CA2190598A1 - Pharmaceutical composition - Google Patents
Pharmaceutical compositionInfo
- Publication number
- CA2190598A1 CA2190598A1 CA002190598A CA2190598A CA2190598A1 CA 2190598 A1 CA2190598 A1 CA 2190598A1 CA 002190598 A CA002190598 A CA 002190598A CA 2190598 A CA2190598 A CA 2190598A CA 2190598 A1 CA2190598 A1 CA 2190598A1
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- CA
- Canada
- Prior art keywords
- cyclodextrin
- beta
- water
- derivative
- steroidal anti
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Abandoned
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Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/0087—Galenical forms not covered by A61K9/02 - A61K9/7023
- A61K9/0095—Drinks; Beverages; Syrups; Compositions for reconstitution thereof, e.g. powders or tablets to be dispersed in a glass of water; Veterinary drenches
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/185—Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
- A61K31/19—Carboxylic acids, e.g. valproic acid
- A61K31/192—Carboxylic acids, e.g. valproic acid having aromatic groups, e.g. sulindac, 2-aryl-propionic acids, ethacrynic acid
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/185—Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
- A61K31/19—Carboxylic acids, e.g. valproic acid
- A61K31/195—Carboxylic acids, e.g. valproic acid having an amino group
- A61K31/196—Carboxylic acids, e.g. valproic acid having an amino group the amino group being directly attached to a ring, e.g. anthranilic acid, mefenamic acid, diclofenac, chlorambucil
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/54—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one sulfur as the ring hetero atoms, e.g. sulthiame
- A61K31/5415—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one sulfur as the ring hetero atoms, e.g. sulthiame ortho- or peri-condensed with carbocyclic ring systems, e.g. phenothiazine, chlorpromazine, piroxicam
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/54—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one sulfur as the ring hetero atoms, e.g. sulthiame
- A61K31/542—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one sulfur as the ring hetero atoms, e.g. sulthiame ortho- or peri-condensed with heterocyclic ring systems
- A61K31/545—Compounds containing 5-thia-1-azabicyclo [4.2.0] octane ring systems, i.e. compounds containing a ring system of the formula:, e.g. cephalosporins, cefaclor, or cephalexine
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/50—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates
- A61K47/69—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the conjugate being characterised by physical or galenical forms, e.g. emulsion, particle, inclusion complex, stent or kit
- A61K47/6949—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the conjugate being characterised by physical or galenical forms, e.g. emulsion, particle, inclusion complex, stent or kit inclusion complexes, e.g. clathrates, cavitates or fullerenes
- A61K47/6951—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the conjugate being characterised by physical or galenical forms, e.g. emulsion, particle, inclusion complex, stent or kit inclusion complexes, e.g. clathrates, cavitates or fullerenes using cyclodextrin
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- B—PERFORMING OPERATIONS; TRANSPORTING
- B82—NANOTECHNOLOGY
- B82Y—SPECIFIC USES OR APPLICATIONS OF NANOSTRUCTURES; MEASUREMENT OR ANALYSIS OF NANOSTRUCTURES; MANUFACTURE OR TREATMENT OF NANOSTRUCTURES
- B82Y5/00—Nanobiotechnology or nanomedicine, e.g. protein engineering or drug delivery
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- Health & Medical Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Medicinal Chemistry (AREA)
- Pharmacology & Pharmacy (AREA)
- Life Sciences & Earth Sciences (AREA)
- General Health & Medical Sciences (AREA)
- Epidemiology (AREA)
- Animal Behavior & Ethology (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Engineering & Computer Science (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Nanotechnology (AREA)
- Biophysics (AREA)
- Biotechnology (AREA)
- General Engineering & Computer Science (AREA)
- Medical Informatics (AREA)
- Molecular Biology (AREA)
- Crystallography & Structural Chemistry (AREA)
- Medicinal Preparation (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
Abstract
A method of making a pharmaceutical composition comprising an inclusion complex of a .beta.-cyclodextrin or a derivative thereof and a sparingly water-soluble non-steroidal anti-inflammatory drug such as diclofenac sodium, the composition being in solid form which is adapted to be dissolved in water to provide a clear or slightly opaque solution for oral administration, includes the steps of forming a paste from the .beta.-cyclodextrin or the derivative thereof and the NSAID with a wetting solution, mixing the paste with addition of further wetting solution if necessary, and drying the product to produce the inclusion complex which dissolves in water to provide a clear or slightly opaque solution.
Description
WO 95132737 PCT/GB9~/01152 .
21 9~598 ., ~HARMACEUTICAL COMPOSITION
BACKGROIJND OF THE INVENTION
lbis invention relates to a method of making a ~ mrcl~AitiAln comprising an inelusion complex of a ~-~y~,loL,.~I;/., or a LI~ y aeeeptable derivative of a ~-cy~,lod~ and a sparingly water-soluble non-steroidal anti-;l n~ y drug (NSAID), and to a ~
mr~ A'n eomprisimg an inelusion eomple~ of a ~-cy-~lod~,AL il- or a derivative thereof and a sparingly water-soluble NSAID, in solid form whieh is adapted to be dissolved in water to provide a elear or siightly opaque solution for oral A.l...;.,;~llAI;....
Non-steroidal anti~ y drugs (NSAID's) are generally praetically insoluble in water. The low solubility impedes the dissolution rate of the drug in the ~_aLIuillt~ traet, resulting in slow absorption. ~ ..lly, for most NSAlD's, peak plasma levels are usually reaehed only after one to several kours after oral All,.,;.l~ depending on the solubility of the drug. NSAlD's commonly formulated as tablets therefore suffer from two dia~lv~ . (i) delayed onset of therapeutic action and (ii) local irritation of the ~;_ L~U;IIt~ l mucosa due to prolonged localised contact of the drug with the mucosa.
21 9~598 ., ~HARMACEUTICAL COMPOSITION
BACKGROIJND OF THE INVENTION
lbis invention relates to a method of making a ~ mrcl~AitiAln comprising an inelusion complex of a ~-~y~,loL,.~I;/., or a LI~ y aeeeptable derivative of a ~-cy~,lod~ and a sparingly water-soluble non-steroidal anti-;l n~ y drug (NSAID), and to a ~
mr~ A'n eomprisimg an inelusion eomple~ of a ~-cy-~lod~,AL il- or a derivative thereof and a sparingly water-soluble NSAID, in solid form whieh is adapted to be dissolved in water to provide a elear or siightly opaque solution for oral A.l...;.,;~llAI;....
Non-steroidal anti~ y drugs (NSAID's) are generally praetically insoluble in water. The low solubility impedes the dissolution rate of the drug in the ~_aLIuillt~ traet, resulting in slow absorption. ~ ..lly, for most NSAlD's, peak plasma levels are usually reaehed only after one to several kours after oral All,.,;.l~ depending on the solubility of the drug. NSAlD's commonly formulated as tablets therefore suffer from two dia~lv~ . (i) delayed onset of therapeutic action and (ii) local irritation of the ~;_ L~U;IIt~ l mucosa due to prolonged localised contact of the drug with the mucosa.
- 2 -Attempts to solubilise NSAlD's via salt formation have been reported, resulting in an improved absorption rate (see Reference 1). Several reports have appeared on nomrl~ Y~ti~n of NSAlD's with cyclod~AL~ a in which the complexes show significantly improved aqueous dissolution ..1,~ r~
(see References 2, ~, 4, 5, 6, 7). Apart from r~ of water solubility, uy~lod~ALIhl fl 1~ has also been shown to increase the rate and extent of NSAID adsorption after oral ~,1,.,;,1,~l.,,l,,,,l (see References 2, 8). A further advantage of uy~,lOd~A~ omrl~Y~tinn is a reduction in the UI~ LU~ Y commonly associated with orally au~ c~r :l NSAlD's (see Reference 9).
Cyclodextrin inclusion complexes may be prepared on the basis of liquidstate, solid state or semi-solid state reaction between the Cu~u~Ju~ L~ (see Reference 10). The first is ~f~"",~ l,rri by dissolving the cyclodextrin and NSAID in a suitable solvent and ~ lly isolating the solid state complex by crystallisation, ~vflJU.~lLiul~, spray drying or freeze drying. In the solid state method, the two ~ may be optionally screened to uniform particle size and thoroughly mixed whereafter they are ground in a high energy mill with optional heating, screened and 1..""..~,~.,;,..1 (see South African Patent No. 91/2282). In the semi-solid state, the two ..,.,1,.~,.,...1~ are Ifneaded in tne presence of small amounts of a suitable solvent, and the complex so-formed, is oven dried, screened and l,.""n", .1;~ d (see Reference 11).
In terms of ~ of the inclusion rnmrl~Y~tinn reaction, the particle size and the water solubility of the final product, the freeze-drying and spray drying methods represent the best methods of inclusion ~ l;fl., (Reference 10). lllese methods however are ~r~mnmi~-~lly ul~flLL~.Liv~ from WO gs/32737 ~ ,S/01152
(see References 2, ~, 4, 5, 6, 7). Apart from r~ of water solubility, uy~lod~ALIhl fl 1~ has also been shown to increase the rate and extent of NSAID adsorption after oral ~,1,.,;,1,~l.,,l,,,,l (see References 2, 8). A further advantage of uy~,lOd~A~ omrl~Y~tinn is a reduction in the UI~ LU~ Y commonly associated with orally au~ c~r :l NSAlD's (see Reference 9).
Cyclodextrin inclusion complexes may be prepared on the basis of liquidstate, solid state or semi-solid state reaction between the Cu~u~Ju~ L~ (see Reference 10). The first is ~f~"",~ l,rri by dissolving the cyclodextrin and NSAID in a suitable solvent and ~ lly isolating the solid state complex by crystallisation, ~vflJU.~lLiul~, spray drying or freeze drying. In the solid state method, the two ~ may be optionally screened to uniform particle size and thoroughly mixed whereafter they are ground in a high energy mill with optional heating, screened and 1..""..~,~.,;,..1 (see South African Patent No. 91/2282). In the semi-solid state, the two ..,.,1,.~,.,...1~ are Ifneaded in tne presence of small amounts of a suitable solvent, and the complex so-formed, is oven dried, screened and l,.""n", .1;~ d (see Reference 11).
In terms of ~ of the inclusion rnmrl~Y~tinn reaction, the particle size and the water solubility of the final product, the freeze-drying and spray drying methods represent the best methods of inclusion ~ l;fl., (Reference 10). lllese methods however are ~r~mnmi~-~lly ul~flLL~.Liv~ from WO gs/32737 ~ ,S/01152
- 3 - .
.
an industrial perspective. Owing to the ~ y~lCu~llclll;~dl nature of NSAlD's it was found that the industrially simple and rrcmnmir~,lly attractive kneading method provided a convenient process for the preparation of NSAID-cyclodextrin complexes with the desired wa~er solubility As stated above, various ~ l compositions containing inclusion compounds or complexes of a iyulod~,ALill and a drug are known.
South African Patent No. 84/10042 to Janssen Pl IA~ 11 IA. I ~ I j ;l ~ N.V discloses a ~ 1 composition comprising an inclusion compound of an unstdble or sparingly water-soluble drug and a partially etherified ~3-cyclodextrin of the formula (j3 - CD) OR
in which the residues are hydroxyalkyl groups and in which part of the residues R may optionally be alkyl groups, the ji3-~,lod~AI;ll ether having a water-solubility of more than 1,8g in 100ml of water. The drug may be a non-steroidal arlti-rheumatic agent. The partially etherified ~-~y~ dcAlfi~
is preferably lIYd1UA~LIIYI or lI~dIUAY~UIU~UYI ~-cyclodextrin The inclusion compound is prepared by dissolving the partially etherified ~-~:y~.lOd~ALlill in water and adding the drug. The ~ CnllllJUi~;liUII
may be formulated for oral :llllll;ll;~llrll;~lll PCT WO/90/02141 to ~ustralian Commercial Research and D~lu~ t Limited teaches inclusion complexes comprising amino ~yclodcAI;
derivatives in which at least one C2, C3 or C6 hydroxyl is substituted with -NH" and a 11ll'.. IIIA. . .1l ;1 iilly active agent such as, fûr example, certain non-steroidal anti-i"n~""~t~y drugs, e.g. in~lr~m~th~rin tolmetin, naproxen, .
wo ss/32~37 ~ .ss5.~ 52
.
an industrial perspective. Owing to the ~ y~lCu~llclll;~dl nature of NSAlD's it was found that the industrially simple and rrcmnmir~,lly attractive kneading method provided a convenient process for the preparation of NSAID-cyclodextrin complexes with the desired wa~er solubility As stated above, various ~ l compositions containing inclusion compounds or complexes of a iyulod~,ALill and a drug are known.
South African Patent No. 84/10042 to Janssen Pl IA~ 11 IA. I ~ I j ;l ~ N.V discloses a ~ 1 composition comprising an inclusion compound of an unstdble or sparingly water-soluble drug and a partially etherified ~3-cyclodextrin of the formula (j3 - CD) OR
in which the residues are hydroxyalkyl groups and in which part of the residues R may optionally be alkyl groups, the ji3-~,lod~AI;ll ether having a water-solubility of more than 1,8g in 100ml of water. The drug may be a non-steroidal arlti-rheumatic agent. The partially etherified ~-~y~ dcAlfi~
is preferably lIYd1UA~LIIYI or lI~dIUAY~UIU~UYI ~-cyclodextrin The inclusion compound is prepared by dissolving the partially etherified ~-~:y~.lOd~ALlill in water and adding the drug. The ~ CnllllJUi~;liUII
may be formulated for oral :llllll;ll;~llrll;~lll PCT WO/90/02141 to ~ustralian Commercial Research and D~lu~ t Limited teaches inclusion complexes comprising amino ~yclodcAI;
derivatives in which at least one C2, C3 or C6 hydroxyl is substituted with -NH" and a 11ll'.. IIIA. . .1l ;1 iilly active agent such as, fûr example, certain non-steroidal anti-i"n~""~t~y drugs, e.g. in~lr~m~th~rin tolmetin, naproxen, .
wo ss/32~37 ~ .ss5.~ 52
- 4 -ketoprofen and the like.
The complex is formed by forming a solution of the cyclodextrin in water or other solYent, which solution is added to a solution of the drug in a solvent, and thereafte} removing the solvent. The inclusion complex may be formulated for oral A, l,,, ;,,; ~ ;""
European Patent Application No. 519 428 to Takeda Chemical Industries teaches a ~ ;nAl romrncitinn comprising a slightly water-soluble drug, a U~IOd~ALI;1I arld a water-soluble organic solvent in an amount of 071 to 10 percent by weight. The ~ , is prepared in powdered form and is suitable for injection.
South African Patent No. 84/81 i6 to Chicsi rA.~ ;. i S.p.A. teaches CU~ u~l~b obtained by 1.".,l.1 I;n" of piroxicam with a-~- or -type ~;y~ In~ in ratios comprised between 1:1 and 1:10 of piroxicam and :y~,lOdl,AL ill~ ,L;~'y The complex may be formulated for oral in the form of capsules, tablets, bags, syrups, solutions and the like, including r rr.. ~ L tablets.
South African Patent No. 91/F~8~ to Chiesi FArrnAr~lltiri S.p.A. teaches a process for preparing piroxicam-~_y.,lod~ALI;Il complexes wherein the piroxicam and the cyclodextrin both in powder form are mixed together in a solid state and optionally degassed; the mixture is co-ground in a high energy mill with the grinding chamber saturated with steam; the product obtained is dried under vacuum and screened to eliminate any a gregates.
Again the complex~roduced by this process may be formulated for oral A,i.,,;" ~l,AI;nn for example in the form of tablets which have a much higher W0 95/32737 r ~ . v 1152 21 9Q~98 ., dissolution rate than commercial f~" " ",IAI If ~ containing piroxicam alone.
~Ithough many types of inclusion complexes of a ~:y~,lod~ and a non-steroidal anti-;~ l y drug are known, there is always the need for a new type of complex or l,ll~.lll~r~ ,.l ff~mroSitif~n containing such a complex and a method for the production of such SUMMA~Y OF THE IN-VENTION
According to a first aspect of the invention, tnere is provided a method of making a ~ ".~ ;f", comprising as an actiYe ingredient an inclusion complex of a ~ ,lod~.ALill or a 1,1,- ,.,=- . .,1;. ~lly acceptable derivative of a ~ "v~lod~A~ . and a sparingly water-soluble non-steroidal anti- '' y drug, the c"",l,.~ ;.... beirlg in solid form which is adapted to be dissolved in water to provide a clear or slightly opaque solution for orai ~1llll;ll~;l, ~;~l.l, which method includes the steps of:
(a) for~ning a paste from the ,i-cyclodextrin or the derivative thereof and the NSAID, with a wetting solution;
(b) mixing the paste with addition of further wetting solution if necessary; and (c) drying the product of step (b) to produce the inclusion complex which dissolves in water to provide a clear or slightly opaque solution.
W095132737 P~ 1152 . .
According to a seeond aspect of the invention, there is provided a l)I,_.,.,~r, .lli. ,.1 n nmrncitinn produeed by the method described above.
ccording to a third aspect of the invention, there is provided a o~ l comprising as an active ingredient an inclusion complex of a !3-cyclodextrin or a 1)~ "~ ly acceptable derivative of a ~ y.lo~ ,l.i.. and a sparingly water-soluble NSAID, the ~J~ o~iLiu~-being in solid form which is adapted to be dissolved in wa~er to provide a clear or slightly opaque solution for oral ;~,I",;";~I,r~;nn Whenever any reference is made to a drug, there is meant the drug as well as its 1.1,- ,~,,,.~,llir~ly acceptable salts The l,I,,~ l rnmrncitinn in solid form may be in the foFm of a powder, granule, tablet or saehet.
Examples of suitable ,~ yclo~l~AL il-~ or derivatives thereof include 13-cyclodextrin, 2-llyLu~yplu~ y~ ill or methylated-~-,lod~,Allill. The 2-lly~u~y~Jlu~yldLc~-B-~y~lOdc~uill preferably has adegree of ~I~hctitl~inn bet~veen 2 and 9, more prefeFably between 3.9 and i. I
2-llydlw~yulu~yl groups per B-uy~ludc.~llill moleeule.
Examples of suitable NSAID elasses inelude arylacetie acids, arylpropionic acids, aminoaryl carboxylic acids and thiazine earboxarnides. Representative NSAlDs include diclofenac sodium, naproxen, ibuprofen, mefenamic acid, piroxicam, tenoxicara and Inrnnxir~nn For NSAlD's, excluding the thiazine ~ r c, the ~ of the WO gs/32737 ~ 52 2~ 90598 invention is preferably non-~rrt~ L.
Step (a) of the method may comprise mixing the ~-cyclodextrin or the derivative thereof in powder form with the NSAID in powder form, and then adding a suitable amount of the wetting solution to the powder mixture to form the paste.
Alternatively, step (a) may comprise mixing the 13-l;y~,lud."~L1 1l~ or the derivative thereof in powder form with a suitable amount of the wetting solution to form a paste and then adding the NSAID in powder form or in the form of an a~ueous suspension or solution in the wetting solution, with mixing, to the paste.
rhe molar ratio of NSAID to ~-cyclodextrin or the derivative thereof is preferably from 1:1 to 1:5, more preferably from 1:1 to 1:2,5.
The wetting solution may be selected from water, a lower alkanol, preferably ethanol or propanol, or a mixture of water and a lower alkanol. When the wetting solution contains water, it may optionally also contain an amount of an aLkali such as sodium hydroxide.
In step (b), the mixing preferably continues for from 0,25 to 5 hours inclusiYe. During this period, the wetting solution is preferably added periodically to. maintain the paste-like ~,ulla;a~ "y of the mixture.
In step (c), the product of step (b) may be dried, for example, under vacuum or in an oven at dLJ~Iu.~ L~ly 40C.
wo g~/32737 P~, I, . ~ i 152 rhe method of the invention may include an additional step, after step (c) of: ,.
(d) forming the product of step (c) into a suitable solid ~ A. ",Af. . ,~
form, optionally with the addition of ~IIIA,,,,A.. ,~I~.AIly acceptable carriers or agents.
BR~EF DE:SCRIPTION OF THE DRAWINGS _ Figure I are differential scannirlg ~"llu~ ,.ly (DSC) I~ of (a) naproxen (b) 2-llydlu~,ulu~yl~ p-~iy~lod~i~.uill, (c) nap}oxen/2-,rdlV.~i~LJIUy,ylG~S_d p-U,y~ IOd~ 11.. I ;C physical mixture and (d) rlaproxen/2-llydlu~lu~y' ' ,~-(;y~,lod~ ill kneaded complex from Example 2;
Figure 2 are DSC Il' '"~'~C'A"'C of (a) ibuprofen (b) methylated ~-~ ,lo~A~iul, (c) ibuprofen/methylated ~ lod~ "~: ~ ;c physica mixture and (d) ibu~lurcl~/lu~,lllyl~ ;y~,lod~".LIill kneaded complex from Example 3;
Figure 3 are DSC th~Afgr-rA.~ of (a) tenoxicam, (b) ~i-cyclodextrin, (c) tenoxicarn/~-cyclodextrin ~1..;. ,,;".... :,;~ physical mixture, and (d) tenoxicam/~-cyclodextrin kneaded complex from Example 7;
Figure 4 are fourier transform infra-red (FTIR) spectra of (a) diclofenac sodium, (b) ~-cyclodextrin, (c) diclofenac sodium/~-uy~,lode,~ulll ,1~." l.,.",.. :.;C physical mixture, and (d) kneaded ir~clusion complex from Example I - Peak A~ c~bu~ylatc stretch (I); aromatic stretch (2,3);
Figure 5 are FTIR spectra of (a) naproxen, (b) 2-1lydlu~y~lu~Jyl .. . . .... .. . ... _ .. .... , ..... . . . .. . . _ .. .
wo 9~132737 Pf~T/GB95,fO1152 2 ~ 93598 g ~.,lod..ALIil~, (c) naproxen/2-lly~uAyululJyl....l-fj3-~y~,lou~ALlill ~l.,;-',;..,,.-:,;.
physical mixture, and (d) Aneaded inclusion complex from Exarnple 2 - Peak """. .,1~ carboxyl stretch (1,2); aromatic stretch (3,4); and Figure 6 are F~IR spectra of (a) piroxicam, (b) 2-hlfdluAy~lu,uyldLGd f3-cyclodextrin, (c) piroxicaml2-hydloAy"lu~ylated-~-cyclodextrin ~I,,i,ll;.llll..,iC physical mixture, and (d) kneaded inclusion complex from Example 6 - Peak A~;f~"",...;~ Amide carbonyl (I); pyridine ring (2);
secondary amine (3); aromatic stretch (4).
DESCE~IPTION OF EMBODI:ME~TS
The crux of the invention is a method of maAing a l~l,- ,., ..,,lf. l ;l ,.", comprising an inclusion complex of a ~3-f~yulod~ALIi~l (BCD) or a ~ y acceptable derivative of a BCD and a sparingly water-soluble NSAID in solid form, which is adapted to be dissolved in water to provide a clear or slightly opaque solution for oral ,./Il,l;l.;~l~rl;l.l~ wllich hds therapeutic advantages as set out in more detail below.
The method of NSAID-BCD f....,l.lf~ ", is based on a semi-solid preparation.
In a fust stage, the NSAID and ~ ,lod~,ALI;.I, both in a uniform finelydivided powder state, af e mixed together in a powder mixer. The particle size of the NSAID and "y' lOdGAL ill is preferably less than Z50 micron. The molar ratio of NSAID to cyclodextrin is between 1:1 and 1:5, but preferably between 1:1 and 1:2,5.
wo95/32737 2 1 90598 ~ 52 In a second stage the powder mixture is triturated with appropriate aliquots of a wetting solution to obtain a paste-like colla;a~ Vigorous mixing is continued for 0,25 to 5 hours mAint~inin~ the paste-like consistency by periodic addition of wetting solution. The said wetting solution may be selected from water, a lower alkanoi, preferably ethanol or propanol, or a mixture of water and a lower alkanol.
When the wetting soluhon contains water, it may optional~y contain an aikaii, preferably sodium hydroxide. The alka~i serves two purposes: firstly.
it causes ionisation of the NSAID resulting in improved wettability and solubility of the NSAID, and secondly, it enhances the solubility of the Atl ;11 Togetiler these factors appear to result in more rapid r~ during the kneading process.
On the other hand, ionisation of NSAlD's has been shown to reduce the degree of cyclodextrin 1l~ in solutiorL However, it has been reported from solution studies that cyclodextrin rnmrlPY~ltirn of ionised NSAlD's can result in much larger totai NSAID cnlllhili~tirln i.e.
50lllhili~tinn of the NSAID both due to ~,1"~ l;r"~ and ionisation, than if either method were used individually (See Reference 1~). Thus, the combined use of ~,yClOd~,~L;II ~ together with salt fomlation of relevant NSAlD's provides for a readily soluble fomm of the NSAID via technically simple m~-thr,~lrgy In an altemative procedure, the NSAID is generally added with mixing toa paste prepared by mixing the cyclodextrin with appropnate aliquots of water which may optionally contain an alkali, preferably sodium hydroxide. The NSAID may be added as a dry powder or suspended or _ _ , .. ... .. . .. .. . . ..... . ..
1, dissolved in a solution which may contain up to 100 percent v/v of a lower alkanol, preferably ethanol or propanol Mixing is continued according to the second stage as descnbed above.
In a third stage tne product obtained is dried either under vacuum and/or in an oven at 40C. The dried product is passed through a 30 mesh screen and mixed in a powder mixer.
The final product is Clldldl,t~ c~ by small particle siæ with significantly enhanced water solubility relative to the pure NSAID. It consists of a NSAlD-cyclodextrin molecular inclusion complex. Evidence for the said complex may be d~ lul~ ,d by differential scanning . ~ , ;( (DSC) and fourier transform infrared (FTIR) ~ ,llvaculJic arlalyses.
The solubility ~ ~Lcl;~lic~ of NSAlD-~,y~,lOd~,ALill complexes according to the invention permit the J~ of orally d~ c,~
.",.,I.~,~;I;I",~havinganti-;.~ ,.,..,-l..,y,analgesicamd~ ,."~ activity.
The said r.,, ." ~ have significant advantages over col~ iull~l oral NSAID treatments. Because the drug is a.L~ t, l~ in tne dissolved state, the problem of slow NSAID dissolution rate is effectively overcome.
CU~I~C~ .,IILIY, the time to reach peak plasma ~ ..,.,./;""~ may be Si~llir~ -ly reduced resulting in a more rapid onset of therapeutic action.
Local gastric irritation due to prolonged contact of the NSAID with the ~ aat~ Lillal mucosa is avoided owing to the widespread dispersion of the drug when adlllill~ lcd according to the invention. Palatable 1.l....l,.,~;l;..,.~
of the complexes may be simply prepared by mixture of the complex powder with suitable water soluble powder excipients which may include a diluent such as sorbitol or lactose. sweeteners and flavours. The ~mr~citi(7n may -21 905q8 be in the form of a powder for Ic~,ULIaLiLULiUII or a soluble tablet, both intended for rapid dissolution in water prior to oral ~ n-~ The said rf~nnr~citinn~ are readily soluble in at least lOOml tap water at room .Lu c In order that the invention may be more fully understood the following examples relatirlg to the preparation of NSAlD-~:yclod~.A~
complexes, their.,ll ~ ll and ~ c ~ l ct~mrocitil~n~ are g;ven In the examples which follow. the following cl-nnro..n~ are designated as indicated:
Diclofenac sodium - (I) Naproxen ~ (II) Ibuproferl ~ (III) Mefen2mic acid - (IV) Piroxicam - (V) Tenoxicarn - (VI) r,nrnn~in~rn - (VII) ~ yl lod~.LIill - (BCD) 2-ll~UAy,ulu~yl.lLcd ~-cy~,lod~,Atlill - (HPB) Methylated-~-cyclodextrin ~ (MBC) EXAMPLE I ~ ~
BCD and I are passed through 60 mesh screen. BCD (15,6g) is vigorously mixed with deiorlised water (6ml) to produce a uniform paste. I (4,4g) is slowly added with mixing. Vigorous rnixing is continued for 0_5 hour ensuring a uniform paste-like Culla;aL~,ll.,y throughout the operation. The mixture is oven dried at 40C. Tbe dried mass is crushed and passed -cl WO 9s/32737 Y~ . c1152 through 30 mesh screen. The powder is hr~mrlgrni~e~ in a powder mixer for 10 minutes. The product contains 21,6 percent m/m I with arl equilibrium water solubility of 3864mg/lOOml as detetmined by HPLC.
To 6,0g HPB in a mortar, 474ml of a IN sodium hydroxide solution is added with vigorous mixing to produce a paste. 11 (I,Og) is passed through a 60 mesh screen and added gradually to the paste with vigorous mixing. The mixture is kneaded for I hour with ~,.u~.i...~, addition of small aliquots of deionised water to maintain a paste-like L,Ulla;~ . The mixture is oven dried at 40C. The dried mass is crushed and passed through 30 mesh screen. The powder is llull~ d in a powder mixer for 10 minutes. The product contains 13,7 percent m/m Il with an ~.l";I;l,l ;"", water solubility of460mg/lOOml as determined by HPLC.
EX.~MPLE 3 To 2,~g MBC in a mortar, 3m~ propan-l-ol containing 0,4g 111 is gradually added with vigorous mixing. The mixture is vigorously kneaded for 0,~
hour with appropriate addition of small aliquots of neat propan-l-ol to maintain a paste-like L~Ullai:~L~ . ThG mixture is dried under vacuum at 40C. The dried mass is crushed and passed through a 30 mesh screen. The powder is 11~ rrl in a powder mixer for 10 minutes. The product contains 12,4 percent m/m 11I with an eqllilibri~lnn water solubility of 400mg/lOOml as determined by HPLC.
WO 95/32737 P~ 1 152 2~ 93S98 To 6,3g HPB in a mortar, 5ml of a IN sodium hydroxide solution is addedwith vigorous mixing to produce a paste. lrl (I,Og) is passed through a 60 mesh screen and added gradually to the paste with vigorous mixing. The mixture is kneaded for I hour with appropriate addition of small aliquots of deionised water to maintain a paste-like culla;au,lll,y. The mixture is dried at 40C. The dried mass is crushed and passed through a 30 mesh screen.
The powder is llulllO~ a~;l in a powder mixer for 10 minutes The product contains 13,1 percent m/m III with an equilibrium water solubility of 1300mg/lOOml as determined by HPLC.
EXAMPLE ~
To 5,7g HPB in a mortar, 4ml of a IN sodium hydroxide solution is addedwith vigorous mixirlg to produce a paste. IV (I,Og) is passed through a 60 mesh screen and added gradually to the paste with vigorous mixing. The mixture is kneaded for I hour with appropriate addition of small aliquots of deionised water to maintain a paste-like Culla;a~ ,y. The mixture is oven dried at 40C. The dried mass is crushed and passed through a 30 mesh screen. The powder is l~ 1 in a powder mixer for 10 minutes. The product contains 14,0 percent mlm IV with an Pqllilihri~lrn water solubility of 430mg/lOOrnl as determined by HPLC
EXAMPLE 6 ~:
HPB (24,0g) and V (2,9g) are passed through 60 mesh screen and tumble mixed for 10 minutes. A 50 percent vlv ,olution of etharlol in deionised w0 ss/32737 r 21 905q8 water (14ml) is gradually added to the mixture witb vigorous mixing to produce a uniform paste. VigorouS mixing is continued for 0,3 hours ensuring a uniform paste-like ~ L~llcy throughout the operation. The mixture is oven dried at 40C under vacuum. The dried mass is crushed and passed through 30 mesh screen. The powder is h~,,.o~ cd in a powder mixer for 10 minutes. The product contains 9,6 percent mlm V with an eq~lilihri-lm water solubility of 120mg/lOOml as determined by HPLC.
To 8,7g BCD in a mortar, 7ml deionised water is gradually added with vigorous mixing to produce a paste. Vl (1,3g) is passed through a 60 mesh screen arld added gradually to the paste with vigorous mixirlg. The mixture is kneaded for 0,25 hours The mixture is oven dried at 40C. The dried mass is crushed arld passed through 30 mesh screen. The powder is J in a powder mixer for 10 minutes. The product contains 22,0 percent mlm Vl with an ~q~lilihri~lm water solubiiity of 14mgllOOml as determined by HPLC.
E2~AMPLE 8 HPB (2,4g) and Vll (0,64g) are passed through 60 mesh screen and tumblemixed for 10 minutes. Deionised water (1-2ml) is gradually added to the mixture with vigorous mixing to produce a uniform paste. Vigorous mixing is continued for 0,3 hours erlsuring a urliform paste-like consistency throughout the operation. The mixture is oven dried at 40C under vacuum.
The dried mass is crushed and passed through 30 mesh screen. The powder is h~ l in a powder mixer for 10 minutes. The product contains wo 95/32737 . ~ .. ~ 1 152 21 905q~ --2079 percent m/m VII with an ~ ilihrillm water solubility of 14,6mg/lOOml as determined by HPLC.
HPB ~21,0g) and IV (2,41g) are passed through a 60 mesh screen and tumble mixed. Deionised water (lOml) is added with vigorous mixing to produce a paste. The mixture is kneaded for 30 minutes with appropriate addition of small aliquots of deionised water to maintain a paste-like consistency. The mixture is vacuum dried at 40C. The dried mass is crushed and passed through a 30 mesh screen. The powder is homogenised in a powder mixer for 10 minutes. The product contains 10,3 percent m/m IV.
According to the procedure of Example 1, 2,2g naproxen sodium and 19,8gBCD were used to form a complex containing 10% m/m naproxen sodium.
PEIYSICO-CHEMICAL CHARACTERISATION OF NSAID
rNCLUSlON COMPLEXES
Table I shows the aqueous solubility of the pure NSAID's ~1, III and V) as their St~ y~ d~ inclusion complexes prepared by kneading and spray drying. It has been shown that inclusion complexes prepared by spray drying represent the best examples in terms of ~ of and highest water solubility (Reference 10). From the table it is evident that the solubility of the complexes prepared according to the ,, , _ . .. .... . . .. .. ..
, ~.~, . 1 152 Wo 95/32737 rc~l 2~ 905~8 - 11 - ' invention compare faYourably with the spray dried complexes indicating tbat acceptable inclusion rrl",l.l. Al;.,l, has taken place, Table I Comparison of the aqueous solubility of NSAID complexes prepared by kneading and spray drying, 'b.' Aqueous Solubility* (mg/lOOml) Compou~d Kneaded Complex~* Spray Dried Complex l-BCD 3864 451?
V-HPB 120 1~6 '~ Determ~ned by ~PLC
** Complex from ~u~ ,ly described examplQ
Differential Scanning Calorimetry (DSC) is the lI~IIICIII~ of the rate of heat evolved or absorbed by a sample durirlg a ~ ll,u~ Lulc program, The tecbnique may be used to ~ inclusion ~ "l~ I in cases where the melting point of the included molecule is below the therrnal rlP~A~i~tir~n r~mge of the cyclodextrin (i,e, < 2'iO~C), Evidence for inclusion c."..~ may be obtained from a diminished and/or shifted thermal event uullc~u~ling to the melting point of the included guest relative to the pure substance. Compared to the pure NSAID or simple ,l.. ;.l,;.. l,;c NSAID/cyclodextrin mixtures, I~,UlC~ lL_~ivc DSC 11.. IIllO~lAllli of the UUllC~lUlalillg kneaded inclusion complexes taken from Examples 7, 3 and 7 show a diminished thermal event ,UII~;~jUUlld;ll~ to the melting point of theNSAID as sho~vn in Figures I to 3 IQ~,Li~ly.
_ _ . . . . .
WO 9S/32737 P~ 'C I I52 219~q~ --. .
Fourier transform infrared (FTIR) ~ u~OI~r is particularly useful in the . " ;`';;..A. of NSAlD/cyclodextrin inclusion complexes owing to the well separated carbonyl band (1680-173ûcm ') or the corresponding ionised carboxylate band (1550-1650cm ') presenl in most NSAlD's which generally undergoes a frequency shift and/or a reduction in intensity upon inclusion cu~llulcAd~iull. The former effect is principally due to disruption of int~rrnr)lreul~r (.NSAID-NS~ID) hydrogen bonds whereas the latter effect is due to vibrational restrictions imposed on the guest molecule in the uyclo~LIill cavity. Additionally, reduced intensity of bands ~ullcaAJulldillg to aromatic -C=C- stretching modes (1460-1650 and 680-850cm l) may also be used as evidence for inclusion ~ ;"l, RclJIcacll~dlivc FTIR
spectra of kneaded complexes from Examples 1, 2 and 6 show the aboYe phenomena relative to the pure NSAID or the cullc uulldlllg ct~irhillrr~ trir NSAlD/uy~,lOd~,Auill physical mixture as illustrated in Figures 4 to 6 Ic,~ ,Liv~ . In the case of Example 2, it is cul~ alJI~ that salt formation has taken place with the NSAID carboxyl, in which case the earbonyl group frequency would shift to a shorter ~a~ lulllb~ of the buAyl_~., anion. However, the ..~ l;r band of the carbonyl or its Cull~uulllillg C~UUAYI.~h are diminished as shown in Figure 5.
P~IARMACEUTICAL COMPOSITIONS
The following r..",,.~l~l;",, was used to prepare readily soluble tablets produeing a pleasant tasting clear solution when added to 100ml tap water:
Kneaded l-BCD complex from Example I was mixed with all other ~...,.,1.~..,..,l~ for 10 minutes, screened through a 30 mesh screen and further
The complex is formed by forming a solution of the cyclodextrin in water or other solYent, which solution is added to a solution of the drug in a solvent, and thereafte} removing the solvent. The inclusion complex may be formulated for oral A, l,,, ;,,; ~ ;""
European Patent Application No. 519 428 to Takeda Chemical Industries teaches a ~ ;nAl romrncitinn comprising a slightly water-soluble drug, a U~IOd~ALI;1I arld a water-soluble organic solvent in an amount of 071 to 10 percent by weight. The ~ , is prepared in powdered form and is suitable for injection.
South African Patent No. 84/81 i6 to Chicsi rA.~ ;. i S.p.A. teaches CU~ u~l~b obtained by 1.".,l.1 I;n" of piroxicam with a-~- or -type ~;y~ In~ in ratios comprised between 1:1 and 1:10 of piroxicam and :y~,lOdl,AL ill~ ,L;~'y The complex may be formulated for oral in the form of capsules, tablets, bags, syrups, solutions and the like, including r rr.. ~ L tablets.
South African Patent No. 91/F~8~ to Chiesi FArrnAr~lltiri S.p.A. teaches a process for preparing piroxicam-~_y.,lod~ALI;Il complexes wherein the piroxicam and the cyclodextrin both in powder form are mixed together in a solid state and optionally degassed; the mixture is co-ground in a high energy mill with the grinding chamber saturated with steam; the product obtained is dried under vacuum and screened to eliminate any a gregates.
Again the complex~roduced by this process may be formulated for oral A,i.,,;" ~l,AI;nn for example in the form of tablets which have a much higher W0 95/32737 r ~ . v 1152 21 9Q~98 ., dissolution rate than commercial f~" " ",IAI If ~ containing piroxicam alone.
~Ithough many types of inclusion complexes of a ~:y~,lod~ and a non-steroidal anti-;~ l y drug are known, there is always the need for a new type of complex or l,ll~.lll~r~ ,.l ff~mroSitif~n containing such a complex and a method for the production of such SUMMA~Y OF THE IN-VENTION
According to a first aspect of the invention, tnere is provided a method of making a ~ ".~ ;f", comprising as an actiYe ingredient an inclusion complex of a ~ ,lod~.ALill or a 1,1,- ,.,=- . .,1;. ~lly acceptable derivative of a ~ "v~lod~A~ . and a sparingly water-soluble non-steroidal anti- '' y drug, the c"",l,.~ ;.... beirlg in solid form which is adapted to be dissolved in water to provide a clear or slightly opaque solution for orai ~1llll;ll~;l, ~;~l.l, which method includes the steps of:
(a) for~ning a paste from the ,i-cyclodextrin or the derivative thereof and the NSAID, with a wetting solution;
(b) mixing the paste with addition of further wetting solution if necessary; and (c) drying the product of step (b) to produce the inclusion complex which dissolves in water to provide a clear or slightly opaque solution.
W095132737 P~ 1152 . .
According to a seeond aspect of the invention, there is provided a l)I,_.,.,~r, .lli. ,.1 n nmrncitinn produeed by the method described above.
ccording to a third aspect of the invention, there is provided a o~ l comprising as an active ingredient an inclusion complex of a !3-cyclodextrin or a 1)~ "~ ly acceptable derivative of a ~ y.lo~ ,l.i.. and a sparingly water-soluble NSAID, the ~J~ o~iLiu~-being in solid form which is adapted to be dissolved in wa~er to provide a clear or slightly opaque solution for oral ;~,I",;";~I,r~;nn Whenever any reference is made to a drug, there is meant the drug as well as its 1.1,- ,~,,,.~,llir~ly acceptable salts The l,I,,~ l rnmrncitinn in solid form may be in the foFm of a powder, granule, tablet or saehet.
Examples of suitable ,~ yclo~l~AL il-~ or derivatives thereof include 13-cyclodextrin, 2-llyLu~yplu~ y~ ill or methylated-~-,lod~,Allill. The 2-lly~u~y~Jlu~yldLc~-B-~y~lOdc~uill preferably has adegree of ~I~hctitl~inn bet~veen 2 and 9, more prefeFably between 3.9 and i. I
2-llydlw~yulu~yl groups per B-uy~ludc.~llill moleeule.
Examples of suitable NSAID elasses inelude arylacetie acids, arylpropionic acids, aminoaryl carboxylic acids and thiazine earboxarnides. Representative NSAlDs include diclofenac sodium, naproxen, ibuprofen, mefenamic acid, piroxicam, tenoxicara and Inrnnxir~nn For NSAlD's, excluding the thiazine ~ r c, the ~ of the WO gs/32737 ~ 52 2~ 90598 invention is preferably non-~rrt~ L.
Step (a) of the method may comprise mixing the ~-cyclodextrin or the derivative thereof in powder form with the NSAID in powder form, and then adding a suitable amount of the wetting solution to the powder mixture to form the paste.
Alternatively, step (a) may comprise mixing the 13-l;y~,lud."~L1 1l~ or the derivative thereof in powder form with a suitable amount of the wetting solution to form a paste and then adding the NSAID in powder form or in the form of an a~ueous suspension or solution in the wetting solution, with mixing, to the paste.
rhe molar ratio of NSAID to ~-cyclodextrin or the derivative thereof is preferably from 1:1 to 1:5, more preferably from 1:1 to 1:2,5.
The wetting solution may be selected from water, a lower alkanol, preferably ethanol or propanol, or a mixture of water and a lower alkanol. When the wetting solution contains water, it may optionally also contain an amount of an aLkali such as sodium hydroxide.
In step (b), the mixing preferably continues for from 0,25 to 5 hours inclusiYe. During this period, the wetting solution is preferably added periodically to. maintain the paste-like ~,ulla;a~ "y of the mixture.
In step (c), the product of step (b) may be dried, for example, under vacuum or in an oven at dLJ~Iu.~ L~ly 40C.
wo g~/32737 P~, I, . ~ i 152 rhe method of the invention may include an additional step, after step (c) of: ,.
(d) forming the product of step (c) into a suitable solid ~ A. ",Af. . ,~
form, optionally with the addition of ~IIIA,,,,A.. ,~I~.AIly acceptable carriers or agents.
BR~EF DE:SCRIPTION OF THE DRAWINGS _ Figure I are differential scannirlg ~"llu~ ,.ly (DSC) I~ of (a) naproxen (b) 2-llydlu~,ulu~yl~ p-~iy~lod~i~.uill, (c) nap}oxen/2-,rdlV.~i~LJIUy,ylG~S_d p-U,y~ IOd~ 11.. I ;C physical mixture and (d) rlaproxen/2-llydlu~lu~y' ' ,~-(;y~,lod~ ill kneaded complex from Example 2;
Figure 2 are DSC Il' '"~'~C'A"'C of (a) ibuprofen (b) methylated ~-~ ,lo~A~iul, (c) ibuprofen/methylated ~ lod~ "~: ~ ;c physica mixture and (d) ibu~lurcl~/lu~,lllyl~ ;y~,lod~".LIill kneaded complex from Example 3;
Figure 3 are DSC th~Afgr-rA.~ of (a) tenoxicam, (b) ~i-cyclodextrin, (c) tenoxicarn/~-cyclodextrin ~1..;. ,,;".... :,;~ physical mixture, and (d) tenoxicam/~-cyclodextrin kneaded complex from Example 7;
Figure 4 are fourier transform infra-red (FTIR) spectra of (a) diclofenac sodium, (b) ~-cyclodextrin, (c) diclofenac sodium/~-uy~,lode,~ulll ,1~." l.,.",.. :.;C physical mixture, and (d) kneaded ir~clusion complex from Example I - Peak A~ c~bu~ylatc stretch (I); aromatic stretch (2,3);
Figure 5 are FTIR spectra of (a) naproxen, (b) 2-1lydlu~y~lu~Jyl .. . . .... .. . ... _ .. .... , ..... . . . .. . . _ .. .
wo 9~132737 Pf~T/GB95,fO1152 2 ~ 93598 g ~.,lod..ALIil~, (c) naproxen/2-lly~uAyululJyl....l-fj3-~y~,lou~ALlill ~l.,;-',;..,,.-:,;.
physical mixture, and (d) Aneaded inclusion complex from Exarnple 2 - Peak """. .,1~ carboxyl stretch (1,2); aromatic stretch (3,4); and Figure 6 are F~IR spectra of (a) piroxicam, (b) 2-hlfdluAy~lu,uyldLGd f3-cyclodextrin, (c) piroxicaml2-hydloAy"lu~ylated-~-cyclodextrin ~I,,i,ll;.llll..,iC physical mixture, and (d) kneaded inclusion complex from Example 6 - Peak A~;f~"",...;~ Amide carbonyl (I); pyridine ring (2);
secondary amine (3); aromatic stretch (4).
DESCE~IPTION OF EMBODI:ME~TS
The crux of the invention is a method of maAing a l~l,- ,., ..,,lf. l ;l ,.", comprising an inclusion complex of a ~3-f~yulod~ALIi~l (BCD) or a ~ y acceptable derivative of a BCD and a sparingly water-soluble NSAID in solid form, which is adapted to be dissolved in water to provide a clear or slightly opaque solution for oral ,./Il,l;l.;~l~rl;l.l~ wllich hds therapeutic advantages as set out in more detail below.
The method of NSAID-BCD f....,l.lf~ ", is based on a semi-solid preparation.
In a fust stage, the NSAID and ~ ,lod~,ALI;.I, both in a uniform finelydivided powder state, af e mixed together in a powder mixer. The particle size of the NSAID and "y' lOdGAL ill is preferably less than Z50 micron. The molar ratio of NSAID to cyclodextrin is between 1:1 and 1:5, but preferably between 1:1 and 1:2,5.
wo95/32737 2 1 90598 ~ 52 In a second stage the powder mixture is triturated with appropriate aliquots of a wetting solution to obtain a paste-like colla;a~ Vigorous mixing is continued for 0,25 to 5 hours mAint~inin~ the paste-like consistency by periodic addition of wetting solution. The said wetting solution may be selected from water, a lower alkanoi, preferably ethanol or propanol, or a mixture of water and a lower alkanol.
When the wetting soluhon contains water, it may optional~y contain an aikaii, preferably sodium hydroxide. The alka~i serves two purposes: firstly.
it causes ionisation of the NSAID resulting in improved wettability and solubility of the NSAID, and secondly, it enhances the solubility of the Atl ;11 Togetiler these factors appear to result in more rapid r~ during the kneading process.
On the other hand, ionisation of NSAlD's has been shown to reduce the degree of cyclodextrin 1l~ in solutiorL However, it has been reported from solution studies that cyclodextrin rnmrlPY~ltirn of ionised NSAlD's can result in much larger totai NSAID cnlllhili~tirln i.e.
50lllhili~tinn of the NSAID both due to ~,1"~ l;r"~ and ionisation, than if either method were used individually (See Reference 1~). Thus, the combined use of ~,yClOd~,~L;II ~ together with salt fomlation of relevant NSAlD's provides for a readily soluble fomm of the NSAID via technically simple m~-thr,~lrgy In an altemative procedure, the NSAID is generally added with mixing toa paste prepared by mixing the cyclodextrin with appropnate aliquots of water which may optionally contain an alkali, preferably sodium hydroxide. The NSAID may be added as a dry powder or suspended or _ _ , .. ... .. . .. .. . . ..... . ..
1, dissolved in a solution which may contain up to 100 percent v/v of a lower alkanol, preferably ethanol or propanol Mixing is continued according to the second stage as descnbed above.
In a third stage tne product obtained is dried either under vacuum and/or in an oven at 40C. The dried product is passed through a 30 mesh screen and mixed in a powder mixer.
The final product is Clldldl,t~ c~ by small particle siæ with significantly enhanced water solubility relative to the pure NSAID. It consists of a NSAlD-cyclodextrin molecular inclusion complex. Evidence for the said complex may be d~ lul~ ,d by differential scanning . ~ , ;( (DSC) and fourier transform infrared (FTIR) ~ ,llvaculJic arlalyses.
The solubility ~ ~Lcl;~lic~ of NSAlD-~,y~,lOd~,ALill complexes according to the invention permit the J~ of orally d~ c,~
.",.,I.~,~;I;I",~havinganti-;.~ ,.,..,-l..,y,analgesicamd~ ,."~ activity.
The said r.,, ." ~ have significant advantages over col~ iull~l oral NSAID treatments. Because the drug is a.L~ t, l~ in tne dissolved state, the problem of slow NSAID dissolution rate is effectively overcome.
CU~I~C~ .,IILIY, the time to reach peak plasma ~ ..,.,./;""~ may be Si~llir~ -ly reduced resulting in a more rapid onset of therapeutic action.
Local gastric irritation due to prolonged contact of the NSAID with the ~ aat~ Lillal mucosa is avoided owing to the widespread dispersion of the drug when adlllill~ lcd according to the invention. Palatable 1.l....l,.,~;l;..,.~
of the complexes may be simply prepared by mixture of the complex powder with suitable water soluble powder excipients which may include a diluent such as sorbitol or lactose. sweeteners and flavours. The ~mr~citi(7n may -21 905q8 be in the form of a powder for Ic~,ULIaLiLULiUII or a soluble tablet, both intended for rapid dissolution in water prior to oral ~ n-~ The said rf~nnr~citinn~ are readily soluble in at least lOOml tap water at room .Lu c In order that the invention may be more fully understood the following examples relatirlg to the preparation of NSAlD-~:yclod~.A~
complexes, their.,ll ~ ll and ~ c ~ l ct~mrocitil~n~ are g;ven In the examples which follow. the following cl-nnro..n~ are designated as indicated:
Diclofenac sodium - (I) Naproxen ~ (II) Ibuproferl ~ (III) Mefen2mic acid - (IV) Piroxicam - (V) Tenoxicarn - (VI) r,nrnn~in~rn - (VII) ~ yl lod~.LIill - (BCD) 2-ll~UAy,ulu~yl.lLcd ~-cy~,lod~,Atlill - (HPB) Methylated-~-cyclodextrin ~ (MBC) EXAMPLE I ~ ~
BCD and I are passed through 60 mesh screen. BCD (15,6g) is vigorously mixed with deiorlised water (6ml) to produce a uniform paste. I (4,4g) is slowly added with mixing. Vigorous rnixing is continued for 0_5 hour ensuring a uniform paste-like Culla;aL~,ll.,y throughout the operation. The mixture is oven dried at 40C. Tbe dried mass is crushed and passed -cl WO 9s/32737 Y~ . c1152 through 30 mesh screen. The powder is hr~mrlgrni~e~ in a powder mixer for 10 minutes. The product contains 21,6 percent m/m I with arl equilibrium water solubility of 3864mg/lOOml as detetmined by HPLC.
To 6,0g HPB in a mortar, 474ml of a IN sodium hydroxide solution is added with vigorous mixing to produce a paste. 11 (I,Og) is passed through a 60 mesh screen and added gradually to the paste with vigorous mixing. The mixture is kneaded for I hour with ~,.u~.i...~, addition of small aliquots of deionised water to maintain a paste-like L,Ulla;~ . The mixture is oven dried at 40C. The dried mass is crushed and passed through 30 mesh screen. The powder is llull~ d in a powder mixer for 10 minutes. The product contains 13,7 percent m/m Il with an ~.l";I;l,l ;"", water solubility of460mg/lOOml as determined by HPLC.
EX.~MPLE 3 To 2,~g MBC in a mortar, 3m~ propan-l-ol containing 0,4g 111 is gradually added with vigorous mixing. The mixture is vigorously kneaded for 0,~
hour with appropriate addition of small aliquots of neat propan-l-ol to maintain a paste-like L~Ullai:~L~ . ThG mixture is dried under vacuum at 40C. The dried mass is crushed and passed through a 30 mesh screen. The powder is 11~ rrl in a powder mixer for 10 minutes. The product contains 12,4 percent m/m 11I with an eqllilibri~lnn water solubility of 400mg/lOOml as determined by HPLC.
WO 95/32737 P~ 1 152 2~ 93S98 To 6,3g HPB in a mortar, 5ml of a IN sodium hydroxide solution is addedwith vigorous mixing to produce a paste. lrl (I,Og) is passed through a 60 mesh screen and added gradually to the paste with vigorous mixing. The mixture is kneaded for I hour with appropriate addition of small aliquots of deionised water to maintain a paste-like culla;au,lll,y. The mixture is dried at 40C. The dried mass is crushed and passed through a 30 mesh screen.
The powder is llulllO~ a~;l in a powder mixer for 10 minutes The product contains 13,1 percent m/m III with an equilibrium water solubility of 1300mg/lOOml as determined by HPLC.
EXAMPLE ~
To 5,7g HPB in a mortar, 4ml of a IN sodium hydroxide solution is addedwith vigorous mixirlg to produce a paste. IV (I,Og) is passed through a 60 mesh screen and added gradually to the paste with vigorous mixing. The mixture is kneaded for I hour with appropriate addition of small aliquots of deionised water to maintain a paste-like Culla;a~ ,y. The mixture is oven dried at 40C. The dried mass is crushed and passed through a 30 mesh screen. The powder is l~ 1 in a powder mixer for 10 minutes. The product contains 14,0 percent mlm IV with an Pqllilihri~lrn water solubility of 430mg/lOOrnl as determined by HPLC
EXAMPLE 6 ~:
HPB (24,0g) and V (2,9g) are passed through 60 mesh screen and tumble mixed for 10 minutes. A 50 percent vlv ,olution of etharlol in deionised w0 ss/32737 r 21 905q8 water (14ml) is gradually added to the mixture witb vigorous mixing to produce a uniform paste. VigorouS mixing is continued for 0,3 hours ensuring a uniform paste-like ~ L~llcy throughout the operation. The mixture is oven dried at 40C under vacuum. The dried mass is crushed and passed through 30 mesh screen. The powder is h~,,.o~ cd in a powder mixer for 10 minutes. The product contains 9,6 percent mlm V with an eq~lilihri-lm water solubility of 120mg/lOOml as determined by HPLC.
To 8,7g BCD in a mortar, 7ml deionised water is gradually added with vigorous mixing to produce a paste. Vl (1,3g) is passed through a 60 mesh screen arld added gradually to the paste with vigorous mixirlg. The mixture is kneaded for 0,25 hours The mixture is oven dried at 40C. The dried mass is crushed arld passed through 30 mesh screen. The powder is J in a powder mixer for 10 minutes. The product contains 22,0 percent mlm Vl with an ~q~lilihri~lm water solubiiity of 14mgllOOml as determined by HPLC.
E2~AMPLE 8 HPB (2,4g) and Vll (0,64g) are passed through 60 mesh screen and tumblemixed for 10 minutes. Deionised water (1-2ml) is gradually added to the mixture with vigorous mixing to produce a uniform paste. Vigorous mixing is continued for 0,3 hours erlsuring a urliform paste-like consistency throughout the operation. The mixture is oven dried at 40C under vacuum.
The dried mass is crushed and passed through 30 mesh screen. The powder is h~ l in a powder mixer for 10 minutes. The product contains wo 95/32737 . ~ .. ~ 1 152 21 905q~ --2079 percent m/m VII with an ~ ilihrillm water solubility of 14,6mg/lOOml as determined by HPLC.
HPB ~21,0g) and IV (2,41g) are passed through a 60 mesh screen and tumble mixed. Deionised water (lOml) is added with vigorous mixing to produce a paste. The mixture is kneaded for 30 minutes with appropriate addition of small aliquots of deionised water to maintain a paste-like consistency. The mixture is vacuum dried at 40C. The dried mass is crushed and passed through a 30 mesh screen. The powder is homogenised in a powder mixer for 10 minutes. The product contains 10,3 percent m/m IV.
According to the procedure of Example 1, 2,2g naproxen sodium and 19,8gBCD were used to form a complex containing 10% m/m naproxen sodium.
PEIYSICO-CHEMICAL CHARACTERISATION OF NSAID
rNCLUSlON COMPLEXES
Table I shows the aqueous solubility of the pure NSAID's ~1, III and V) as their St~ y~ d~ inclusion complexes prepared by kneading and spray drying. It has been shown that inclusion complexes prepared by spray drying represent the best examples in terms of ~ of and highest water solubility (Reference 10). From the table it is evident that the solubility of the complexes prepared according to the ,, , _ . .. .... . . .. .. ..
, ~.~, . 1 152 Wo 95/32737 rc~l 2~ 905~8 - 11 - ' invention compare faYourably with the spray dried complexes indicating tbat acceptable inclusion rrl",l.l. Al;.,l, has taken place, Table I Comparison of the aqueous solubility of NSAID complexes prepared by kneading and spray drying, 'b.' Aqueous Solubility* (mg/lOOml) Compou~d Kneaded Complex~* Spray Dried Complex l-BCD 3864 451?
V-HPB 120 1~6 '~ Determ~ned by ~PLC
** Complex from ~u~ ,ly described examplQ
Differential Scanning Calorimetry (DSC) is the lI~IIICIII~ of the rate of heat evolved or absorbed by a sample durirlg a ~ ll,u~ Lulc program, The tecbnique may be used to ~ inclusion ~ "l~ I in cases where the melting point of the included molecule is below the therrnal rlP~A~i~tir~n r~mge of the cyclodextrin (i,e, < 2'iO~C), Evidence for inclusion c."..~ may be obtained from a diminished and/or shifted thermal event uullc~u~ling to the melting point of the included guest relative to the pure substance. Compared to the pure NSAID or simple ,l.. ;.l,;.. l,;c NSAID/cyclodextrin mixtures, I~,UlC~ lL_~ivc DSC 11.. IIllO~lAllli of the UUllC~lUlalillg kneaded inclusion complexes taken from Examples 7, 3 and 7 show a diminished thermal event ,UII~;~jUUlld;ll~ to the melting point of theNSAID as sho~vn in Figures I to 3 IQ~,Li~ly.
_ _ . . . . .
WO 9S/32737 P~ 'C I I52 219~q~ --. .
Fourier transform infrared (FTIR) ~ u~OI~r is particularly useful in the . " ;`';;..A. of NSAlD/cyclodextrin inclusion complexes owing to the well separated carbonyl band (1680-173ûcm ') or the corresponding ionised carboxylate band (1550-1650cm ') presenl in most NSAlD's which generally undergoes a frequency shift and/or a reduction in intensity upon inclusion cu~llulcAd~iull. The former effect is principally due to disruption of int~rrnr)lreul~r (.NSAID-NS~ID) hydrogen bonds whereas the latter effect is due to vibrational restrictions imposed on the guest molecule in the uyclo~LIill cavity. Additionally, reduced intensity of bands ~ullcaAJulldillg to aromatic -C=C- stretching modes (1460-1650 and 680-850cm l) may also be used as evidence for inclusion ~ ;"l, RclJIcacll~dlivc FTIR
spectra of kneaded complexes from Examples 1, 2 and 6 show the aboYe phenomena relative to the pure NSAID or the cullc uulldlllg ct~irhillrr~ trir NSAlD/uy~,lOd~,Auill physical mixture as illustrated in Figures 4 to 6 Ic,~ ,Liv~ . In the case of Example 2, it is cul~ alJI~ that salt formation has taken place with the NSAID carboxyl, in which case the earbonyl group frequency would shift to a shorter ~a~ lulllb~ of the buAyl_~., anion. However, the ..~ l;r band of the carbonyl or its Cull~uulllillg C~UUAYI.~h are diminished as shown in Figure 5.
P~IARMACEUTICAL COMPOSITIONS
The following r..",,.~l~l;",, was used to prepare readily soluble tablets produeing a pleasant tasting clear solution when added to 100ml tap water:
Kneaded l-BCD complex from Example I was mixed with all other ~...,.,1.~..,..,l~ for 10 minutes, screened through a 30 mesh screen and further
5/01152 WO 95132737 PCr/GB9 21 ~0598 . .
mixed for a suitable time period. The mixture obtained was formed into oval shaped tablets with high surface area The unit ~nmrncition of each tablet is as follows:
Kneaded l-BCD complex 120 mg PEC 6000 5 mg Spray dried natural orange flavour 30 mg Sodium cyclamate 30 mg Sodium saccharin 15 mg Sorbitol 300 m~
Total: 500 mg The tablets have a hardness of about 30 N and dissoive vith swirling in a time of 3 minules.
The following r.~"~ "~ was used to prepare a readily soluble powder producing a pleasarlt tasting clear solution when added to lOOml tap water:
Kneaded Il-HPB complex from Example 2 waS mixed with all othe~
col.lLuul.~ for 10 minutes, screened through a 30 mesh screen and further mixed for a suitable time period. The mixture obtained was packed into sachets. The unit ~ , of each sachet is as follows:
wo 95/32737 ' ~ ,5, ~ 1 152 2 ~ 90598 Kneaded ~I-HPB complex 1465 mg Sucrose 3365 mg Spray dried natural cherry flavour 90 mg Sodium cyclamate 40 mg Sodium saccharin 40 m~
Total: 5000 mg =
The following ro",. ~ .,. was used to prepare a readily soluble powder prvducing a pleasant tasting slightly opaque solution when added to lOOml tap water: Kneaded III-HPB complex from Example 4 was mixed with all other ~ for 10 minutes, screened through a 30 rnesh screen and further mixed for a suitable time period. The mixture obtained was packed into sachets. The unit ~ of each sachet is as follows:
Kneaded III-HPB complex 1524 mg Spray dried natural cherry flavour 90 mg Sodium saccharin 115 m~
Total : 1729 mg The following r~."""l~ " was used to prepare a readily solubl~ powder producing a pleasant tasting slightly opaque solution when added to lOOml tap water: Kneaded V-HPB complex from Example 6 was mixed with all other (,:.,,,l~v, ,l~ for 10 minutes, screened through a 30 mesh screen and w09sl32737 r~ ll52 2~ q3S98 .
further mixed for a suitable time period. The mixture obtained was packed into sachets. The unit cnnnrn~iti~n of each sachet is as follows:
Kneaded V-HPB complex 210 mg Spray dried natural orange flavour 5 mg Sodium saccharin 15 mg Sodium cyclarnate 30 mg Spray dried lactose ~mg Total: 2000 mg E~AMPLE 15 The following fnrn~ tinn was used to prepare a readily soluble powder producmg a pleasant tasting slightly opaque solution when added to lOOml tap water: Kneaded IV-HPB complex from Example 9 was mixed with the other component for 10 minutes, screened through a 30 mesh screen and further mixed for a suitable time period. The mixture obtained was packed into sachets. The unit ~ o~ of each sachet is as follows:
Kneaded IV-HPB complex 2,425 g Trusil cherry flavour 0~050 ~
Total 2,475 g The following r.., ~ , was used to prepare a readily soluble powder , . . .... . . .. . .
Wo ssl32737 P~l,~,~ ilS2 producing a pleasant tasting slightly opaque solution when added to 100ml tap water: Kneaded naproxen sodiurn-BCD complex from Example 10 was mixed with the other ~ yull~llb for 10 minutes, screened through a 30 mesh screen and further mixed for a suitable time period. The mixture obtained was packed intû sachets The unit rrmrncitinn of each sachel is as followS:
Kneaded naproxen sodium-BCD complex 2,20g Passion fruit flavour 0,07sg Sodiurn cyclamate 0~005 Total 2,280g R~FERENCES
1. Ceppi Monti, N. et al Activity and phs~rm~rnkin~tirs of a New Oral Dosage Form of Soluble Ibuprofen, ~r7n.-imitt~1 Forschung 1992, 42 (1), Nr. 4, 556-559.
2. Chow, D.D. and Karara, A.H. ('1~ i".~ , dissolution and bioavailability in rats of ibuprofen-~-~y.,lodcALll~l complex system.
T"l~ ..,,.l Journal of Fll~ 1986, 28, 95-101.
3. Erden, N. and Çelebi, N. A study of the inclusion complex of naproxen with l3-cyclodextrin. T ~ l Journal of 1988, 48, 83-89.
4. R~rl~n~ . T. et al. Interaction of NSA with cyclodextrins and lly~LuAyyluyyl ~ ,lod.,AI;I. derivatives. Tnt~rn~tinn~l Journal of . _ . ... . . . .. .. . .. . ... . .. ... ... . ... . . ..
wo 9~13273~ P~ 52 r l, 1 9 9 1, 7 4, 8 5 9 3 5. Senel, S. et al. Preparation and I~ ;aLiull of the Tenoxicam/~-Cyclodextrin Complex. Journal of Inclusion Phenomena and Molecular Recognition in Chemistr~ 1992, 14, 171-179.
mixed for a suitable time period. The mixture obtained was formed into oval shaped tablets with high surface area The unit ~nmrncition of each tablet is as follows:
Kneaded l-BCD complex 120 mg PEC 6000 5 mg Spray dried natural orange flavour 30 mg Sodium cyclamate 30 mg Sodium saccharin 15 mg Sorbitol 300 m~
Total: 500 mg The tablets have a hardness of about 30 N and dissoive vith swirling in a time of 3 minules.
The following r.~"~ "~ was used to prepare a readily soluble powder producing a pleasarlt tasting clear solution when added to lOOml tap water:
Kneaded Il-HPB complex from Example 2 waS mixed with all othe~
col.lLuul.~ for 10 minutes, screened through a 30 mesh screen and further mixed for a suitable time period. The mixture obtained was packed into sachets. The unit ~ , of each sachet is as follows:
wo 95/32737 ' ~ ,5, ~ 1 152 2 ~ 90598 Kneaded ~I-HPB complex 1465 mg Sucrose 3365 mg Spray dried natural cherry flavour 90 mg Sodium cyclamate 40 mg Sodium saccharin 40 m~
Total: 5000 mg =
The following ro",. ~ .,. was used to prepare a readily soluble powder prvducing a pleasant tasting slightly opaque solution when added to lOOml tap water: Kneaded III-HPB complex from Example 4 was mixed with all other ~ for 10 minutes, screened through a 30 rnesh screen and further mixed for a suitable time period. The mixture obtained was packed into sachets. The unit ~ of each sachet is as follows:
Kneaded III-HPB complex 1524 mg Spray dried natural cherry flavour 90 mg Sodium saccharin 115 m~
Total : 1729 mg The following r~."""l~ " was used to prepare a readily solubl~ powder producing a pleasant tasting slightly opaque solution when added to lOOml tap water: Kneaded V-HPB complex from Example 6 was mixed with all other (,:.,,,l~v, ,l~ for 10 minutes, screened through a 30 mesh screen and w09sl32737 r~ ll52 2~ q3S98 .
further mixed for a suitable time period. The mixture obtained was packed into sachets. The unit cnnnrn~iti~n of each sachet is as follows:
Kneaded V-HPB complex 210 mg Spray dried natural orange flavour 5 mg Sodium saccharin 15 mg Sodium cyclarnate 30 mg Spray dried lactose ~mg Total: 2000 mg E~AMPLE 15 The following fnrn~ tinn was used to prepare a readily soluble powder producmg a pleasant tasting slightly opaque solution when added to lOOml tap water: Kneaded IV-HPB complex from Example 9 was mixed with the other component for 10 minutes, screened through a 30 mesh screen and further mixed for a suitable time period. The mixture obtained was packed into sachets. The unit ~ o~ of each sachet is as follows:
Kneaded IV-HPB complex 2,425 g Trusil cherry flavour 0~050 ~
Total 2,475 g The following r.., ~ , was used to prepare a readily soluble powder , . . .... . . .. . .
Wo ssl32737 P~l,~,~ ilS2 producing a pleasant tasting slightly opaque solution when added to 100ml tap water: Kneaded naproxen sodiurn-BCD complex from Example 10 was mixed with the other ~ yull~llb for 10 minutes, screened through a 30 mesh screen and further mixed for a suitable time period. The mixture obtained was packed intû sachets The unit rrmrncitinn of each sachel is as followS:
Kneaded naproxen sodium-BCD complex 2,20g Passion fruit flavour 0,07sg Sodiurn cyclamate 0~005 Total 2,280g R~FERENCES
1. Ceppi Monti, N. et al Activity and phs~rm~rnkin~tirs of a New Oral Dosage Form of Soluble Ibuprofen, ~r7n.-imitt~1 Forschung 1992, 42 (1), Nr. 4, 556-559.
2. Chow, D.D. and Karara, A.H. ('1~ i".~ , dissolution and bioavailability in rats of ibuprofen-~-~y.,lodcALll~l complex system.
T"l~ ..,,.l Journal of Fll~ 1986, 28, 95-101.
3. Erden, N. and Çelebi, N. A study of the inclusion complex of naproxen with l3-cyclodextrin. T ~ l Journal of 1988, 48, 83-89.
4. R~rl~n~ . T. et al. Interaction of NSA with cyclodextrins and lly~LuAyyluyyl ~ ,lod.,AI;I. derivatives. Tnt~rn~tinn~l Journal of . _ . ... . . . .. .. . .. . ... . .. ... ... . ... . . ..
wo 9~13273~ P~ 52 r l, 1 9 9 1, 7 4, 8 5 9 3 5. Senel, S. et al. Preparation and I~ ;aLiull of the Tenoxicam/~-Cyclodextrin Complex. Journal of Inclusion Phenomena and Molecular Recognition in Chemistr~ 1992, 14, 171-179.
6. Zecchi, V. et al. Control of NSAID Dissolution by ~-Cyclodextrin ('.nmrlrYslti~ln. Pl,~ Acta Helvetia 1988, 63, Nr. I l, 299-302.
7. Kurozumi, M. et al. Inclusion ('r,mro~nrC of Non-Steroidal A - n y and Other Slightly Water Soluble Drugs vith a-and ,B-Cy~,lod~ ills in Powdered Form. Chemical and pl,,""~ ,-1 Bulletin 1975, 23, 3062-3068.
8. Acerbi, D. et al. Rapid oral absorption profile of Piroxicam from its 3-Cyclûdextrin Complex. Drug l.~ .l 1990, 2 (Suppl. 4), 50-55.
9. Otero Espinar, F.J. et al. Reduction in the ulcerogenicity of naproxen by r"mri~YI-ti~-n with 13-Cyc~odextrin. Tntrm~til~n~l Journal of Fl, ", - ~ 1991, 70, 35-41.
10. Blanco, J. et al. Influence of method of preparation on inclusion complexes of naproxen with different cyrlr~ irYtrinc Drug D~,v~lv~ and Industrial Pharmacy 1991, 17, 943-957.
I l. Toricelli, C., Martini, A., Muggetti, L., Eli, M. and De Ponti, R.
... . . . .
WO gsl3Z737 PCTIGB9510115~
2 1 90598 ~
r~ 1 lournal of Pl~ 1991~ 75, 147-153, IZ. Loftsson, T. et al, Cyclodextrin f`l.,,,~ ;.," o~ NS~lDs:
Plly ~ , European lournal of PI ~ ~ " " ~
Sclences, 19S13, 1~ 95-101.
I l. Toricelli, C., Martini, A., Muggetti, L., Eli, M. and De Ponti, R.
... . . . .
WO gsl3Z737 PCTIGB9510115~
2 1 90598 ~
r~ 1 lournal of Pl~ 1991~ 75, 147-153, IZ. Loftsson, T. et al, Cyclodextrin f`l.,,,~ ;.," o~ NS~lDs:
Plly ~ , European lournal of PI ~ ~ " " ~
Sclences, 19S13, 1~ 95-101.
Claims (23)
1. A method of preparing a pharmaceutically active inclusion complex of a .beta.-cyclodextrin or a pharmaceutically acceptable derivative of a .beta.-cyclodextrin and a non-steroidal anti-inflammatory drug selected from diclofenac sodium, naproxen, ibuprofen, mefenamic acid, piroxicam, tenoxicam and lornoxicam, the complex being in solid form and such that, when dissolved in water, it forms a clear or slightly opaque solution for oral administration, which method includesthe steps of:
(a) forming a paste from the .beta.-cyclodextrin or the derivative thereof and the non-steroidal anti-inflammatory drug, with a wetting solution, the wetting solution being either a mixture of water and an alkali, or a lower alkanol, or a mixture of water and lower alkanol;
(b) mixing the paste with addition of further wetting solution if necessary; and(c) drying the product of step (b) to produce the inclusion complex.
(a) forming a paste from the .beta.-cyclodextrin or the derivative thereof and the non-steroidal anti-inflammatory drug, with a wetting solution, the wetting solution being either a mixture of water and an alkali, or a lower alkanol, or a mixture of water and lower alkanol;
(b) mixing the paste with addition of further wetting solution if necessary; and(c) drying the product of step (b) to produce the inclusion complex.
2. A method according to claim 1, wherein the complex is such that it will dissolve in water at room temperature to provide a clear or slightly opaquesolution for oral administration.
3. A method according to claim 1 or 2, wherein the non-steroidal anti-inflammatory drug is naproxen.
4. A method according to any of claims 1 to 3, wherein the .beta.-cyclodextrin or the derivative thereof is .beta.-cyclodextrin, 2-hydroxypropylated-.beta.-cyclodextrin or methylated-.beta.-cyclodextrin.
5. A method according to any of claims 1 to 4, wherein in step (a) the .beta.-cyclodextrin or the derivative thereof is mixed in powder form with the non-steroidal anti-inflammatory drug in powder form, and the wetting solution is then added to the powder mixture to form the paste.
6. A method according to any of claims 1 to 4, wherein in step (a) the .beta.-cyclodextrin or the derivative thereof is mixed in powder form with the wetting solution to form a paste, and there is then added to the paste with mixing the non-steroidal anti-inflammatory drug in powder form or in the form of an aqueous suspension or solution in the wetting solution.
7. A method according to any of claims 1 to 6, wherein the molar ratio of the non-steroidal anti-inflammatory drug to the .beta.-cyclodextrin or the derivative thereof is from 1:1 to 1:5.
8. A method according to claim 7, wherein the molar ratio of the non-steroidal anti-inflammatory drug to the .beta.-cyclodextrin or the derivative thereof is from 1:1 to 1:2.5.
9. A method according to any of claims 1 to 8, wherein the wetting solution comprises water and an alkali, and the alkali is sodium hydroxide.
10. A method according to any of claims 1 to 8, wherein the wetting solution comprises a lower alkanol or a mixture of water and a lower alkanol, and the lower alkanol is ethanol or propanol.
11. A method according to any of claims 1 to 10, wherein in step (b) the mixing is continued for from 0.25 to 5 hours inclusive.
12. A method according to claim 11, wherein in step (b) the mixing is continued with periodic additions of the wetting solution to maintain the paste-like consistency of the mixture.
13. A method according to any of claims 1 to 12, wherein in step (d) the product of step (b) is dried under vacuum or in an oven at approximately 40°C.
14. A method according to any of claims 1 to 12, wherein after step (d) there is included the further step of: (e) forming the product of step (d) into a suitable solid pharmaceutical form, optionally with the addition of pharmaceutically acceptable carrier or agent.
15. A pharmaceutical composition which comprises, as an active ingredient, an inclusion complex of .beta.-cyclodextrin or a pharmaceutically acceptable derivative of a .beta.-cyclodextrin and a non-steroidal anti-inflammatory drug selected from diclofenac sodium, naproxen, ibuprofen, mefenamic acid, piroxicam, tenoxicam and lornoxicam, and a pharmaceutically acceptable carrier therefor, the complex being in solid form such that, when dissolved in water at room temperature, it forms a clear or slightly opaque solution for oral administration.
16. A composition according to claim 15, wherein the complex is such that it will dissolve in water at room temperature to provide a clear or slightly opaque solution for oral administration.
17. A method according to claim 15 or 16, wherein the non-steroidal anti-inflammatory drug is naproxen.
18. A method according to claim 15,16 or 17, wherein the .beta.-cyclodextrin or the derivative thereof is .beta.-cyclodextrin, 2-hydroxypropylated-.beta.-cyclodextrin or methylated-.beta.-cyclodextrin.
19. A composition according to any of claims 15 to 18, wherein the molar ratio of the non-steroidal anti-inflammatory drug to the .beta.-cyclodextrin or the derivative thereof is from 1:1 to 1:5.
20. A composition according to claim 19, wherein the molar ratio of the non-steroidal anti-inflammatory drug to the .beta.-cyclodextrin or the derivative thereof is from 1:1 to 1:2.5.
21. A composition according to any of claims 15 to 20, which is in the form of a powder, granule, tablet or sachet.
22. A composition according to any of claims 15 to 20, which is in the form of a clear or slightly opaque solution in water for oral administration.
23. A composition according to claim 15, wherein the inclusion complex has been made by the method of any of claims 1 to 13.
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|---|---|---|---|
| ZA94/3740 | 1994-05-27 | ||
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| EP (1) | EP0760680A1 (en) |
| JP (1) | JPH10500982A (en) |
| AU (1) | AU2531295A (en) |
| BR (1) | BR9507768A (en) |
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| WO (1) | WO1995032737A1 (en) |
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| ZA959469B (en) * | 1994-11-15 | 1996-05-15 | South African Druggists Ltd | Pharmaceutical composition |
| IT1283029B1 (en) * | 1996-05-17 | 1998-04-03 | Resa Farma | PHARMACEUTICAL COMPOSITIONS BASED ON DICLOFENAC |
| IL122482A (en) * | 1995-06-07 | 1999-10-28 | Quadrant Holdings Cambridge | Methods for stably incorporating substances within dry foamed glass matrices and compositions obtained thereby |
| WO1996041646A2 (en) * | 1995-06-13 | 1996-12-27 | Dyer, Alison, Margaret | Pharmaceutical compositions containing lornoxicam and cyclodextrin |
| IT1294205B1 (en) * | 1997-07-23 | 1999-03-24 | Farmigea Spa | PROCEDURE FOR THE SOLUBILIZATION IN WATER AND IN AQUEOUS VEHICLES OF PHARMACOLOGICALLY ACTIVE SUBSTANCES |
| US8231899B2 (en) * | 1998-09-10 | 2012-07-31 | Nycomed Danmark Aps | Quick release pharmaceutical compositions of drug substances |
| TR200100708T2 (en) | 1998-09-10 | 2001-07-23 | Nycomed Danmark A/S | Quick-release pharmaceutical compositions for pharmaceutical agents. |
| ITMI20012749A1 (en) * | 2001-12-21 | 2003-06-21 | Chiesi Farma Spa | PROCEDURE FOR THE PREPARATION BY MICROWAVE TREATMENT OF INCLUSION COMPOUNDS BETWEEN DRUG AND CYCLODESTRINE AND PRODUCTS OBTAINED |
| CN100518831C (en) * | 2002-08-15 | 2009-07-29 | 刘云清 | Solid nano-medicine and preparing method thereof |
| JO3352B1 (en) | 2005-06-17 | 2019-03-13 | Apr Applied Pharma Res Sa | Diclofenac formulations and methods of use |
| KR20160033796A (en) | 2006-03-28 | 2016-03-28 | 자블린 파머슈티칼스 인코포레이티드 | Formulations of low dose diclofenac and beta-cyclodextrin |
| EP2394641A1 (en) | 2010-05-30 | 2011-12-14 | Abdi Ibrahim Ilac Sanayi ve Ticaret Anonim Sirketi | Pharmaceutical formulations of lornoxicam |
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| AT52263B (en) * | 1911-04-22 | 1912-02-26 | Jean Baptiste Feilner | Process for making combination photographic negatives. |
| HU176215B (en) * | 1978-01-27 | 1981-01-28 | Chinoin Gyogyszer Es Vegyeszet | Process for preparing a cyclodextrin-indomethacin inclusion complex with a ratio of at about 2:1 |
| JPS5920230A (en) * | 1982-07-19 | 1984-02-01 | チバ−ガイギ−・アクチエンゲゼルシヤフト | Drug containing piruprophen |
| DE3346123A1 (en) * | 1983-12-21 | 1985-06-27 | Janssen Pharmaceutica, N.V., Beerse | PHARMACEUTICAL PREPARATIONS OF SUBSTANCES MEDICAL OR UNSTABLE IN WATER AND METHOD FOR THE PRODUCTION THEREOF |
| YU43290B (en) * | 1986-11-13 | 1989-06-30 | Lek Tovarna Farmacevtskih | Process for preparing inclusioned complex of ibuproxane with beta-cyclodextrine |
| GB8813682D0 (en) * | 1988-06-09 | 1988-07-13 | Reckitt & Colmann Prod Ltd | Pharmaceutical compositions |
| FR2647343B1 (en) * | 1989-05-24 | 1994-05-06 | Rhone Poulenc Sante | NOVEL POROUS PHARMACEUTICAL FORM AND ITS PREPARATION |
| EP0491812A4 (en) * | 1989-09-14 | 1992-11-04 | Australian Commercial Research & Development Limited | Drug delivery compositions |
| FR2660195B1 (en) * | 1990-03-28 | 1994-10-07 | Crinex Sa Laboratoires | PHARMACEUTICAL CHEWING, ANTI-INFLAMMATORY AND / OR ANALGESIC COMPOSITION. |
| DE69231457T2 (en) * | 1991-06-21 | 2001-05-23 | Takeda Chemical Industries Ltd | Cyclodextrin composition containing fumagillol derivatives |
| GB9207990D0 (en) * | 1992-04-10 | 1992-05-27 | Smithkline Beecham Plc | Pharmaceutical composition |
-
1995
- 1995-05-22 AU AU25312/95A patent/AU2531295A/en not_active Abandoned
- 1995-05-22 EP EP95919524A patent/EP0760680A1/en not_active Withdrawn
- 1995-05-22 WO PCT/GB1995/001152 patent/WO1995032737A1/en not_active Application Discontinuation
- 1995-05-22 CA CA002190598A patent/CA2190598A1/en not_active Abandoned
- 1995-05-22 JP JP8500478A patent/JPH10500982A/en active Pending
- 1995-05-22 BR BR9507768A patent/BR9507768A/en not_active Application Discontinuation
Also Published As
| Publication number | Publication date |
|---|---|
| JPH10500982A (en) | 1998-01-27 |
| EP0760680A1 (en) | 1997-03-12 |
| BR9507768A (en) | 1997-09-02 |
| WO1995032737A1 (en) | 1995-12-07 |
| AU2531295A (en) | 1995-12-21 |
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| Date | Code | Title | Description |
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