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
• • 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

Definitions

• This invention relates to a method of making a pharmaceutical composition comprising an inclusion complex of a ⁇ -cyclodextrin, or a pharmaceutically acceptable derivative of a ⁇ -cyclodextrin and a sparingly water-soluble non- steroidal anti-inflammatory drug (NSAID), and to a pharmaceutical composition comprising an inclusion complex of a ⁇ -cyclodextrin or a derivative thereof 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 administration.
• NSAID sparingly water-soluble non- steroidal anti-inflammatory drug
• Non-steroidal anti-inflammatory drugs are generally practically insoluble in water.
• the low solubility impedes the dissolution rate of the drug in the gastrointestinal tract, resulting in slow absorption. Consequently, for most NSAID's, peak plasma levels are usually reached only after one to several hours after oral administration, depending on the solubility of the drug.
• NSAID's commonly formulated as tablets therefore suffer from two disadvantages: (i) delayed onset of therapeutic action and (ii) local irritation of the gastrointestinal mucosa due to prolonged localised contact of the drug with the mucosa. Attempts to solubilise NSAID's via salt formation have been reported, resulting in an improved absorption rate (see Reference 1).
• Cyclodextrin inclusion complexes may be prepared on the basis of liquid state, solid state or semi-solid state reaction between the components (see Reference 10). The first is accomplished by dissolving the cyclodextrin and NSAID in a suitable solvent and subsequently isolating the solid state complex by crystallisation, evaporation, spray drying or freeze drying.
• the two components 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 homogenized (see South African Patent No. 91/2282).
• the two components are kneaded in the presence of small amounts of a suitable solvent, and the complex so-formed, is oven dried, screened and homogenized (see Reference 11).
• the freeze-drying and spray drying methods represent the best methods of inclusion complexation (Reference 10). These methods however are economically unattractive from an industrial perspective. Owing to the physicochemical nature of NSAID's it was found that the industrially simple and economically attractive kneading method provided a convenient process for the preparation of NSAID-cyclodextrin complexes with the desired water solubility.
• compositions containing inclusion compounds or complexes of a cyclodextrin and a drug are known.
• South African Patent No. 84/10042 to Janssen Pharmaceutica N.V. discloses a pharmaceutical composition
• a pharmaceutical composition comprising an inclusion compound of an unstable or sparingly water-soluble drug and a partially etherified ⁇ - cyclodextrin of the formula ( ⁇ - CD) OR in which the residues are hydroxyalkyl groups and in which part of the residues R may optionally be alkyl groups, the ⁇ -cyclodextrin ether having a water-solubility of more than l,8g in 100ml of water.
• the drug may be a non-steroidal anti-rheumatic agent.
• the partially etherified ⁇ -cyclodextrin is preferably hydroxyethyl or hydroxypropyl ⁇ -cyclodextrin.
• the inclusion compound is prepared by dissolving the partially etherified ⁇ - cyclodextrin in water and adding the drug.
• the pharmaceutical composition may be formulated for oral administration.
• PCT WO/90/02141 to Australian Commercial Research and Development Limited teaches inclusion complexes comprising amino cyclodextrin derivatives in which at least one C2, C3 or C6 hydroxyl is substituted with - NH 2 , and a pharmaceutically active agent such as, for example, certain non- steroidal anti-inflammatory drugs, e.g. indomethacin, tolmetin, naproxen, ketoprofen and the like.
• a pharmaceutically active agent such as, for example, certain non- steroidal anti-inflammatory drugs, e.g. indomethacin, tolmetin, naproxen, ketoprofen and the like.
• the complex is formed by forming a solution of the cyclodextrin in water or other solvent, which solution is added to a solution of the drug in a solvent, and thereafter removing the solvent.
• the inclusion complex may be formulated for oral administration.
• European Patent Application No. 519 428 to Takeda Chemical Industries teaches a pharmaceutical composition comprising a slightly water-soluble drug, a cyclodextrin and a water-soluble organic solvent in an amount of 0, 1 to 10 percent by weight.
• the composition is prepared in powdered form and is suitable for injection.
• South African Patent No. 84/8156 to Chiesi Farmaceutici S.p.A. teaches compounds obtained by complexation of piroxicam with ⁇ - ⁇ - or ⁇ -type cyclodextrins, in ratios comprised between 1 : 1 and 1:10 of piroxicam and cyclodextrins respectively.
• the complex may be formulated for oral administration in the form of capsules, tablets, bags, syrups, solutions and the like, including effervescent tablets.
• South African Patent No. 91/2282 to Chiesi Farmaceutici S.p.A. teaches a process for preparing piroxicam-cyclodextrin 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 aggregates.
• the complex produced by this process may be formulated for oral administration for example in the form of tablets which have a much higher dissolution rate than commercial formulations containing piroxicam alone.
• a method of making a pharmaceutical composition comprising as an active ingredient an inclusion complex of a ⁇ -cyclodextrin or a pharmaceutically acceptable derivative of a ⁇ -cyclodextrin and a sparingly water-soluble non-steroidal anti-inflammatory drug, 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, which method includes the steps of:
• step (c) drying the product of step (b) to produce the inclusion complex which dissolves in water to provide a clear or slightly opaque solution.
• . impart * -. create pressate * 95/32737
• a pharmaceutical composition comprising as an active ingredient an inclusion complex of a ⁇ -cyclodextrin or a pharmaceutically acceptable derivative of a ⁇ -cyclodextrin and a sparingly water-soluble NSAID, 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.
• any reference is made to a drug there is meant the drug as well as its pharmaceutically acceptable salts.
• the pharmaceutical composition in solid form may be in the form of a powder, granule, tablet or sachet.
• Suitable ⁇ -cyclodextrins or derivatives thereof include ⁇ - cyclodextrin, 2-hydroxypropylated- ⁇ -cyclodextrin or methylated- ⁇ - cyclodextrin.
• the 2-hydroxypropylated- ⁇ -cyclodextrin preferably has a degree of substitution between 2 and 9, more preferably between 3.9 and 5.1 2-hydroxypropyl groups per ⁇ -cyclodextrin molecule.
• Suitable NSAID classes include arylacetic acids, arylpropionic acids, aminoaryl carboxylic acids and thiazine carboxamides.
• Representative NSAIDs include diclofenac sodium, naproxen, ibuprofen, mefenamic acid, piroxicam, tenoxicam and lomoxicam.
• composition of the invention is preferably non-effervescent.
• 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.
• step (a) may comprise mixing the ⁇ -cyclodextrin 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 aqueous suspension or solution in the wetting solution, with mixing, to the paste.
• the 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.
• a lower alkanol preferably ethanol or propanol
• a mixture of water and a lower alkanol may optionally also contain an amount of an alkali such as sodium hydroxide.
• step (b) the mixing preferably continues for from 0,25 to 5 hours inclusive. During this period, the wetting solution is preferably added periodically to. maintain the paste-like consistency of the mixture.
• step (c) the product of step (b) may be dried, for example, under vacuum or in an oven at approximately 40°C.
• the method of the invention may include an additional step, after step (c) of:
• step (d) forming the product of step (c) into a suitable solid pharmaceutical form, optionally with the addition of pharmaceutically acceptable carriers or agents.
• Figure 1 are differential scanning calorimetry (DSC) thermograms of (a) naproxen (b) 2-hydroxypropylated ⁇ -cyclodextrin, (c) naproxen/2- hydroxypropylated ⁇ -cyclodextrin stoichiometric physical mixture and (d) naproxen/2-hydroxypropylated ⁇ -cyclodextrin kneaded complex from Example 2;
• DSC differential scanning calorimetry
• Figure 2 are DSC thermograms of (a) ibuprofen (b) methylated ⁇ - cyclodextrin, (c) ibuprofen/methylated ⁇ -cyclodextrin stoichiometric physical mixture and (d) ibuprofen/methylated ⁇ -cyclodextrin kneaded complex from Example 3;
• Figure 3 are DSC thermograms of (a) tenoxicam, (b) ⁇ -cyclodextrin, (c) tenoxicam ⁇ -cyclodextrin stoichiometric 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/ ⁇ -cyclodextrin stoichiometric physical mixture, and (d) kneaded inclusion complex from Example 1 - Peak assignments: carboxylate stretch (1); aromatic stretch
• Figure 5 are FTIR spectra of (a) naproxen, (b) 2-hydroxypropylated ⁇ - cyclodextrin, (c) naproxen/2-hydroxypropylated- ⁇ -cyclodextrin stoichiometric physical mixture, and (d) kneaded inclusion complex from Example 2 - Peak assignments: carboxyl stretch (1,2); aromatic stretch (3,4); and Figure 6 are FTIR spectra of (a) piroxicam, (b) 2-hydroxypropylated ⁇ - cyclodextrin, (c) piroxicam/2-hydroxypropylated- ⁇ -cyclodextrin stoichiometric physical mixture, and (d) kneaded inclusion complex from Example 6 - Peak Assignments: Amide carbonyl (1); pyridine ring (2); secondary amine (3); aromatic stretch (4).
• the crux of the invention is a method of making a pharmaceutical composition
• a pharmaceutical composition comprising an inclusion complex of a ⁇ -cyclodextrin (BCD) or a pharmaceutically 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 administration which has therapeutic advantages as set out in more detail below.
• BCD ⁇ -cyclodextrin
• NSAID sparingly water- soluble NSAID
• the method of NSAID-BCD complexation is based on a semi-solid preparation.
• the NSAID and cyclodextrin are mixed together in a powder mixer.
• the particle size of the NSAID and cyclodextrin is preferably less than 250 micron.
• the molar ratio of NSAID to cyclodextrin is between 1 : 1 and 1 :5, but preferably between 1:1 and 1:2,5.
• the powder mixture is triturated with appropriate aliquots of a wetting solution to obtain a paste-like consistency. Vigorous mixing is continued for 0,25 to 5 hours maintaining the paste-like consistency by periodic addition of wetting solution.
• the said wetting solution may be selected from water, a lower alkanol, preferably ethanol or propanol, or a mixture of water and a lower alkanol.
• the wetting solution may optionally contain an alkali, preferably sodium hydroxide.
• the alkali 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 cyclodextrin. Together these factors appear to result in more rapid complexation during the kneading process.
• the NSAID is generally added with mixing to a paste prepared by mixing the cyclodextrin with appropriate aliquots of water which may optionally contain an alkali, preferably sodium hydroxide.
• the NSAID may be added as a dry powder or suspended or 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 described above.
• the product obtained is dried either under vacuum and/or in an oven at 40°C.
• the dried product is passed through a 30 mesh screen and mixed in a powder mixer.
• the final product is characterised by small particle size with significantly enhanced water solubility relative to the pure NSAID. It consists of a NSAID-cyclodextrin molecular inclusion complex. Evidence for the said complex may be demonstrated by differential scanning calorimetric (DSC) and fourier transform infrared (FTIR) spectroscopic analyses.
• DSC differential scanning calorimetric
• FTIR Fourier transform infrared
• NSAID-cyclodextrin complexes permit the formulation of orally administered pharmaceutical compositions having anti-inflammatory, analgesic and antirheumatic activity.
• the said formulations have significant advantages over conventional oral NSAID treatments. Because the drug is administered in the dissolved state, the problem of slow NSAID dissolution rate is effectively overcome. Consequently, the time to reach peak plasma concentrations may be significantly reduced resulting in a more rapid onset of therapeutic action. Local gastric irritation due to prolonged contact of the NSAID with the gastrointestinal mucosa is avoided owing to the widespread dispersion of the drug when administered according to the invention.
• Palatable compositions 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 composition may be in the form of a powder for reconstitution or a soluble tablet, both intended for rapid dissolution in water prior to oral administration.
• the said compositions are readily soluble in at least 100ml tap water at room temperature.
• BCD and I are passed through 60 mesh screen.
• BCD (15,6g) is vigorously mixed with deionised water (6ml) to produce a uniform paste.
• I (4,4g) is slowly added with mixing. Vigorous mixing is continued for 0.25 hour ensuring a uniform paste-like consistency throughout the operation.
• the mixture is oven dried at 40°C. The dried mass is crushed and passed through 30 mesh screen.
• the powder is homogenised in a powder mixer for 10 minutes.
• the product contains 21,6 percent m/m I with an equilibrium water solubility of 3864mg/100ml as determined by HPLC.
• HPB (24,0g) and V (2,9g) are passed through 60 mesh screen and tumble mixed for 10 minutes.
• a 50 percent v/v solution of ethanol in deionised water (14ml) is gradually added to the mixture with vigorous mixing to produce a uniform paste. Vigorous mixing is continued for 0,3 hours ensuring a uniform paste-like consistency throughout the operation.
• the mixture is oven dried at 40°C under vacuum. The dried mass is crushed and passed through 30 mesh screen.
• the powder is homogenised in a powder mixer for 10 minutes.
• the product contains 9,6 percent m/m V with an equilibrium water solubility of 120mg/100ml as determined by HPLC.
• HPB (2,4g) and VII (0,64g) are passed through 60 mesh screen and tumble mixed for 10 minutes.
• Deionised water (l-2ml) is gradually added to the mixture with vigorous mixing to produce a uniform paste. Vigorous mixing is continued for 0,3 hours ensuring a uniform paste-like consistency throughout the operation.
• the mixture is oven dried at 40°C under vacuum. The dried mass is crushed and passed through 30 mesh screen.
• the powder is homogenised in a powder mixer for 10 minutes.
• the product contains 20,9 percent m/m VII with an equilibrium water solubility of 14,6mg/ 100ml as determined by HPLC.
• HPB (21,0g) and IV (2,4 lg) are passed through a 60 mesh screen and tumble mixed.
• Deionised water (10ml) 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 40°C.
• 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.
• Table 1 shows the aqueous solubility of the pure NSAID's (I, III and V) as their stoichiometric cyclodextrin 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 completeness of complexation and highest water solubility (Reference 10). From the table it is evident that the solubility of the complexes prepared according to the invention compare favourably with the spray dried complexes indicating that acceptable inclusion complexation has taken place.
• DSC Differential Scanning Calorimetry
• the technique may be used to characterise inclusion complexation in cases where the melting point of the included molecule is below the thermal degradation range of the cyclodextrin (i.e. ⁇ 250°C).
• Evidence for inclusion complexation may be obtained from a diminished and/or shifted thermal event corresponding to the melting point of the included guest relative to the pure substance.
• FTIR Fourier transform infrared
• the following formulation was used to prepare readily soluble tablets producing a pleasant tasting clear solution when added to 100ml tap water: Kneaded I-BCD complex from Example 1 was mixed with all other components for 10 minutes, screened through a 30 mesh screen and further mixed for a suitable time period. The mixture obtained was formed into oval shaped tablets with high surface area.
• the unit composition of each tablet is as follows:
• the tablets have a hardness of about 30 N and dissolve with swirling in a time of 3 minutes.
• Kneaded II-HPB complex from Example 2 was mixed with all other components 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 composition of each sachet is as follows: Kneaded II-HPB complex 1465 mg
• Kneaded III-HPB complex from Example 4 was mixed with all other components 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 composition of each sachet is as follows:
• Kneaded V-HPB complex from Example 6 was mixed with all other components 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 composition of each sachet is as follows:
• 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 composition of each sachet is as follows:
• Kneaded naproxen sodium-BCD complex from Example 10 was mixed with the other components 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 composition of each sachet is as follows:

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• 1995
  • 1995-05-22 AU AU25312/95A patent/AU2531295A/en not_active Abandoned
  • 1995-05-22 BR BR9507768A patent/BR9507768A/pt not_active Application Discontinuation
  • 1995-05-22 CA CA002190598A patent/CA2190598A1/en not_active Abandoned
  • 1995-05-22 EP EP95919524A patent/EP0760680A1/en not_active Withdrawn
  • 1995-05-22 JP JP8500478A patent/JPH10500982A/ja active Pending
  • 1995-05-22 WO PCT/GB1995/001152 patent/WO1995032737A1/en not_active Application Discontinuation

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