsin) of 950 mL and 1% Tween 20, USP Method II, 100 rpm, produced a 77% dissolution in only 10 min. Once again, this cor"pared to a relatively low 3.7% dissolution when the bulk drug substance was tested. See Figure 4.
~ MPl ,F 7 - ~XTRUSIO N M ~nNG
The water-soluble polymer, EUDRAGIT E 100 was ground from pellet form to a fine powder and sized by passage through a 60 mesh sieve. The resulting sized powder was mixed with the ~ntifi-ng~l agent at a ratio of 1:1 and blended in a grinding mill.
The res-llting powder blend was processed in a twin screw extruder fitted with a 1 cm nozzle. A clear extrudate was produced by the process. The appearance of the material quickly turned to an opaque, hard, and brittle rope. Microsclopic c,~ l ;on of the resulting extrudate in sim~ ted gastric fluid (no pepsin) revealed the release of a considerable number of very fine particles, having a size of well below I ,um. The extrudate disappeared completely with a milky dispersion ~ i"g thereafter.
Dissolution testing of the material in sim~ ted gastric fluid (no pepsin) of 900 rnL and 1% Tween 20, USP Method II, 100 rpm, produced a 94% dissolution in 10 min. This compared to only 3.7% dissolution when the bulk drug substance was tested. See Figure 4.
CA 022310~0 1998-03-03 F,X ~ M P~,F,8- C~PSU~,~,FOR~UT,~TIO N
Ten grams (10 g) ofthe 50/50 ~ntifilng~l/EUDRAGIT E solid dispersion of Example was ground using a rotary blade, and then sieved through a 20 mesh screen. We were able to load 400 mg ofthe solid dispersion in a O size capsule, to give a capsule co..l~ g 200 mg of 5 the ~ntifilng~l agent. The material was free flowing, having all of the p~upel Lies of an ideal material for capsule filling.
FXAMP~ ~ 9 - TAR~ ~T FORMU~ ON
The acid-soluble polymer, EUDRAGIT E 100 was ground from pellet form to a fine powder and sized by passage through a U. S. Standard 60 mesh sieve. The resulting powder 10 was mixed with the ~ntifi~ng~l agent at a ratio of 1:1 and blended in a grinding mill.
The powder blend was processed in a twin screw extruder fitted with a 1 cm nozzle.
This extrudate was cooled and the material was ground in a high shear grinding mill to reduce particle size. Microcrystalline cellulose NF(AVICEL PH101) and croscarmellose sodium NF
were blended with the solid dispersion to provide 15.0% and 3 .00% of the blend, respectively.
15 The antifimg~l agent and EUDRAGIT E each were 41% ofthe blend.
The tablet premix was co---p~essed on a Specac hydraulic press at 13,000 psi using an 11 mm tablet die, to give 236 milligram tablets. These tablets provided a target dose of 100 mg ofthe ~ntifilng~l agent. The tablet had a di~intçgration time of 13 min in sim~ ted gastric fluid (no pepsin) at 37~C.
EXAMP~,~, 10 - PARTICLE SIZE DISTRIBUTION
A sample of a solid dispersion of the antifungal agent prepared by flash heat processing according to Example 6 above was subjected to particle sizing. Two hundred milligrams (200 mg) of the solid dispersion was dissolved in 900 mg of 0.1 N HCI. Af[er 9 min. an aliquot was removed and tested using a standard photon correlation method. Computerized analysis indicated that the mean particle size in the sample was 196.8 nm, with a monomodal distribution of particle sizes offrom about 155 nm to about 255 nm. These particles clearly qualify as "nanoparticles" as described hereinabove.
The compositions of all of the examples can be easily be molded into tablets by using opposed roller dies or regular dies following the co-processing (flash flow or co-extrusion) W 097108950 PCT~US96/14457 steps. Experience shows the material is readily compl es~;l,le into tablets of pressures of less than 80,000 psi and pl ~rel ~bly of pressures of from about 500 psi to about 40,000 psi.
The rOI~goillg examples make it abundantly clear thalt dissolution of the solid dispersions of the invention in an aqueous envh u~ lc;lll~ is very efficient. Moreover, tablets or 5 capsules made according to the invention provide very convenient delivery of s~ lly non~ ol~lble bio-a~e~iLing agents. Accordingly, the composition and method of the invention advantageously improve the bio-availability of substantially non-dissoluble bio-affecting agents.
Thus, Applicants have described what are pl~selllly believed to be the pl~relled10 embodiments ofthe present invention, and other and further embodimen~s ofthe invention will be appreciated by those skilled in the art, and it is intenrled to include other modifications and changes which come within the true scope of the invention as pointed out in the appended claims.
RIo-AFFE~cTING AGI~NTS BIO-AVArl,~Bl,F, This application is a continuation-in-part of copending application Serial No.
08/524,531, filed on September 7, 1995, the entire disclosure of which is incorporated herein by reference.
BACKGROUND OF TEIE INVI~ N
The present invention relates to the art of ~-lminicter~ng bio-affecting agents to bio-systems, and, in particular, for rendering agents, which a.re ~ub~ lially non-dissoluble in an aqueous environment, available for interaction with a host bio-system, e.g., a human or animal.
lBio-systems, such as hllm~nc, plants, insects, fish, birds, and m~-nm~lc, are primarily aqueous systems. In order to effectively ~(1minictçr an bio-affecting agent to such bio-systems, it is necess~ry to make the agent available for interaction with physiological activity in the bio-system. This is referred to herein as "bio-availability." ]n the case of bio-affecting agents which are non-dissoluble in an aqueous environment, as welll as in the case of those which are only poorly water-soluble, effective ~minictration ofthe bio-affecting agent can be difficult due to inadequate bio-availability of the agent and consequent low pharmacological activity.
These solubility problems affect many parameters of adll~ Lion, such as the method of ?~dmini.ctration, the rate of a(lmini.ctration, the concentration of ~dmini~ration, etc.
It is known that rate of dissolution of drug particulates can be increased by increasing the surface area ofthe solid, i.e., decreasing the particle size. Consequently, methods of making finely divided drugs have been studied and efforts have been made to control the size and size range of drug particles in pharmaceutical compositions. For example, dry milling techniques have been used to reduce particle size and thereby infl~l~nce drug absorption.
However, in conventional dry milling, as discussed by T .?l~hm~n et al., The Theory and Pracfice of Industrial Pharmacy, Chapter 2, "Milling", p. 4~5 (1986), the limit of fin~nçcc is reached in the region of about 100 ,um (= 100,000 nm), where the milled material begins to cake onto the surfaces of the milling chamber. Lachman et al. note that wet grinding is beneficial in further reducing particle size, but that flocculation restricts the lower particle size CA 022310~0 1998-03-03 I;mit to applox;~ çly 10,um (= 10,000 nm). There tends to be a bias in the pharm~cel/t art against wet milling due to concerns associated with co~ AI;on. Co""l~elcial airjet milling techniques have provided particles ranging in average particle size from as low as about 1,um to 50 ~m (= 1,000 nm to 50,000 nm).
Other techniques for p,epa,illg pharm~ce~ltical compositions with enhanced aqueous solubility pl op~l lies include loading drugs into liposomes or polymers, e.g., during emulsion poly",e, i~alion. However, such techniques have problems and limitations. For example, a lipid-soluble drug is often required in plepali..g suitable liposomes. Further, unacceptably large amounts of the liposome or polymer are often required to prepare unit drug doses.
10 Further still, techniques for pl~ lillg such pharm~.;e~tical compositions tend to be co--l~ ,x.
A principal technical difficulty encountered with emulsion polymerization is the removal of CO..~ i"~ , such as unreacted monomer or h.i~id~or (which can be toxic) at the end ofthe m~mlf~ct-lring process.
U.S. Patent No. 4,540,602 (Motoyama et al.) discloses a solid drug pulverized in an 15 aqueous solution of a water-soluble high molecular weight substance using a wet grinding m~chine. However, Motoyama et al. teach that, as a result of such wet grinding, the drug is formed into finely divided particles ranging from 0.5 ~m (500 nm) to less than 5 ,um (5,000 nm) in diameter.
EPO 275,796 describes the production of colloidally dispersible systems comprising a 20 substance in the form of spherical particles smaller than 500 nm. However, the method involves a precipitation effected by mixing a solution of the substance and a miscible non-solvent for the substance, and results in the formation of non-crystalline nanoparticles.
Furthermore, precipitation techniques for pl~ .-hlg particles tend to provide particles co..~ ed with solvents. Such solvents are often toxic and can be very difficult, if not 25 impossible, to adequately remove to pharmaceutically acceptable levels. Accordingly pl e.;i~ lion methods are usually impractical.
U.S. Patent No. 4,107,288 describes particles in the size range from 10 to 1,000 nm co..~ a biologically or pharmacodynamically active material. However, the particles comprise a crosslinked matrix of macromolecules having the active material supported on or 30 incol~,o,~ted into the matrix.
CA 022310~0 1998-03-03 W O 97/OX950 PCTrUS96/14~57 U.S. Patent No. 5,145,684 describes a method for providing drug particles having an effective average particle size of less than about 400 nm. Th,e method includçs wet milling the drug in the presence of a grinding medium in conjunction with a surface modifier. As in previous methods, the '684 protocol requires grinding or milling to produce size reduction.
5 The method further requires the use of an additive in the forrrl of a surface modifier.
Moreover, drugs pl ~al c;d by milling, even wet milling such as that described in the '684 disclosure, are subject to degradation resulting from hea.t as well as physical and chemical trauma associated with fracture. Grinding also creates "hot spots," i.e., volumes of localized higher telll~)el ~LIlres which can exceed the melting point or degradation of the drug. The 10 process is also lengthy, requiring attrition exposure over several days. This type of process effectively exposes the drug to a long "heat history", wherein exposure to elevated temperatures has been significant, and the purity and potency ofthe drug is rl;",;".~ d to a significant extent. Furthermore, particles reduced by milling ~re often co..~ ed by the residue of the grinding operations, especially when ball milling is used and the grinding balls 15 are worn down by abrasion.
It has also been known in the art of drug delivery to improve bio-availability by aggregating substantially non-dissoluble active ingredients on the surface of soluble sub~ es, such as water-soluble beads. The active ingredient can be deposited on such substrates by spraying a solution of the active ingredient over a fl~ ed bed while "flashing off" the solvent 20 used for the active ingredient. This method is highly inefficient in that it requires several hours to deposit a sufficient amount of active ingredient to prepare a useable delivery system.
Furthermore, an additional ingredient which is unnecessary to the system must be used, i.e., the solvent required to dissolve the active ingredient. As previously mentioned, the solvent must be flashed offduring agglegation. Thus, this system is a long and cumbersome process 25 and does not provide efficiency of dosage delivery.
Solubilization techniques for drugs which have low aqueous solubility require the use of organic solvents for processing in a solution state. This requires the use of expensive recove~y systems for solvent h~ntlling capability. When general melt processing techniques are used to form dispersions, bulk melting and mixing steps often expose the drug to a prolonged 30 heat history.
CA 022310~0 1998-03-03 It is desirable to provide stable dispersible drug particles in the sub-micrometer size range which can be readily p~ epal ed in the absence of size reduction by grinding or milling.
Moreover, it ~,vould be highly desirable to provide pharm~ceutical compositions having Pnh~nced bio-availability.
It is, Il-el erol e, an object of the present invention to overcome the disadvantages associated with methods for pl epa- ;ng delivery systems for bio-~ g ingredients, especially those which are subsl~Lially non-dissoluble. As a consequence of o~el co",ing the drawbacks known in the art, it has been found that other and further objects which enh~nçe the art of delivery systems have been realized as a result of the present invention.
SUMM~RY OF T~ INVFl~TION
The invention is a composition for delivery of a bio-arr~ g agent to a bio-system, and a methods of making and using a delivery system which in~ludçs a bio-affecting agent.
The composition and method include the use of:
a solid dispersion of the bio-affecting agent in an increased-energy state in a water-soluble (or water-dispersible) polymer which is eo-"~alible with the agent and which has a glass transition te"")e~ re (Tg) in the range of from about 0~C to about 200~C, whereby the agent is rendered bio-available in an aqueous envholu~w~l.
Preferably, the water-soluble polymer is any polymer which has a glass transition temperature in the range offrom about 25~C to about 150~C, and more preferably in the range offrom about 40~C to about 100~C.
Pl ere, l ed water-soluble polymers include polymethacrylic acid polymers. Preferably, the polymeth~crylic acid polymers have the structure:
----C--CH2--C--CH2--C--CH2--(~--CH2---Cl=O IC=O ~=0 ~=0 (1) CA 022310~0 1998-03-03 W O 97/0~950 PCTAUS96/14457 wLere;n: Rl, R2, R3, R4 are any substituents provided that the polymer has a glass transition temperature in desired range. Accordingly, Rl, R2, R3, R4 preferably are independently hydrogen ~IH) or any alkyl, airyl, alkaryl, aralkyl, alrninoalkyl, a.lkyl-substituted aiminoalkyl, ~..l"onioalkyl, or alkyl-substituted ammonioalkyl group. Still more plere.~bly, R', R2, R3, R4 5 in Structure (1) are independently H, Cl-C6 alkyl, ~mino~likyl, methyl- or dirnethyl-aminoallyl, or methyl-, di nethyl-, or trimethyl-ammonioalkyl. Yet more ~ f~l~bly, in Structure (1):
Rl is H, CH3;
R2 is H, CH3, C2H5, CH2CH2N(CH3)2;
R3 is H, CH3; and R4 is CH3, C2H5, C3H" C~Hg, CH2CH2N(CH3)3+X-, wherein X~ is any monovalent anion.
A highly prere" ed water-soluble polymer is a terpolymer of butyl methP~c.rylate, (2-dimethyl aminoethyl) methacrylate, and methyl methacrylate in relative proportions 1:2:1.
Preferably, the water-soluble polymer is a polymer having pH-ser.sitive solubility in 15 aqueous media. The water-soluble polyirners pl e~ Lially have solubility in aqueous media having a pH of from about 1 to about 11. More p~c;rel~bly, the water-soluble polymer has solubi1ity in acidic aqueous media, i.e., having a pH of about 7 or less.
The bio-affecting agent can be any agent known to have an effect in a biologicalsystem. Plerelably, the bio-affechng agent is substantially non-dissoluble in an aqueous 20 envholll"~ L. More preferably, the bio-affecting agent has a solubility which is defined as practically insoluble or insoluble according to the USP. The bio-affecting agent is preferably selected from the group consisting of antifungals, anti-infl,.mm~tories, anti-hypertensives, antimicrobials, steroidal drugs, hormones, prost~gl~n-1in~, interferons, and mixtures thereof.
Moreover, the composition comprising the bio-affect;ng agent and the water-soluble 25 polymer preferably mee$s or exceeds USP dissolution standards for the agent.
The composition of this embodiment can include a solid dispersion provided by flash-flow processing a feedstock including the bio-affecting agent and the polymer. The flash-flow processing can be flash heat processing or flash shear processing. The flash heat processing method is particularly pl erel ~ ~d when processing bio-affecting agents which are 30 heat-sensitive. Alternatively, the solid dispersion can be provided by extrusion mixing for a time sufficient to form the solid dispersion. Preferably, the t;me of extrusion mixing is less s CA 022310~0 1998-03-03 W O 97/08950 PCT~US96/14457 than about 2 minllt~s, more preferably, less than about 30 seconds. When the solid dispersion is provided by extrusion mixing, it is highly pl crel I cd that the bio-affecting agent is an ~ntifimg~l, anti-;.,ll;t~ oly, or anti-hypertensive agent.
The composition of the invention incllld~s the bio-affecting agent in an at least 5 s~L~,lially uniform or amorphous solid dispersion. Preferably, the bio-~rc.;lil~g agent is present in the form of nanoparticles distributed throughout the solid dispersion. More plcrel~bly, the nano~al licles have an average particle size of less than about 1000 nm. Still more p~ crcl ~bly, the average particle size of the nanoparticles is less than about 400 nm. The bio-affecting agent can be dispersed in the water-soluble polymer at the molecular level.
The composition can be prepared as a controlled-release particulate by mççh~nically red~lcing the solid dispersion. Preferably, the particulate is part of a dosage unit, which is plcrcl~ly selected from the group consisting of ç~psllle~J tablets, and rapid-dissolve tablets.
Alternatively, the solid dispersion is sized and shaped for fixation in an intravascular (or other ,(JalCnlCI ~1) delivery apl)al~lus. Moreover, the solid dispersion can be provided in the form of a slow dissolving structures such as a suppository or a lozenge or the like.
The method inr,llldçs .~imlllt~neously l~nsrol.l,ing the bio-~rrcclillg agent to an increased-energy state and fixing the agent in that state. The method can include ~imlllt~neously ~ n~rull"h~g and fixing by flash-flow processing. This method inr,ludçs use of flash heat processing or flash shear processing. Heat-sensitive agents are beneficially processed by flash heat processing. Alternatively, the ~iml~lt~neous L,~n~ro,."i"g and fixing can be effected by extrusion mixing for a time sufficient to form the solid dispersion, plercl~bly for a time of less than about 2 minllte~, more preferably less than about 30 seconds.
In the latter approach, the bio-affecting agent is most prcre,~,bly an ~ntifilng~
anti-;..... ....n~ tory, or anti-hypertensive agent.
The method of tran~rol Illhlg the bio-affecting agent into the increased-energy state can include redllc.ing in the absence of mechanical attrition, the bio-affecting agent to dispersed nanoparticles having an average particle size of less than about 1000 nm. More preferably, the mer.h~nical re~ucing yields an average particle size of the nanoparticles of less than about 400 nm. Alternatively, the method can be used to disperse the bio-affecting agent at a molecular level to provide a solid solution.
CA 022310~0 1998-03-03 W O 97/08950 PCTrUS96/14457 The method can further include mechanically re~u~ing the solid dispersion to particulates. Thus, the rnethod can further include incorpora!ting the particulates in a dosage unit, such as a capsule or a rapid-dissolve tablet. Alternativc:ly, the method can further include sizing and shaping the solid dispersion for fixation in an intra.venous (or other l)a~ tel~l) fluid 5 delivery device. Lozenges, suppositories, and other slow release delivery structures can also be employed to deliver the bio-affecting agent.
The invention filrther inrl~ldçs method and composition for delivery of a bio-affecting agent. The composition produced by the method includes:
a) a carrier comprising a water-soluble polymer having a glass transition temperature 10 in the range offrom about 0~C to about 200~C; and b) a bio-affecting agent microscopically disl,e. ~ed in said water-soluble polymer.
Plt;rel~bly, the water-soluble polymer has pH-sensitive solubility in aqueous media. In particular, it is pl~rel I ed that the water-soluble polymer be substantially indissoluble in saliva but soluble in gastric fluid.
The invention is also a method for delivering a composition of a bio-affecting agent, as described, to a bio-system. The method includes ~ rlmini~tering to the bio-system a solid dispersion cOIlllplisillg the bio-affecting agent fixed in an increased-energy state in a water-soluble polymer having a glass transition temperature in the range offrom about 0~C to about 200~C, wherein the solid dispersion 20 renders the bio-affecting agent bio-available to the bio-systern.
The method and composition of the invention possess numerous advantages over theprior art. For example, the method of processing a bio-affecting agent with a water-soluble polymer to form a solid dispersion according to the invention avoids use of solvents or mech~nic~l attrition or co.. ~ tion~ which methods have various disadvantages detailed 25 hereinabove. Moreover, the method substantially decreases the heat history of the bio-a~eling agent, with the advantage that the agent remains substantially less degraded or decomposed throughout the processing. The method and composition of the invention also dr~m~tic~lly enhance the bio-availability of bio-affecting agents which are otherwise substantially non-dissoluble in aqueous environments, thereby enabling delivery of such agents 30 to bio-systems with greater ease and simplicity and through more routes than has heretofore been possible.
CA 022310',0 1998-03-03 These and further advantages will be appreciated by those skilled in the art in view of the following detailed description of the invention and the drawings as set forth below, and the scope of the invention will be pointed out in the appended claims.
RRTF,F DF.~CI~TPTION OF T~ DR~WINGS
Figure 1 is a graph which shows the effectiveness of the present invention by depicting the profile of the dissolution characteristics of a solid dispersion prepared by flash heat procç~ing according to the present invention.
Figure 2 is a graph showing the dissolution profile of bulk niredi~ .c which has not been prepared for çnh~nced dissolution.
Figure 3 is a graph which shows the effectiveness ofthe present invention by depicting the profile of the dissolution characteristics of a solid dispersion of niredipine pl epal ed by extrusion processing according to the present invention.
Figure 4 is a graph which shows the effectiveness of the present invention by depicting the dissolution profile for solid dispersions of an ~ntifilng~l drug pl~palt;d according to the present invention as contrasted against the dissolution profile of a known delivery system for the ~ntifilng~l agent and the dissolution profile ofthe bulk antifilng~l agent which has not been plepaled for çnh~ncecl dissolution.
Dli'T~n,li'D DF.~C~TPTION OF T~F INV~NTION
The present invention is a composition and method of pl epaling a composition for delivering a bio-affecting agent and rendering the bio-affecting agent bio-available in an aqueous environment. The composition of the present invention can be referred to as a solid dispersion of the bio-affecting agent in a water-soluble polymer.
The present invention is both a composition and method for delivery of a bio-affecting agent to a s--bslallLially aqueous bio-envilonlllel.l. The present invention renders the bio-affecting agent more bio-available in the aqueous environment. The method for plepa-i--g the unique composition of the present invention inçl~ldeo, 1 ) ll ansrc l l-lh~g the bio-affecting agent to an "increased-energy" state, and 2) fixing the bio-affecting agent in the "increased-energy" state in a water-soluble polymer. The terrns "increased-energy" or "higher energy" state refer to the stable dispersion of a bio-affecting agent or drug in a solid matrix, CA 022310~0 1998-03-03 such that the bio-affecting agent is either dispersed at a molecular level or is dispersed in microscopic particulate domains having an average particle size of less than 1000 nm, and p,t;~.~bly less than about 400 nm. The increased energy state is achieved by modifying particle formation rather than by size reduction through grinding or attrition. Generally, the 5 invention l~ ~n~r" ~s the bio-affecting agent into solution form or n~op&~ licle form which has a higher surface energy or free energy than, for example, native crystals which can have an average size of over 10 ,um.
The composition of the present invention is described herein as a solid dispersion of the bio-affecting agent in the water-soluble polymer. Upon dissolution of the polymer in the 10 bio-system, the bio-affecting agent is rendered bio-available to the host. "Bio-availability" as used herein means that the bio-affecting agent is taken up by the host bio-system for interaction with the bio affecting agent. The me~ ", for being "taken up" in~ludes, but is not limited to, absorption, adsorption, tran~Çe,~l~ce, cohesion, adhesion, chemical, biological, and biochemical reactions, etc.
The invention inrlproves the bio-availability of bio-affecting agents, especially those whose activity is otherwise limited or çlimin~ted because of their relative inability to be dissolved into aqueous media. The term "substantially non-dissoluble" is applied to materials which are either substantially insoluble in water or are not w;ater-soluble to any appreciable degree. Thus, substantially non-dissoluble bio-affecting agellts include those bio-affecting agents which are either non-soluble or only sparingly soluble in biological fluids, such as blood, Iymph, gastrointçstin~l fluids, cerebrospinal fluid, plant saps, and the likê. The bio-affecting agents typically are not enterosoluble as defined hereinbelow.
A material may be said to be "substantially non-dissoluble" if it has a solubility of less than 10 mg/rnL in water (or other aqueous merlium) having a pH of from about I to about 8.
The solubility of any substance in an aqueous me~ m is a property which is readily determined by a skilled artisan. In fact, thê solubilities of many substances, including drugs, are known and published in compendia such as The Merck I~i~dex, 1 2th edition ( 1996). Most preferably, the bio-affecting agent has a solubility low enough to qualify the agent as "practically insoluble, or insoluble" as defined by the USP. According to this definition, the bio-affecting agent is substantially non-dissoluble if it has a solubility requiring at least 10,000 parts of solvent (aqueous medium) for I part of the solute (bio-affecting agent).
CA 022310~0 1998-03-03 W O 97/08950 PCT~US96/14457 It is believed that all bio-affecting agents can be used in the present invention, bu~ t~e invention is particularly directed to col"bining a subst~nti~lly non-dissoluble bio-affecting agent with a water-soluble polymer in a unique manner to render the non-dissoluble agent bio-available. Substances which would otherwise be capable of being bio-afIe~ g as defined S herein, but which qualify as substantially non-dissoluble, are pl erel I t;d for delivery accol .lillg to the invention. It is also contemplated that a subst~nti~lly non-dissoluble bio-affecting agent can be used in collll~illalion with other substances, incl~ ing other bio-a~eclillg agents, which are s~sla,llially more soluble in aqueous media.
The polymers which are useful as "water-soluble polyrners" in the present invention 10 include polymers, copolymers, terpolymers, interpolymers, polymeric ~m~lg~m.e, etc., having molecular weights which range from oligomers to high molecular weight polymeric substances and polymers having pH dependent solubility characteristics.
"Water-soluble," as used herein, applies to polymers which readily dissolve or disperse in water and other aqueous media at any or all pH values without the ~Csict~nce of a 15 dissolution-promoting substances such as surf~ct~nte, emulsifiers, etc. The fact that the polymer does not require an agent to mediate its dissolution in an aqueous envil un~ lll does not mean, however, that delivery systems pl epal ed in accordance with the present invention do not include such agents. In order to engineer the apl)l op, iate delivery system, any additional substances which are required to control, promote, mediate, or modulate the 20 bio-availability of the bio-affecting agent(s) can be used. These substances are referred to herein as "bio-availability promoters." Furthermore, col,lbillaLions of bio-availability promoters can be used in the present delivery systems.
By virtue of the present invention the bio-availability of a bio-affecting agent is çnh~n~ed by altering the physicochemical condition of the bio-affecting agent. This is 25 achieved by processing the bio-affecting agent with a water-soluble polymeric carrier to produce a solid dispersion of the bio-affecting agent in the polymer. By "solid dispersion" is meant an appal enlly homogeneous solid substance which consists of a microscopically heterogenous mixture of the bio-affecting agent and the water-soluble polymer (and other materials as otherwise defined herein). In conventional terminology, the bio-affecting agent 30 conctitutto.s the "dispersed phase", while the water-soluble polymer con.etitutçc the "dispersion medium" or"continuous phase."
CA 022310~0 1998-03-03 W O 97/08950 PCTrUS96/144~7 1[ he method(s) of the present invention can be used to make solidl dispersion col,.po~iLions which are either:
a) Solution systems where at least a portion, and pl ere. ~bly all of the bio-affecting agent is in solution phase with the polymer or dispersed at thle molecular level (i.e., "molecular dispersions"); or b) Heterogenous systems where the bio-affecting agent is present in more or lessdiscrete supramolecular domains (nanoparticles), which may be aggregates of molecules, ulllrul ~ y dispersed within the polymer. Furthermore, as a result of the q~lenchin~ of the water-soluble polymer in accordance with the present invention, the bio-a~i~in~ agent is prevented from forming macro-scale distinct phases or large domains in the final product.
As noted, the solid dispersion can include discrete domains of the bio-~ffec~ingsubstance distributed substantially homogeneously throughout the polymeric me~ m When present, these discrete domains are generally referred to herein as "nanoparticles." In the case of cryst~lli7~hle bio-affecting agents, the domains of the bio-affecting agent might be desi~n~ted "nanocrystals." These terms connote the extraordinarily small dimensionality of the dispersed phase of the solid dispersions of the invention. Specifically, the particles of dispersed phase in the solid dispersions are typically of the order of nanometers (~I x 10-9 m) to hundreds of nanometers (~100 x 10-9 m). Thus, the scale of such particles is conveniently referred to as "nanometer-scale" or "nanoscale." It is believed that this feature of the proceccin~ method of the invention significantly contributes to increasing the bio-availability of the bio-affecting agent.
Other solid dispersions according to the invention include the bio-affecting agent dispersed at the molecular level through the water-soluble polymer. These solid dispersions of the invention may be characterized as solid solutions, since they meet the criteria conventionally reserved for solutions. Typically, little or no supramolecular o~gani~alion is present in such solutions. However, it must be recognized that a solid dispersion according to the invention can include the bio-affecting agent in a range of physical states ranging from molecular dispersion to amorphous or pre-crystalline associat.ions of molecules to nanoparticulate domains.
The solid dispersions of the invention, therefore, refer to intim~te mixtures of two or more colllpollenLs which form a contin~n-m wherein substantially all domains of the CA 022310~0 1998-03-03 bio-* rr~.~ g agent have a higher entropy than the entropy of the agent in its native condition.
As a result of forming the solid dispersions of the present invention, the bio-affecting agent is fixed or frozen in the solid water-soluble polymer in an increased-energy state."Increased-energy state" as used herein means a physicochemical condition of the bio-affecting 5 agent which has a higher entropy than the bio-affecting agent would have in its native con-1ition For CA~ C~ the bio-a~e~;ling agent is, in a pl~;relled embodiment, converted to a s .l,sl~-lially amorphous form and dispersed throughout the water-soluble polymer in the melt condition such that, when the agent crystallizes (if, in fact, it does crystallize), the average clystal size will constitute particles of nanoscale dimension, i.e., nanop~ Licles. The 10 bio-~rrec~;.u agent is thereby captured in a highly randomized condition as co---,~a~ed to the bio-affecting agent in its native form. The increased energy state of the present invention is sufficient to render the drug more bio-available in an aqueous enviloll---e-". As previously cl~ssed herein, bio-available means a condition which permits the active ingredient to interact with, i.e., become available for use in, the target bio-system, i.e., the body of the host lS animal or human patient.
The composition of the present invention, referred to herein as a solid dispersion, can be formed by a number ofter.hniqlles In one plere..ed embodiment the solid dispersion is formed by subjecting a feedstock which includes both the agent and the polymer to flash-flow processing. Flash-flow processing is defined hereinbelow and incl~ldes both flash-heat processing and flash-shear processing. Alternatively, it has been found that the solid dispersion of the present invention can be provided by extrusion mixing the agent and the polymer for a time sufficient to l- ~n~ro~ ~-- and fix the agent during quenching. In a ~. ~re. . ed embodiment, the time required to extrusion mix the ingredients is less than about two minutes (2 min), and is preferably less than about thirty seconds (30 sec).
As a result of the present invention, the bio-affecting agent can be provided as a solid dosage form which has an ~.nh~nced dissolution rate which can often be ~imlll~ted by in vi~ro data. It is theorized that the increases in dissolution rate are achieved by a combination of effects, the most significant being the reduction of particle size to an extent not achieved by conventional comminution approaches. The smaller size particle (i.e., the nanoparticles of the invention) appalenlly imparts to the bio-affecting agent a higher surface energy or free energy than the agent has in its original or native state, providing for enhanced solubility in water, CA 022310~0 1998-03-03 W O 97/08950 PCTnUS96/14457 generally co~ onding to çnh~nced bio-availability in the bio-system. As previously mentioned, techniques known to date for producing dispersions in the prior art generally require either the solubilization or melting of a drug with a freely soluble carrier in a water-like (low viscosity) state, followed by further processing to p~ ecip~ le or congeal the material into 5 a solid forrn.
The technique and composition of the present invention has inherent advantages in the production of solid dispersions of bio-aa~ g agents. As a result of the present invention, the bio-~cl~ agent and the carrier polymer can be combined in a process which mixes, melts, forms, and solidifies in a continuous process, to provicle the bio-affecting agent in a 10 solid solution or dispersion and having an increased energy clondition as defined hel~i--ab~/e.
The resulting compositions are easily employed to make any of a variety of delivery systems, inc~ 1in~ tablets, etc., which would otherwise be incapable of effectively delivering the bio-affecting agent.
Another very important advantage of the invention is that the bio-affecting agent is 15 exposed to a lower heat history during the process of being rendered bio-available. The heat history required in the inventive process is very short co...pa.ed to conventional teçhniques used in the formation of congealed materials. Consequently, the process of the invention induces less degradation or decomposition of the bio-affecting agent, meaning that purity and potency are improved over prior art systems. This is particu]larly beneficial for those 20 bio-affecting agents which are heat-sensitive.
The systems of the present invention are implemented by the use of bio-affectingagents and water-soluble polymers which are "compatible" v~ith each other. The term "compatible" is used herein to mean that the polymer has physical characteristics which render it processable according to the invention. Specifically, the water-soluble polymer must be 25 capable of being processed at ternperatures at or above the melting point (Tm) of the bio-affecting agent but below the temperature of decomposition (Td) of the bio-affecting agent and the polyrner. Consequently, it is preferable to use a polymer which is flowable (generally, thermoplastic) at a temperature which is equal to or above the melting point of the bio-affecting agent, but below the decomposition temperature of either the agent or the 30 polymer itself.
CA 022310~0 1998-03-03 WO 97/08950 PCTrUS96/14457 Moreover, bio-affecting agents and polymers are said to be "con~paLible" if they ~re soluble or dispersible in each other in the flowable/non-decomposition stage. For example, if one were to visualize the bio-affecting agent/water-soluble polymer composition immediately after soli~ific~tion, in many cases it would appear substantially as a lran,l,a~enl or tr~nclllc~nt 5 glass, i.e., any inhomogeneities are of a scale such that one cannot visually di~tin~ h the solubilized bio-arrecLi,-g agent from the water-soluble polymer.
Co---palil,ility herein also means that the polymer and bio-affecting agent solidify such that the bio-affecting agent is captured in an "increased-energy" condition and held stably in that state following completion of solidification. The bio-a~.;li"g agents may later crystallize, 10 but any crystals which form are of the order of nal opa. Licles, i.e., the crystals will have a condition of considerably higher entropy than the native crystals of the agent, which have an average particle size generally in the range of from about 10 ~m to about 50 ,um. If the polymer and bio-affecting agent solidify at rates which permit the bio-affecting agent to form domains which es.~enti~lly return the bio-affecting agent to a lower entropy form, e.g., a crystal 15 size which appr xim~tes the agent in its native condition, then the combil-~lion is not considered col--palil)le as defined herein. More importantly, little or no improvement in bio-availability is obtained by such incol--palible co...l)inalions. Thus, compatibility further means that the polymer is capable of being quenched or formed into a solid along with the bio-affecting agent such that the bio-affecting agent is not permitted to return to a lower 20 energy state, or to a condition of particles having an average size of greater than about 1000 nm.
It is, of course, pl er~- l ed that the polymer have physical characteristics which promote the formation of solid dispersions described herein. Applicants have unexpecte-lly found that glass transition temperature (Tg) is a property of polymers which correlates well with the 25 ~ fillness of polymers in the method of the invention. In particular, Applicants have found it to be pl ere- ~ ed that the polymer has a Tg in the range of from about 0~C to about 200~C.
More preferably, the polymer has a Tg in the range offrom about 25~C to about 150~C. Still more preferably, the polymer has a Tg in the range offrom about 40~C to about 100~C.
Applicants have found that Tg is related to the flowability or processability of the 30 polymer, with a lower Tg generally correlating with a lower viscosity at a given temperature.
Polymers having a Tg outside of the temperature ranges set forth above are less desirable. On I
the one hand, if the T8 is too high, the polymer will tend to be too viscous, making the polymer difficult to process. On the other hand, if the T,~ is too low, the polymer may not be viscous enough to effectively capture or freeze the bio-affecting agent in the desired increased-energy state. Moreover, Applicants have found that the polymers ch~aracterized by the T8 ranges 5 given above tend to have solubilities in aqueous em/i~onlme"L j sufficient to render them effective for ~nh~n(ing the bio-availability of nor-dissoluble Ibio-a~e~ g agents.
The polymers useful according to the invention generally also meet other physicochemical characteristics. For example, the polymers useful in this invention generally have an average molecular weight of above 500 daltons (Da), and p, ert;l,lbly above 1500 Da.
Polymers having molecular weights of 100,000 Da or more mlay be p,~r~"ed for particular applications. Also, the water-soluble polymers of the presenl; invention preferably have an intrinsic viscosity of from about 1,000 centipoise (cP) to millions of cP, and a melt viscosity of from about 50 cP to about 100,000 cP. The viscosity ofthe polymer can be measured by a Brookfield Viscometer. It is also believed that polymers which do not crystallize are probably 15 preferable to those which do crystallize, but this property is not well understood.
Polymeth~crylic acid polymers (also I~Ç~lled to herein as "polymethacrylates") are among the water-soluble polymers p-er~ d for use accordimg to the invention. For example, p,erel-ed polymethacrylates have the general structure:
Rl R3 Rl R3 --CH2~--CH2~--CH2~ CH2---C=O ~=0 IC=O IC=~O (I) 1~ ~ 1~
20 wherein: R', R2, R3, R4 are independently hydrogen (H) or any alkyl, aryl, alkaryl, aralkyl, aminoalkyl, alkyl-substituted aminoalkyl, ammonioalkyl, or alkyl-substituted ammonioalkyl group.
Preferably, Rl, R2, R3, R4 are independently H, Cl-C6 alkyl, amino (Cl-C6)-alkyl, methyl- or dimethyl-aminoalkyl, or methyl-, dimethyl-, or trirnethyl-amrnonioalkyl.
CA 022310~0 1998-03-03 W O 97/08950 PCT~US96/14457 More preferably the polymethacrylates of Structure (1) have the following substit~l~nt~
Rl is H, CH3;
R2 is H, CH3, C2H5, CH2CH2N(CH3)2;
R3 is H, CH3; and R4 is CH3, C2H5, C3H" C4Hg~ CH2CH2N(CH3)3+X-. wherein X~ is any monovalent anion, preferably Cl~.
Exemplary polymethacrylic acid polymers are described in detail in A.J. Shukla, "Polymeth~rylates", pp. 362-366 in Handbook of Pharm~( et~fic~ ~cipients, 2d ed., Ainley Wade and Paul J. Weller, eds. (1994). A large number ofthese polymers are available as coating materials under the EUDRAGIT trade name from Rohm GmbH. One polymer found to be particularly effective is a methacrylic acid ester terpolymeric product of butyl mP.th~rylate, (2-dimethyl aminoethyl) methacrylate, and methyl methacrylate in proportions 1:2:1, sold as EUDRAGIT E.
It is ~l~;rel-ed that the water-soluble polymers be polymers whose solubility ispH-sensitive. Specifically, the polymer is said to be pH-sensitive if its solubility in an aqueous m~rlillm is affected by pH. Preferably, the water-soluble polymers used in the method and composition of the invention have higher solubility at pH 1 to pH 10, than at a pH outside this range. More pre~--ed polymers are those which are subst~nti~lly more soluble at acid pH
than at neutral or basic pH. Thus, the water-soluble polymer is desirably soluble below pH 7.
By sPlectin~ a water-soluble polymer havirig a pH-sensitive solubility, specifically an acid-sensitive solubility, solubility ofthe solid dispersions ofthe invention can be .~ d until the material are exposed to acid conditions. Thus, materials can be m~mlfs~ctllred which are subsla~lLially indissoluble in saliva but soluble in gastric fluid, thereby permitting selective control over the bio-availability of the bio-affecting agent. (In certain applications, namely delivering the bio-affecting agent to the intestine, the water-soluble polymer preferably has an alkali-sensitive solubility.) All such polymers are terrned ~'enterosoluble."
Plerell~d enterosoluble polymers can also be defined according to the comonomersfrom which they are prepared. For example, the copolyrners and terpolymers of methacrylic acid with methyl acrylate and/or methyl methacrylate are highly pler~ d, having solubilities in CA 022310~0 1998-03-03 W O 97/08950 PCTAUS96/14~57 the range offrom about pH 5.5 to about pH 7.2. Such polymers have been described for use as enteric coatings for tablet plepa,~ion. T ~çhm~nn et al., "New methacrylic acid copolyrners for improved coating technology," Presentation from AAPS Tenth Annual Meeting (1995), published by Huls America Inc.
S The EUDRAGIT polymers possess solubilities which are sensitive to pH, meAning that their solubilities may be higher at certain pHs and lower at otlhers. Depending upon pH, the solubility of these polymers can vary over an order of mAgnitlJIde or more. Certain of the polymetllAcryla~es have high aqueous solubility under acidic c,onditions, and have been used to promote rapid release of active agents in the gastric region of the ga~ e~ tract. The EUDRAGIT E product has such acid-sensitive solubility, being soluble in gastric fluid and weakly acidic buffer solutions (i.e., less that about pH ~). Others are p~erere,llially soluble in mild alkali (e.g., pH 6-7) and therefore are suitable for delivel ing bio-affecting substances to the i~.le~ e while bypassing the gastric region. However, thlese polymethacrylates have not been employed as solid solution carrier materials for bio-arre~,ling agents, a new application to which Applicants have unexpectedly found them to be very v~rell adapted.
Preferably, the bio-affecting agents suitable for use in the method and composition of the invention are drugs which are potentially bio-affecting to slnim~lc, incl~ltling humans and other m~mmA1e A non-limiting list ofthese bio-affecting agents in~ludçc, for example:
antitl-e~iives~ Antihi~tAmine~, deconge~L~Ls, alkaloids, mineral supplements, laxatives, vitamins, AntAritl~, ion f~Y~.h~nge resins, anti-cholesterolemics, anti-lipidl agents, anlia"l,~thrnics, antipyretics, analgesics, appetite sllpplessal-ls, expectorants, anti-anxiety agents, anti-ulcer agents, anti-inflAmmAtory substances, coronary dilators, cerebral dilators, peripheral vasodila~ors, anti-infectives, antifungals, antivirals, psychotropics, A.,l;...Al-ics, sfimulAnt~
gastroin~-estinAl agents, sedatives, antidiarrheal plepa,~Lions, anti-anginal drugs, vasodilators, 25 anti-hypertensive drugs, vasoconstrictors, migraine ll~inlll~ 7 antibiotics, tranquilizers, anti-psychotics, antitumor drugs, anticoA~ nt~i, antithrombotic drugs, hypnotics, anti-emetics, anti-nAnc~nt~, anti-convulsants, neuromll~clllAr drugs, hyper- and hypoglycemic agents, thyroid and anti-thyroid preparations, diuretics, antispasmodics, uterine relaxants, mineral and nutritional additives, anti-obesity drugs, anabolic drugs, erythropoietic drugs, 30 anti-A~thmAtics, cough supplessal-ls, mucolytics, anti-uricemic drugs, prostAElAndin~
il.Le,~el-ons, cytokines, steroidal and peptide hormones, ploteii,l-s, and mixtures thereof.
CA 022310~0 1998-03-03 W O 97/08950 PCT~US96/14457 Other bio-affecting agents for use in the present invention include antidiarrheals such as IMODIUM AD, ~ntihi~ es, ~ntitllssives, deconpe~ vitamins, and breath r,c;shelle, ~. Also contemplated for use herein are anxiolytics such as XANAX; antipsychotics such as CLOZARIL and HALDOL; non-steroidal anti-il.n~.. ~lories (NSAID's) such as S VOLTAREN and LODINE; antihi~ .;..Fs such as SELDANE, HISMANAL, RELAFEN, and TAVIST; antiemetics such as KYTRIL and ces~met; bronchodilators such as bentolin, PROVENTlL; antidel.ressa.,L~ such as PROZAC, ZOLOFT, and PAXIL; anti-migraines such as imigran; ACE-inhibitors such as VASOTEC, CAPOTEN and ZESTRIL; anti-Alzheimer's agents such as nicergoline; and CaH-antagonists such as PROCARDIA, ADALAT, and 10 CALAN.
The popular H2-antagonists which can be used include ~imetitlin~ r~niti~ine hydrochloride, famotidine, ni7~ti~ine, ebrotidine, mifentidine, rox~titline, pi~til1ine and ace~ l ;(1inP
The invention is especially useful for the following sul,~a"~ially non-dissoluble 15 compounds: vasodilators such as nicergoline; anti-infl~mm~tories, antipyretics, and ~n~lgPcics such as indometh~in; antiarthritics such as diacerin; progestogens, palliative lle~ P~-t compounds for breast and endometrial carcinoma, and estrus regulators such as megestrol;
sedatives and hypnotics such as barbitals; ~n~lgesics, anticonvulsants such as ca,ba...~7epine;
antihy~e, lensi~es such as niredi~ e; uricosurics such as probenecid; anti-~ngin~l~ such as 20 felodipine; ~nti~p~modics such as fenalamide; plant fungicides such as fenarimol; and anti-h~ l.ics such as ferldçn(l~7Qle.
In prere,.ed embodiments the bio-affecting agents include ~ntifi~ng~lc7 anti-;.. n;~.. ~ories, anti-hypertensives, antimicrobials, steroidal drugs, hormones, prost~gl~ndin~, interferons, and mixtures thereof.
In the case of one pl er~ d embodiment, it has been found that the substantiallynon-dissoluble bio-affecting agents ibuprofen and nifedipine are each coml,d~ible with the acid soluble polymer known as EUDRAGIT E, a copolymer based on dimethylaminoethyl mPth~crylate and other neutral methacrylic acid esters, and marketed by Rohm GmbH. This polymer is available in solvent free granules (EUDRAGIT E 100) and in a 12.5% solution in propan-2-ol/acetone (60:40) (EUDRAGIT E 12.5). EUDRAGIT E has high aqueous solubility especially under acidic conditions (below pH 5) and provides for rapid release of the CA 022310~0 1998-03-03 drug in the gastric region of the gastrointestin~l tract. Although the polymer is principally amorphous, microcrystalline domains of the polymer can be identified in the virgin polyrner.
Irl a p.ere,-ed embodiment, the process of the present invention can be implem~onted by flash-flow processing. Flash-flow processing is achieved by subjecting feedstock to S ~imlllt~neoll~ application of heat and shear sufficient to perrnit L~ rol.llaLion ofthe morphology of the feedstock. Flash-flow processing creates a. condition of internal flow which means that the feedstock material is enabled to move and separate at a sub-particle level. In this embodiment, the feedstock would include a water-soluble polymer and a sub~ ally non-dissolub1e bio-affecting agent.
Flash-flow processing can be effected by flash-heat processing or flash-shear processing. In a pl~r~ d embodiment, the present invention collle~ lates flash-flow processing by the flash-shear method which is described in con~ ol-ly known U.S. Patent No.
5,380,473 to lBogue et al., the contents of which is incorporat~d herein by reference. The process reported in the Bogue et al. '473 patent is characterized by increasing the temperature of a non-solubilized feedstock carrier to a point at which it undergoes internal-flow, followed by forcibly expelling or ejecting a stream of the feedstock and. subjecting the stream to disruptive fluid shear force which separates the stream into separate masses having tran~-.--ed morphology.
In an alternative embodiment to the flash-shear method, the components of the present invention can be mixed and processed in a mix extrusion method without the benefit of forming disrupted masses as in the flash-shear method. As a rnost pl ~re. . ~d mode of operation of this alternative embodiment, the feedstock materials e.g., a water-soluble polymer and a subst~nti~lly non-dissoluble bio-affecting agent (without solubilizing additives) are subjected to mix extrusion over a very short period of time, ~ erel ~bly not more than about two min~ltes7 and most preferably not more than about thirty seconds.
Another contemplated embodiment includes processing the co.llponents in a flash-heat process which creates conditions such as those found in cotton candy m~c.hines. In this process, the feedstock is introduced to a spinner head in which it is subject to heat and shear created by centrifugal force from the spinning head. Disclosures which relate to methods and appal~L~Is suitable for spinning substances include the following: U.S. Pa~ent No. 4,855,326;
CA 022310~0 1998-03-03 W O 97/08950 PCTrUS96/14457 U.S. Patent No. 4,873,08S; U.S. Patent No. 5,034,421; U.S. Patent No. 4,997,856; and U.S.
PatentNo. 5,028,632.
Examples in the U.S. patents listed above describe processing feedstock material by subjecting it to high speed spinning on spinning head in which the feedstock is also subjected 5 to heat provided by a heating element. The change of temperature is quite large, which is believed to be occasioned by the spinning head quickly and efficiently spreading the feedstock material against the heating element circu",~ere"Lially disposed around the perimeter of the spinning head. Thus, extensive surface contact of the feedstock against the heating element is provided. Nonetheless, the spinning procedure is sufflciently fast that the heat history of the 10 bio-a~-,ling agent is not significantly prolonged.
As previously ~1iccn~ed herein, carriers used in the systems ofthe present invention are water-soluble polymers which are compalil)le with the bio-affecting agents selected herein.
These carriers have sufficient heat stability for flash-flow processing and can range from low molecular weight crystalline or amorphous materials to high molecular weight thermoplastic 15 polymers. Thermoplastic polymers, while having no defined melting point, can be processed in a temperature region above its glass transition temperature, where the polymers elastomeric properties are sufficient to allow elongation and dissolution of the active ingredient therein.
The present invention includes the co-l-bi,-alion ofthe active ingredient with the coll")~ le polymer (and other excipients) in a melt form to enable the active ingredient to be 20 captured in an increased-energy condition upon qu~nc.hing Thus, the bio-affecting agent is solubilized in the substrate or polymer and does not separate into its own crystalline domains.
The drug may form very fine crystals (nanoparticles) in the carrier as a result of being qu~n~hed in the increased-energy condition, such crystals having significantly enhanced dissolution and/or dispersibility. In the present invention, the carriers themselves have good 25 aqueous solubility. As a result of the system described herein, the poorly soluble drug is liberated from the solid solution or dispersion as nanoparticles as the carrier is solubilized. It is the nanoparticulate dispersion which provides the enh~n~ed bio-availability in vivo.
It is further contemplated that the present invention can be used to provide products from the compositions resulting herein. Delivery systems can be çngineered to provide the 30 delivery profile which renders the bio-affecting agent available at the rate and intensity required to treat the host. For example, fibers which are obtained as a result of processing in CA 022310~0 1998-03-03 acco~ dallce with the present invention can be ground to proviide small particles of drug-bearing polyrner. (Note that it is not the grinding of the fibers which provides a sub~lall~ially homogeneous distribution of the bio-affecting agent in the carrier. Rather, unlike the prior art, the distribution of the bio-affecting agent has been effected in the ~ntecedent process in which the fibers were formed.) The drug-bearing particles can then be coated by tech~iques known in the art. For example, the particles can be coated by means of the method set forth in commonly-owned copending U.S. Application Serial No. 08t334,729 which was filed on November 4, 1994, entitled "Delivery of Controlled-Release Systems," tlle disclosure of which is incorporated herein by reference. The once-coated particles can be used as controlled-release particles for capsules.
Alternatively, the drug-bearing particles resulting frorn grinding product processed in accordance with the present invention can be used to make tablets, ~ bly rapidlydissolving tablets, according to known techniques. A 1)l ere, . ed tableting technique is the method set forth in commonly-owned copending U.S. Application Serial No. 08/259,496, filed June 14, 1994, and Application Serial No. PCT/US95/07194, filed June 6, 1995, both entitled "Process and Apparatus for Making Rapidly-Dissolving Dosage Units and Product Therefrom," the entire disclosures of which are incorporated herein by reference.
The present invention incl~lcles both the controlled-release particles resulting from grinding the fibers produced in accordance with the present invention and capsules and rapid dissolved tablets co~ g the controlled-released particles. With respect to these products, it should be noted that fragile fibers bearing the bio-affecting agent are easily disrupted by application of physical stress, implying that the bio-affecting ,agent is exposed to minim~l heat during grinding to produce reducéd particle size of drug bea~ing polymer. This is, indeed, a vast improvement over grinding raw active ingredients whichl generates significant heat usually encountered in forced attrition. The heat which is generated by conventional direct grinding of drugs can be sufficient to cause recryst~lli7~tion, which would work to increase the average particle size. Thus, using the fragile fibers resulting from the process of the present invention, the lowest average particle size of the bio-affecting agent can be attained for delivery to the bio-system, thereby maximi7.ing the bio-availability of the bio-affecting agent.Tablets produced in accordance with the present invention can be processed to provide yet further desired characteristics. For example, the tablets of the present invention can be CA 022310~0 1998-03-03 coated with a semi-permeable membrane to achieve controlled-release of the active.
Furthermore, the tablets of the present invention can be form~ ted to contain tablet çh~nnçlin~ agents or dissolution agents (bio-availability promoters) to increase or control breakdown of the tablet. Typical of such bio-availability promoters are cellulosics such as S h~droxyell,~yl cellulose, hydroxypropylmethyl cellulose, etc.
Moreover, in certain embo-limPnte, the compositions resulting from processing inaccol dance ~,vith the present invention can also be ground or pulverized and subjected to further procee.eing to make agglomerates which can be tableted. This is especially useful where additional excipients are required to be added before labl-ling or where the composition itself is not directly tabletable.
Yet other uses of the present invention include intravascular (e.g., intravenous, intra-arterial) delivery of drugs. It is known that substantially non-dissoluble agents must be reduced significantly in size before intravascular delivery. Indeed, some agents cannot be delivered intravascularly. As a result of the present invention, however, a mass of drug-bearing water-soluble polymer can be contacted with intravascularly fed fluid for delivery to the patient. The mass can be placed directly in the stream of flow of the fluid.
Alternatively, the mass can be housed in a compa, ~ ent by which the intravascular fluid passes in such a manner so that the drug is delivered by the fluid. In the embodiments in which the bio-affecting agents are used in intravascular applications, a colloid stabilizer is generally used to keep the particles of bio-affecting agents dispersed.
The composition and method of the present invention is a highly efficient system for providing a drug delivery system as a commercial product. The compositions of the invention can be used for intr~m~-~ec~ r injection, parenteral dosage, intranasal, in osmotic pumps, erodible systems which erode to release the bio-affecting agent, inh~l~nts transdermal patch systems, subcutaneous injection, vaginal pessary, suppositories, powders, intravenous (IV) ~rlminietration, lozenges or other oral delivery systems, and for topical applications.
Especially p, t;re, I ed uses are those wherein the composition is exposed to a body fluid such as pe, ~ ion or internal body fluids which solubilize the polymer and release the bio-affecting agent.
The present invention has been exemplified below in examples in which co-processed compositions of substantially non-dissoluble bio-affecting agents, e.g., ibuprofen or niredip-ne, CA 022310~0 1998-03-03 W O 97/08950 PCT~US96/14457 have been prepared in combination with a commercially obtained water-soluble polyrnP,th~crylate polymer. The dissolution rate of orally adnninistered drugs which have low aqueous solubility is quite slow. Low solubility is the result of a low rate of departure of drug molecules from the undispersed state. In accordance with the present invention, formulation 5 techniqu~ have been provided which produce solid dispersions (or solid solutions) of a bio-~ffe~in~ agent. The system formed by these forrn~ tionl techniques has been found to be valuable for making non-dissoluble agents bio-available to host bio-systems.
The examples set forth heteinbelow exemplify the pre sent composition, method, and duw~ ea-ll products resulting therefrom. The examples ha~e been set forth to satisfy 10 obligations under the statute, but are not in any way intçndecl to limit the scope of protection provided herein.
FX~MP~
l[buprofell is an excellent non-steroidal anti-infl~mm~lory drug. ~iretli,oh~e is a potent ~nti~ngin~l and antihypertensive drug. Both of these drugs are substantially insoluble in water 1~ and other aqueous media, as defined in the USP. These two compounds were, therefore, selected as model agents to demonstrate the capability of the present invention.It was discovered that a polymethacrylate aqueous p~lymer used in pharm~ceutical flm coating, EUDRAGIT E, was miscible with ibuprofen or nife~ipine under melt flow conditions.
The specific polymer used is a copolymer based on dimethylaminoethyl methacrylate and 20 methacrylic acid esters marketed by Rohm GmbH as EUDRAGIT E. This polymer has compendial status in the USP/NF.
FXAMPLE 1 - FLASH-EIEAT P]ROCESS
In this example, the polymethacrylate polymer EUDR AGIT E (EUDRAGIT E 100;
pellet form) obtained from Rohm GmbH, Darmstadt, Germany, was ground to a powder and 25 sized by passing the powder through a 60 mesh screen sieve. Ibuprofen (Product Code IBlD472, grade 25) obtained from BHC HBMC Advanced Materials Group, Bishop, Texas, was added to the resulting EUDRAGIT powder and blended together to form a blend in-.lu(ling 20 wt% ibuprofen in 80 wt% EUDRAGIT polyrner.
CA 022310~0 1998-03-03 The powder blend was processed in a 5" pharm~ceutiçRl spinning head with 36 heaters. The mRchine parameters included a spinning speed of 3,600 rpm, a power setting of 20.5%, and a m~im-lm temperature of 1 50~C. A fine, clear, and colorless floss was produced from the flash-heat process.
S Micloscopic ~ Al;on ofthe material in ~im~ ted gastric fluid (no pepsin) revealed the release of inmlmerable nanoparticles as the polymer solubilized. The size of the nanoparticles was not measurable by optical means, but was well below 1 ,um. It is believed that the size ofthe nanoparticles are ofthe order of 100 nm to 600 nm (i.e., 0.1 ,um to 0.6 ~4m).
One gram (1 g) ofthe ibuprofen-co.~ g solid dispersion (= 200 mg of ibuprofen) was added to 900 mL of 0.1 N HCI and stirred at 100 rpm for 0.5 h. Samples were taken and ibuprofen collc~llLl ~ion was measured by E~'LC UV. The solid dispersion gave an ibuprofen concentration of 0.066 ,ug/mL. This corresponds to an increase in solubility of over 100%
compared to the solubility of the raw drug as tested by the same analytical method (0.030 ~g/rnL).
~ E~AMPL~ 2 - EXTRUSION M~XING
The water-soluble polymer, EUDRAGIT E 100 was ground from pellet form to a fine powder and sized by passage through a 60 mesh sieve. The resulting sized powder was mixed with ibuprofen and blended to form a blend including 20 wt% ibuprofen in 80 wt%
EUDRAGIT polymer.
The resulting powder blend was processed in an APV-Baker MP2015 twin screw extruder with multiple heater zones and fitted with a 1 cm nozzle. The temperature of each of the four heating zones was set to 100~C, and the following temperatures were recorded: Zone 1 = 98 ~ C; Zone 2 = 102 ~ C; Zone 3 = 100 ~ C; Zone 4 = 105 ~ C . The speed of the twin screw was 120 rpm. The extruded product was a solid dispersion of ibuprofen in the polymethacrylate, having a continuous rod structure.
One gram (1 g) of the ibuprofen-contRining solid dispersion (= 200 mg of ibuprofen) was added to 900 mL of 0.1 N HCI and stirred at 100 rpm for 0.5 h. Samples were taken and il)u~ en concentration was measured by HPLC W. The solid dispersion gave an ibuprofen concentration of 0.067 ~g/mL. This corresponds to an increase in solubility of over 100%
co.,.l~al ed to the solubility of the raw drug as tested by the sarne analytical method (0.030 ~g/mL) I
~,X ~ M P~,F,3- Fl,~S~-~F,~T PR~O CF,~S
Once again, the water-soluble polymer, EUDRAGIT ]E, 100, was ground from pellet size to a fine powder and sized by passing the ground powdeî through a 60 mesh sieve.
Nifedipine (Product Code 15620, lot 55, Sanofi) obtained from InterChem Corp., Paramus, New Jersey, was added to the resulting EUDRAGIT powder ~nd blended together to form a b1end ins;l~ in~ 20 wt% ~.iredipi~.e in 80 wt% EUDRAGIT polyrner.
The powder blend was processed in a 5" pharm~c.e~ltical spinning head with 36 heaters. The m~chine parameters in~.indçd a spilllling speed a,:f 3,600 rpm, a power setting of 30%, and a maximum temperature of 183 ~C. The spun product was a solid dispersion of "iredipi~le in the polymethacrylate polymer, in the form of a ylellowish floss.
Dissolution testing of the rnaterial was pe, ~o"l,ed using a sim~ ted gastric fluid (no pepsin): 900 mL 0.1 N HCI, with 1% TWEEN 20., USP Method II. The sample was ~f,ri at 37~C, using 50 rpm for 30 min, and then using 200 rpm for 15 min. This solid dispersion was found to be 78% dissolved in 5 min, and 80% dissolved at 45 mLin. See Figure 1. This co",paled to a meager 1% dissolution at 5 min, and no more than 16% dissolution at 45 min, when the bulk (raw) drug was tested. See Figure 2.
F.X~nlp~,F,4- F~xTRuslo N-Ml~yIN G
The water-soluble polymer, EUDRAGIT E 100 was ground from pellet form to a fine powder and sized by passage through a 60 mesh sieve. The res-llting sized powder was mixed with nifedipine and blended to form a blend incl~l~ing 20 wt% nifedipine in 80 wt%
EUDRAGIT polymer.
The r~c--lting powder blend was processed in an APV-Baker MP2015 twin screw extruder with multiple heater zones and fitted with a 1 cm nozzle. The temperature of each of the four heating zones was set to 1 75~C, and the following temperatures were recorded: Zone 1 = 172~C; Zone 2 = 1 77~C; Zone 3 = 175 ~C; Zone 4 = 1 80~C. The speed of the twin screw was 120 rpm. The extruded product was a clear, yellow, solid dispersion of nifedipine in the polymeth~rylate~ having a discontinuous rod structure.
CA 022310~0 1998-03-03 WO 97/08950 PCTrUS96/14457 Dissolution testing of the extruded material was performed using a ~imnl~ted gastric fluid (no pepsin): 900 mL 0.1 N HCI, with 1% TWEEN 20, USP Method II. The sample was ~git~tell, at 37~C, using 50 rpm for 30 min, and then using 200 rpm for 15 min. This solid dispersion was found to be 76% dissolved in 5 min, and 81% dissolved at 45 min. See Figure 3. This co,.~palt;d to a meager 1% dissolution at 5 min, and no more than 16% dissolution at 45 min, when the bu1k (raw) drug was tested. See Figure 2.
~,X~MPI,F 5 - F~ ~SH-~F,~T PROC~ S
In this example, the polymer EUDRAGIT E 100 (in pellet form) was ground to a powder and sized by passing the powder through a 60 mesh screen sieve. An ~ntifilng~l agent was added to the r~ ting EUDR~GIT powder and blended together. The two ingredients were coml)il~ed on a 1: 1 ratio, i.e., the resulting blend had 50% antifungal agent and 50%
EUDRAGIT E polymer by weight.
The powder blend was processed in a spinning head operated at 60 Hz and 50% power cycling. Thus, the speed ofthe head was approximately 3,500-3,700 rpm and the t~---pe~ re at the perimeter of the head was m~int~ined at an average of approximately 218~C.
A fine clear floss was produced from the flash-heat process. Mic~oscopic e~ ;on of the material in sim~ ted gastric fluid (no pepsin) revealed the release of innnmerable nanoparticles as the polymer solubilized. The size of the nanoparticles was not measurable by optical means and was well below 1,um. It is believed that the size of the nanoparticles is of the order of 100 nm to 600 nm.
Dissolution testing ofthe material in sim-ll~ted gastric fluid (no pepsin) 900 mL and 1% TWEEN 20, USP Method II, 100 rpm, gave 88% dissolution in 10 min. This co-llpal~d to a meager 3.7% dissolution when the bulk drug substance was tested. See Figure 4.
F~AMpl .F 6 - FLASH-S~l~R PROCESS
Once again, the water-soluble polymer, EUDRAGIT E 100, was ground from pellet size to a fine powder and sized by passing the ground powder through a 60 mesh sieve. The resulting EUDRAGIT powder was mixed with the ~ntifi~ng~l agent and blended in a grinding mill. The powder blend was then processed in a flash-shear process using an extruder barrel CA 022310~0 1998-03-03 W O 97/08950 PCT~US96/144~7 temperature gradient from 164~C to a 185~CI which a nozzle temperature of 185~C~ and an ato,l,i~ion air pressure of 10 psi.
The Flash Shear nozzle at the exit end of extruder is of the type described in copending commonly-owned Application Serial No. 08/269,679, filed September 6, 1994, where the air was heated to 170~C and was at a pressure of 1.5 psi to 3 psi.
A thick fibrous rnaterial was produced by the process. Microscopic c,~ ion in .~im~ ted gastric fluid (no pepsin) revealed that a considerable number of nanoparticles were re1eased from the water-soluble polymer as the polymer became solubilized. The size of the nanoparticles was well below 1 ~m. It is believed that the si;z:e of the nallop~, licles produced as a result of the present process is in the range of about 100 nm to about 600 nm. The material disappeared completely, with a milky dispersion r~ ing thereafter.
Dissolution testing of the material in ~im-ll~ted gastric fluid (no pepsin) of 950 mL and 1% Tween 20, USP Method II, 100 rpm, produced a 77% dissolution in only 10 min. Once again, this cor"pared to a relatively low 3.7% dissolution when the bulk drug substance was tested. See Figure 4.
~ MPl ,F 7 - ~XTRUSIO N M ~nNG
The water-soluble polymer, EUDRAGIT E 100 was ground from pellet form to a fine powder and sized by passage through a 60 mesh sieve. The resulting sized powder was mixed with the ~ntifi-ng~l agent at a ratio of 1:1 and blended in a grinding mill.
The res-llting powder blend was processed in a twin screw extruder fitted with a 1 cm nozzle. A clear extrudate was produced by the process. The appearance of the material quickly turned to an opaque, hard, and brittle rope. Microsclopic c,~ l ;on of the resulting extrudate in sim~ ted gastric fluid (no pepsin) revealed the release of a considerable number of very fine particles, having a size of well below I ,um. The extrudate disappeared completely with a milky dispersion ~ i"g thereafter.
Dissolution testing of the material in sim~ ted gastric fluid (no pepsin) of 900 rnL and 1% Tween 20, USP Method II, 100 rpm, produced a 94% dissolution in 10 min. This compared to only 3.7% dissolution when the bulk drug substance was tested. See Figure 4.
CA 022310~0 1998-03-03 F,X ~ M P~,F,8- C~PSU~,~,FOR~UT,~TIO N
Ten grams (10 g) ofthe 50/50 ~ntifilng~l/EUDRAGIT E solid dispersion of Example was ground using a rotary blade, and then sieved through a 20 mesh screen. We were able to load 400 mg ofthe solid dispersion in a O size capsule, to give a capsule co..l~ g 200 mg of 5 the ~ntifilng~l agent. The material was free flowing, having all of the p~upel Lies of an ideal material for capsule filling.
FXAMP~ ~ 9 - TAR~ ~T FORMU~ ON
The acid-soluble polymer, EUDRAGIT E 100 was ground from pellet form to a fine powder and sized by passage through a U. S. Standard 60 mesh sieve. The resulting powder 10 was mixed with the ~ntifi~ng~l agent at a ratio of 1:1 and blended in a grinding mill.
The powder blend was processed in a twin screw extruder fitted with a 1 cm nozzle.
This extrudate was cooled and the material was ground in a high shear grinding mill to reduce particle size. Microcrystalline cellulose NF(AVICEL PH101) and croscarmellose sodium NF
were blended with the solid dispersion to provide 15.0% and 3 .00% of the blend, respectively.
15 The antifimg~l agent and EUDRAGIT E each were 41% ofthe blend.
The tablet premix was co---p~essed on a Specac hydraulic press at 13,000 psi using an 11 mm tablet die, to give 236 milligram tablets. These tablets provided a target dose of 100 mg ofthe ~ntifilng~l agent. The tablet had a di~intçgration time of 13 min in sim~ ted gastric fluid (no pepsin) at 37~C.
EXAMP~,~, 10 - PARTICLE SIZE DISTRIBUTION
A sample of a solid dispersion of the antifungal agent prepared by flash heat processing according to Example 6 above was subjected to particle sizing. Two hundred milligrams (200 mg) of the solid dispersion was dissolved in 900 mg of 0.1 N HCI. Af[er 9 min. an aliquot was removed and tested using a standard photon correlation method. Computerized analysis indicated that the mean particle size in the sample was 196.8 nm, with a monomodal distribution of particle sizes offrom about 155 nm to about 255 nm. These particles clearly qualify as "nanoparticles" as described hereinabove.
The compositions of all of the examples can be easily be molded into tablets by using opposed roller dies or regular dies following the co-processing (flash flow or co-extrusion) W 097108950 PCT~US96/14457 steps. Experience shows the material is readily compl es~;l,le into tablets of pressures of less than 80,000 psi and pl ~rel ~bly of pressures of from about 500 psi to about 40,000 psi.
The rOI~goillg examples make it abundantly clear thalt dissolution of the solid dispersions of the invention in an aqueous envh u~ lc;lll~ is very efficient. Moreover, tablets or 5 capsules made according to the invention provide very convenient delivery of s~ lly non~ ol~lble bio-a~e~iLing agents. Accordingly, the composition and method of the invention advantageously improve the bio-availability of substantially non-dissoluble bio-affecting agents.
Thus, Applicants have described what are pl~selllly believed to be the pl~relled10 embodiments ofthe present invention, and other and further embodimen~s ofthe invention will be appreciated by those skilled in the art, and it is intenrled to include other modifications and changes which come within the true scope of the invention as pointed out in the appended claims.
Claims (63)
1. A composition for delivery of a bio-affecting agent to a bio-system, comprising:
a solid dispersion of said bio-affecting agent in an increased-energy state in awater-soluble polymer which is compatible with said agent and has a glass transition temperature in the range of from about 0°C to about 200°C, whereby said agent is rendered bio-available in an aqueous environment.
a solid dispersion of said bio-affecting agent in an increased-energy state in awater-soluble polymer which is compatible with said agent and has a glass transition temperature in the range of from about 0°C to about 200°C, whereby said agent is rendered bio-available in an aqueous environment.
2. The composition of Claim 1, wherein said water-soluble polymer is a polymethacrylic acid polymer.
3. The composition of Claim 2, wherein said polymethacrylic acid polymer has thestructure:
wherein: R1, R2, R3, R4 are independently hydrogen (H) or any alkyl, aryl, alkaryl, aralkyl, aminoalkyl, alkyl-substituted aminoalkyl, ammonioalkyl, or alkyl-substituted ammonioalkyl group.
wherein: R1, R2, R3, R4 are independently hydrogen (H) or any alkyl, aryl, alkaryl, aralkyl, aminoalkyl, alkyl-substituted aminoalkyl, ammonioalkyl, or alkyl-substituted ammonioalkyl group.
4. The composition of Claim 3, wherein R1, R2, R3, R4 are independently H, C1-C6alkyl, aminoalkyl, methyl- or dimethyl-aminoalkyl, or methyl-, dimethyl-, or trimethyl-ammonioalkyl.
5. The composition of Claim 4, wherein:
R1 is H, CH3;
R2 is H, CH3, C2H5, CH2CH2N(CH3)2;
R3 is H, CH3; and R4 is CH3, C2H5, C3H7, C4H9, CH2CH2N(CH3)3+X-, wherein X- is any monovalent anion.
R1 is H, CH3;
R2 is H, CH3, C2H5, CH2CH2N(CH3)2;
R3 is H, CH3; and R4 is CH3, C2H5, C3H7, C4H9, CH2CH2N(CH3)3+X-, wherein X- is any monovalent anion.
6. The composition of Claim 2, wherein said water-soluble polymer is a terpolymer of butyl methacrylate, (2-dimethyl aminoethyl) methacrylate, and methyl methacrylate in relative proportions 1:2:1.
7. The composition of Claim 1, wherein the water-soluble polymer has pH-sensitive solubility in aqueous media.
8. The composition of Claim 7, wherein the water-soluble polymer has solubility in aqueous media having a pH of from about 1 to about 10.
9. The composition of Claim 8, wherein the water-soluble polymer has solubility in aqueous media having acid pH.
10. The composition of Claim 1, wherein said bio-affecting agent is selected from the group consisting of antifungals, anti-inflammatories, anti-hypertensives, antimicrobials, steroidal drugs, hormones, prostaglandins, interferons, and mixtures thereof.
11. The composition of Claim 1, wherein said bio-affecting agent is substantially non-dissoluble in aqueous media.
12. The composition of Claim 1, wherein said composition meets or exceeds USP
dissolution standards for the bio-affecting agent.
dissolution standards for the bio-affecting agent.
13. The composition of Claim 1, wherein said solid dispersion is provided by flash-flow processing a feedstock comprising said bio-affecting agent and said polymer.
14. The composition of Claim 13, wherein said flash-flow processing is flash heat processing.
15. The composition of Claim 14, wherein the bio-affecting agent is heat-sensitive.
16. The composition of Claim 13, wherein said flash-flow processing is flash shear processing.
17. The composition of Claim 1, wherein said dispersion is provided by extrusionmixing for a time sufficient to form said solid dispersion.
18. The composition of Claim 17, wherein said time is less than about 2 minutes.
19. The composition of Claim 18, wherein said time is less than about 30 seconds.
20. The composition of Claim 17, wherein the bio-affecting agent is an antifungal, anti-inflammatory, or anti-hypertensive agent.
21. The composition of Claim 1, wherein said bio-affecting agent is dispersed in said water-soluble polymer as nanoparticles having an average particle size of less than about 1000 nm.
22. The composition of Claim 21, wherein said average particle size is less than about 400 nm.
23. The composition of Claim 1, wherein said bio-affecting agent is dispersed in said water-soluble polymer at the molecular level.
24. The composition according to Claim 1, which is a controlled-release particulate prepared by mechanically reducing said solid dispersion.
25. The composition of Claim 24, wherein said particulate is part of a dosage unit.
26. The composition of Claim 25, wherein said dosage unit is selected from the group consisting of capsules, tablets and rapid-dissolve tablets.
27. The composition of Claim 1, wherein said solid dispersion is processed for fixation in an intravascular delivery apparatus.
28. The composition of Claim 1, wherein said solid dispersion is processed to provide a suppository, lozenge, or other slow dissolving delivery structure.
29. The composition of Claim 1, wherein said solid dispersion is processed to provide a tablet.
30. A method for preparing a system for delivery of a bio-affecting agent to a bio-system, comprising:
transforming said agent to an increased-energy state and fixing said agent in said state in a water-soluble polymer having a glass transition temperature in the range of from about 0°C to about 200°C, whereby a solid dispersion of said agent in said polymer is formed which renders said agent bio-available in an aqueous environment.
transforming said agent to an increased-energy state and fixing said agent in said state in a water-soluble polymer having a glass transition temperature in the range of from about 0°C to about 200°C, whereby a solid dispersion of said agent in said polymer is formed which renders said agent bio-available in an aqueous environment.
31. The method of Claim 30, wherein said water-soluble polymer is a polymethacrylic acid polymer.
32. The method of Claim 31, wherein said polymetharylic acid polymer has the structure:
wherein: R1, R2, R3, R4 are independently hydrogen (H) or any alkyl, aryl, alkaryl, aralkyl, aminoalkyl, alkyl-substituted aminoalkyl, or ammonioalkyl, or alkyl-substituted ammonioalkyl group.
wherein: R1, R2, R3, R4 are independently hydrogen (H) or any alkyl, aryl, alkaryl, aralkyl, aminoalkyl, alkyl-substituted aminoalkyl, or ammonioalkyl, or alkyl-substituted ammonioalkyl group.
33. The method of Claim 32, wherein R1, R2, R3, R4 are independently H, C1-C6 alkyl, aminoalkyl, methyl- or dimethyl-aminoalkyl, or methyl-, dimethyl-, or trimethyl-ammonioalkyl.
34. The method of Claim 33, wherein:
R1 is H, CH3;
R2 is H, CH3, C2H5, CH2CH2N(CH3)2;
R3 is H, CH3; and R4 is CH3, C2H5, C3H7 C4H9, CH2CH2N(CH3)3+X-, wherein X- is any monovalent anion.
R1 is H, CH3;
R2 is H, CH3, C2H5, CH2CH2N(CH3)2;
R3 is H, CH3; and R4 is CH3, C2H5, C3H7 C4H9, CH2CH2N(CH3)3+X-, wherein X- is any monovalent anion.
35. The method of Claim 31, wherein said water-soluble polymer is a terpolymer of butyl methacrylate, (2-dimethyl aminoethyl) methacrylate, and methyl methacrylate in relative proportions 1:2:1.
36. The method of Claim 30, wherein said water-soluble polymer has pH-sensitive solubility in aqueous media.
37. The method of Claim 36, wherein said water-soluble polymer has solubility inaqueous media having a pH of from about 1 to about 10.
38. The method of Claim 37, wherein said water-soluble polymer has solubility inaqueous media having acid pH.
39. The method of Claim 30, wherein said non-dissoluble agent is selected from the group consisting of antifungals, anti-inflammatories, anti-hypertensives, antimicrobials, steroidal drugs, hormones, prostaglandins, or interfeons, and mixtures thereof.
40. The method of Claim 30, wherein said bio-affecting agent is substantially non-dissoluble in aqueous media.
41. The method of Claim 30, wherein said simultaneous transforming and fixing iseffected by flash-flow processing.
42. The method of Claim 41, wherein said flash-flow processing is flash heat processing.
43. The method of Claim 42, wherein the bio-affecting agent is heat-sensitive.
44. The method of Claim 41, wherein said flash-flow processing is flash shear processing.
45. The method of Claim 30, wherein said simultaneous transforming and fixing iseffected by extrusion mixing for a time sufficient to form said solid dispersion.
46. The method of Claim 45, wherein said time is less than about 2 minutes.
47. The method of Claim 46, wherein said time is less than about 30 seconds.
48. The method of Claim 45, wherein said bio-affecting agent is an antifungal, anti-inflammatory, or anti-hypertensive agent.
49. The method of Claim 30, wherein said transforming to said increased-energy state includes reducing, in the absence of mechanical attrition, said bio-affecting agent to nanoparticles dispersed in said water-soluble polymer, said nanoparticles having an average particle size of less than about 1000 nm.
50. The method of Claim 48, wherein said average particle size is less than about 400 nm.
51. The method of Claim 30, wherein said wherein said transforming to said increased-energy state includes reducing, in the absence of mechanical attrition, said bio-affecting agent to a molecular dispersion in said water-soluble polymer.
52. The method of Claim 30, which further comprises mechanically reducing said solid dispersion to particulates.
53 . The method of Claim 52, which further comprises incorporating said particulates in a dosage unit.
54. The method of Claim 52, wherein said incorporating comprises including said particulates in a capsule.
55. The method of Claim 54, wherein said incorporating comprises forming a rapid-dissolve tablet.
56. The method of Claim 30, which further comprises sizing and shaping said solid dispersion for fixation in an intravascular fluid delivery device.
57. A composition for delivery of a bio-affecting agent, comprising:
a) a carrier comprising a water-soluble polymer having a glass transition temperature in the range of from about 0°C to about 200°C; and b) a bio-affecting agent microscopically dispersed in said water-soluble polymer.
a) a carrier comprising a water-soluble polymer having a glass transition temperature in the range of from about 0°C to about 200°C; and b) a bio-affecting agent microscopically dispersed in said water-soluble polymer.
58. The composition of Claim 57, wherein the water-soluble polymer has pH-sensitive solubility in aqueous media.
59. The composition of Claim 58, wherein the water-soluble polymer is substantially indissoluble in saliva but is soluble in gastric fluid.
60. The composition of Claim 57, wherein said bio-affecting agent is dispersed in the water-soluble polymer as nanoparticles having an average particle size of less than about 1000 nm.
61. The composition of Claim 60, wherein said bio-affecting agent is dispersed in the water-soluble polymer as nanoparticles having an average particle size of less than about 400 nm.
62. The composition of Claim 57, wherein said bio-affecting agent is dispersed in the water-soluble polymer at the molecular level.
63. A method for delivering a bio-affecting agent to a bio-system, comprising:
administering to said bio-system a solid dispersion comprising said bio-affecting agent fixed in an increased-energy state in a water-soluble polymer having a glass transition temperature in the range of from about 0°C to about 200°C, wherein said solid dispersion renders said bio-affecting agent bio-available to said bio-system.
administering to said bio-system a solid dispersion comprising said bio-affecting agent fixed in an increased-energy state in a water-soluble polymer having a glass transition temperature in the range of from about 0°C to about 200°C, wherein said solid dispersion renders said bio-affecting agent bio-available to said bio-system.
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| US52453195A | 1995-09-07 | 1995-09-07 | |
| US08/524,531 | 1995-09-07 |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CA2231050A1 true CA2231050A1 (en) | 1997-03-13 |
Family
ID=24089609
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CA 2231050 Abandoned CA2231050A1 (en) | 1995-09-07 | 1996-09-09 | System for rendering substantially non-dissoluble bio-affecting agents bio-available |
Country Status (5)
| Country | Link |
|---|---|
| EP (1) | EP0952770A4 (en) |
| JP (1) | JPH11514979A (en) |
| AU (1) | AU7106996A (en) |
| CA (1) | CA2231050A1 (en) |
| WO (1) | WO1997008950A1 (en) |
Families Citing this family (16)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CA2273272C (en) * | 1997-10-07 | 2004-09-21 | Fuisz Technologies Ltd. | Immediate release drug delivery forms |
| US6013280A (en) * | 1997-10-07 | 2000-01-11 | Fuisz Technologies Ltd. | Immediate release dosage forms containing microspheres |
| US6350786B1 (en) * | 1998-09-22 | 2002-02-26 | Hoffmann-La Roche Inc. | Stable complexes of poorly soluble compounds in ionic polymers |
| FR2795326B1 (en) † | 1999-06-28 | 2001-08-31 | Adir | SOLID THERMOFORMABLE PHARMACEUTICAL COMPOSITION WITH CONTROLLED RELEASE |
| JP2001247408A (en) * | 2000-03-08 | 2001-09-11 | Hodogaya Chem Co Ltd | Feeding type insect pest-controlling composition using acid-soluble polymer |
| FR2818552B1 (en) * | 2000-12-26 | 2003-02-07 | Servier Lab | SOLID THERMOFORMABLE PHARMACEUTICAL COMPOSITIONS FOR THE CONTROLLED RELEASE OF IVABRADINE |
| JP2004534812A (en) | 2001-06-22 | 2004-11-18 | ファイザー・プロダクツ・インク | Pharmaceutical composition of dispersion of drug and neutral polymer |
| US7811606B2 (en) | 2003-04-16 | 2010-10-12 | Dey, L.P. | Nasal pharmaceutical formulations and methods of using the same |
| US8912174B2 (en) | 2003-04-16 | 2014-12-16 | Mylan Pharmaceuticals Inc. | Formulations and methods for treating rhinosinusitis |
| US9808471B2 (en) | 2003-04-16 | 2017-11-07 | Mylan Specialty Lp | Nasal pharmaceutical formulations and methods of using the same |
| ES2325591T3 (en) * | 2004-03-10 | 2009-09-09 | Bayer Schering Pharma Aktiengesellschaft | COMPOSITIONS THAT INCLUDE MOLECULARLY DISPERSED DROSPIRENONE. |
| WO2005117834A1 (en) * | 2004-05-27 | 2005-12-15 | Janssen Pharmaceutica N.V. | Solid dispersions of a basic drug compound and a polymer containing acidic groups |
| AU2007264418B2 (en) * | 2006-06-30 | 2012-05-03 | Iceutica Pty Ltd | Methods for the preparation of biologically active compounds in nanoparticulate form |
| AR077975A1 (en) | 2009-08-28 | 2011-10-05 | Irm Llc | PIRAZOL PYRIMIDINE DERIVATIVES AND COMPOSITIONS AS PROTEIN KINASE INHIBITORS |
| JP5953646B2 (en) * | 2009-11-24 | 2016-07-20 | 大正製薬株式会社 | Solid formulation containing ibuprofen |
| AR088936A1 (en) * | 2011-11-23 | 2014-07-16 | Novartis Ag | PHARMACEUTICAL FORMULATIONS |
Family Cites Families (11)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US3146167A (en) * | 1961-10-05 | 1964-08-25 | Smith Kline French Lab | Method of preparing sustained release pellets and products thereof |
| US3829564A (en) * | 1970-07-17 | 1974-08-13 | Commw Scient Ind Res Org | Coated products for veterinary use |
| DE3612212A1 (en) * | 1986-04-11 | 1987-10-15 | Basf Ag | METHOD FOR PRODUCING SOLID PHARMACEUTICAL FORMS |
| US4755397A (en) * | 1986-12-24 | 1988-07-05 | National Starch And Chemical Corporation | Starch based particulate encapsulation process |
| FR2634397B2 (en) * | 1986-12-31 | 1991-04-19 | Centre Nat Rech Scient | PROCESS FOR THE PREPARATION OF DISPERSIBLE COLLOIDAL SYSTEMS OF A PROTEIN IN THE FORM OF NANOPARTICLES |
| US4855326A (en) * | 1987-04-20 | 1989-08-08 | Fuisz Pharmaceutical Ltd. | Rapidly dissoluble medicinal dosage unit and method of manufacture |
| US4948586A (en) * | 1987-11-02 | 1990-08-14 | Lim Technology Laboratories, Inc. | Microencapsulated insecticidal pathogens |
| JP3802555B2 (en) * | 1991-12-17 | 2006-07-26 | フイズ テクノロジーズ リミテッド | Ulcer prevention and treatment composition and method |
| GB9200607D0 (en) * | 1992-01-13 | 1992-03-11 | Ethical Pharma Ltd | Pharmaceutical compositions containing nifedipine and process for the preparation thereof |
| US5518730A (en) * | 1992-06-03 | 1996-05-21 | Fuisz Technologies Ltd. | Biodegradable controlled release flash flow melt-spun delivery system |
| JPH08291063A (en) * | 1995-04-21 | 1996-11-05 | Maruho Kk | Readily absorbable pharmaceutical preparation and its production |
-
1996
- 1996-09-09 EP EP96932188A patent/EP0952770A4/en not_active Withdrawn
- 1996-09-09 AU AU71069/96A patent/AU7106996A/en not_active Abandoned
- 1996-09-09 CA CA 2231050 patent/CA2231050A1/en not_active Abandoned
- 1996-09-09 WO PCT/US1996/014457 patent/WO1997008950A1/en not_active Application Discontinuation
- 1996-09-09 JP JP9511444A patent/JPH11514979A/en active Pending
Also Published As
| Publication number | Publication date |
|---|---|
| JPH11514979A (en) | 1999-12-21 |
| EP0952770A1 (en) | 1999-11-03 |
| WO1997008950A1 (en) | 1997-03-13 |
| AU7106996A (en) | 1997-03-27 |
| EP0952770A4 (en) | 1999-12-22 |
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