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
  • A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
  • A61K9/141—Intimate drug-carrier mixtures characterised by the carrier, e.g. ordered mixtures, adsorbates, solid solutions, eutectica, co-dried, co-solubilised, co-kneaded, co-milled, co-ground products, co-precipitates, co-evaporates, co-extrudates, co-melts; Drug nanoparticles with adsorbed surface modifiers
  • A61K9/146—Intimate drug-carrier mixtures characterised by the carrier, e.g. ordered mixtures, adsorbates, solid solutions, eutectica, co-dried, co-solubilised, co-kneaded, co-milled, co-ground products, co-precipitates, co-evaporates, co-extrudates, co-melts; Drug nanoparticles with adsorbed surface modifiers with organic macromolecular compounds
• • 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
  • A61K47/51—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 non-active ingredient being a modifying agent
  • A61K47/56—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 non-active ingredient being a modifying agent the modifying agent being an organic macromolecular compound, e.g. an oligomeric, polymeric or dendrimeric molecule

Definitions

• This invention relates to a pharmaceutical composition containing active agents which are maintained in a solid amorphous form.
• Drug substances ranging from slightly or sparingly soluble to insoluble, have been found to decrease in crystallinity when mixed with various polymers and diluents.
• Sekizaki et al., Chem. Pharm. Bull , 43(6):988-993 (1995) it was found that ibuprofen became amorphous when the crystalline powder was mixed with polyvinylpyrrolidone.
• Kaneniwa et al. Chem. Pharm. Bull , 26(9): 2734-2743 (1978) a decrease in crystallinity was observed when amobarbital was treated in the presence of diluents. This decrease in crystallinity can enhance the solubility, dissolution rates and bioavailability of these substances.
• the amorphous form of drug substances are generally unstable, and can convert to a crystalline form.
• Some investigators have attempted to stabilize the amorphous form of drug substances by utilizing solid dispersion techniques. For example, in Imaizumi et al. , Chem. Pharm. Bull. , 31(7): 2510- 2512 (1983), the stability of the amorphous form of indomethacin was enhanced by solid dispersion of the indomethacin in polyvinylpolypyrrolidone. Additionally, in Thakkar et al., J. Pharm.
• WO 99/00131 published on January 7, 1999, teaches a process for preparing a solid state dispersion of paroxetine or its acid addition salts using a solvent or fusion process.
• paroxetine free base is dissolved in a polymer/solvent solution, contacted with dry hydrochloride gas and then the non-aqueous solvent is removed by evaporation under vacuum.
• Preparation of a solid state dispersion, by the fusion technique is taught to involve mixing a polymer with paroxetine free base, melting the mixture, contacting the melt with dry hydrogen chloride and then cooling the mixture.
• WO 99/00131 does not teach the use of a complexing agent to reduce and/or destroy the crystallinity of the crystalline form of an active drug nor does it teach the use of a co-solvent to prevent and/or reduces recrystallization.
• pharmaceutically active agents in crystalline form, can be combined with a complexing agent and a co-solvent in order for the active agents to be converted to and maintained in a solid amorphous form.
• one aspect of the present invention is a pharmaceutical composition
• a pharmaceutical composition comprising: an active agent in solid amorphous form, a complexing agent, and a non- volatile co-solvent; wherein the complexing agent converts the active agent from crystalline form to solid amorphous form, and the active agent, in the absence of the co- solvent, can recrystallize in the presence of the complexing agent.
• a first preferred embodiment of the invention is that the active agent is a drug substance, preferably in crystalline form prior to its conversion to amorphous form. More preferably, the active agent is paroxetine, salts of paroxetine, spironolactone, etodolac, diclofenac or salts of diclofenac.
• a second preferred embodiment of the invention is that the complexing agent is selected from the group consisting of crospovidone, povidone, cyclodextrin and a combination thereof.
• a third preferred embodiment of the invention is that the non-volatile co- solvent is compatible with the active agent and miscible with the solvent.
• a more preferred embodiment is that the co-solvent is polyethylene glycol.
• a fourth preferred embodiment is that the solvent is either an organic and volatile substance or water.
• the organic and volatile solvent is selected from the group consisting of ethanol, methanol, acetone, methylene chloride and a combination thereof.
• An additional aspect of the invention is a pharmaceutical composition
• a pharmaceutical composition comprising: paroxetine hydrochloride in a solid amorphous form, a complexing agent selected from the group consisting of crospovidone, povidone, cyclodextrin and a combination thereof, and polyethylene glycol 300.
• a further aspect of the invention is a method for producing a pharmaceutical composition which comprises an active agent that is maintained in a solid amorphous form, comprising: mixing a crystalline form of an active agent with a solvent; adding a complexing agent and a co-solvent to the mixture; and removing the solvent from the mixture so as to obtain the active agent in solid amorphous form.
• Another aspect of the invention is a method for producing a pharmaceutical composition which comprises paroxetine hydrochloride that is maintained in a solid amorphous form, comprising: mixing a crystalline form of paroxetine hydrochloride with ethanol; adding a complexing agent selected from the group consisting of crospovidone, povidone, cyclodextrin and a combination thereof, and polyethylene glycol 300 to the mixture; and removing the ethanol from the mixture so as to obtain the paroxetine hydrochloride in solid amorphous form.
• Figure 1 represents the results of DSC run of paroxetine hydrochloride anhydrate showing a peak at 115° C, the melting point of the crystal.
• Figure 2 represents the results of a DSC run on a sample containing a 1:3 ratio of paroxetine hydrochloride .-crospovidone (Sample 1).
• Figure 3 represents the results of a DSC run on a sample containing a 1:3: 1 ratio of paroxetine hydrochloride: crospovidone: PEG 300 (Sample 2).
• Figure 4 represents the results of a DSC run on a sample containing a 1: 10 ratio of paroxetine hydrochloride: crospovidone (Sample 3).
• Figure 5 represents the results of a DSC run on a sample containing a 1: 10: 1 ratio of paroxetine hydrochloride: crospovidone: PEG 300 (Sample 4).
• Figure 6 represents the results of a DSC run on a sample containing a 1:3 ratio of paroxetine hydrochloride: crospovidone that was mixed with a spatula (Sample 5).
• Figure 7 represents the results of a DSC run on a sample containing a 1:2: 1: 1 ratio of paroxetine hydrochloride: crospovidone: povidone: PEG 300.
• Figure 8 represents the results of DSC run of spironolactone showing a melting range of the crystal at 198-207 °C, the melting point of the crystal.
• Figure 9 represents the results of a DSC run on a sample containing a 1:3 ratio of spironolactone: crospovidone (Sample 6).
• Figure 10 represents the results of a DSC run on a sample containing a 1:3: 1 ratio of spironolactone : crospovidone : PEG 300 (Sample 7) .
• Figure 11 represents the results of DSC run of etodolac showing a melting range of the crystal at 146-151 °C.
• Figure 12 represents the results of a DSC run on a sample containing a 1: 1:3: 1 ratio of etodolac: povidone: crospovidone: PEG 300.
• Figure 13 represents the results of DSC run of diclofenac sodium showing a melting range of the crystal at 283-285 °C.
• Figure 14 represents the results of a DSC run on a sample containing a 1 : 1:3: 1 ratio of diclofenac sodium:povidone:crospoviddone:PEG 300.
• the inventors have surprisingly found that active agents in solid amorphous form, which can recrystallize in the presence of a complexing agent, can be stabilized or maintained in its amorphous state by combining the amorphous form of the active agent with a complexing agent and a co-solvent.
• active agent is defined as an active ingredient that is intended for use in the diagnosis, cure, mitigation, treatment or prevention of disease in humans or other animals.
• active agents include, but are not limited to, crystalline forms of active agents which have appreciable solubilities in a solvent wherein the solvent is ultimately removed from the final product.
• the solvent is preferably either an organic and volatile substance or water. More preferably, the organic and volatile solvent includes, but is not limited to, ethanol, methanol, acetone, methylene chloride or a combination thereof.
• the active agents of the present invention also include drug substances such as paroxetine, salts of paroxetine (e.g., acid addition salts such as paroxetine hydrochloride), spironolactone, etodolac, diclofenac and salts of diclofenac (e.g., sodium or potassium salts of diclofenac).
• drug substances such as paroxetine, salts of paroxetine (e.g., acid addition salts such as paroxetine hydrochloride), spironolactone, etodolac, diclofenac and salts of diclofenac (e.g., sodium or potassium salts of diclofenac).
• Other active agents will be recognized by those skilled in the art.
• the active agent is present in a pharmacologically effective amount.
• a pharmacologically effective amount is any amount of active agent sufficient to provide pharmacological activity or otherwise sufficient to affect the structure or function of the body in humans or other animals.
• paroxetine and its salts e.g., acid addition salts
• paroxetine and its salts are known to have an anti-depressant effect, utility as an analgesic, and an anti-obesity effect.
• the indications include depression, obsessive compulsive disorders and panic disorders.
• Spironolactone for example, acts both as a diuretic and as an antihypertensive drug.
• the indications include primary hyperaldosteronism, edematous conditions, essential hypertension and hypokalemia.
• the drug substance etodolac is, for instance, a nonsteroidal anti- inflammatory drug that exhibits anti-inflammatory, analgesic and antipyretic activies.
• the indications include acute and long term use for osteoarthritis and rheumatoid arthritis and management of pain.
• Diclofenac and its salts are also nonsteroidal anti-inflammatory drugs that exhibit the same properties as listed for etodolac.
• Diclofenac and its salts are used to treat osteoarthritis, rheumatoid arthritis, ankylosing spondylitis, management of pain and primary dysmenorrhea. Other pharmacological activities will be recognied by one skilled in the art.
• an effective amount depends on various factors well known to those skilled in the art such as the nature and severity of the condition to be treated, the frequency and route of administration, and the weight of the human or animal requiring treatment. However, it is believed that an amount from about 0.01 to 100 mg/kg of body weight per day of any one of the preferred active agents should be effective for producing the intended pharmacological effect.
• the pharmaceutical composition of the present invention can be presented as a unit dose.
• a unit dose of the pharmaceutical composition containing any one of the preferred active agents can generally contain from about 0.1 to 1000 mg of the active agent.
• Such unit dose compositions may be administered once or more times a day. It is to be understood that the amounts set forth herein are exemplary and they do not, to any extent, limit the scope or practice of the invention.
• complexing agent is a substance which associates with the active agent through either chemical binding or physical interaction to reduce or destroy the crystallinity of the active agent.
• the complexing agent is crospovidone, povidone, cyclodextrin or any combination thereof.
• a preferred amount of complexing agent to be used in the present invention ranges from 10/1 - 1/100 wt/wt (drug/complexing agent). Parameters which may affect the ratio include molecular weights of the drug and the complexing agent as well as the molecular structure of the drug and the complexing agent.
• a co-solvent is defined as a substance which has an appreciable solubility for the drug substance and which enhances the complexation and/or stabilizes the complex formed.
• the co-solvent should be nonvolatile. Non- volatile means that there should not be a significant amount of co- solvent loss under processing conditions, including the process to remove the solvent.
• the co-solvent should be compatible with the active agent and miscible with the solvent.
• co-solvents include, but are not limited to, polyethylene glycols, propylene glycol, glycerol, liquid petrolatum and lauryl alcohol. Other co-solvents will be apparent to those skilled in the art.
• a preferred amount of co-solvent to be used in the present invention ranges from 10/1 - 1/10 wt/wt (drug/co-solvent).
• the range of co-solvent may depend on the type of drug, complexing agent and co-solvent used.
• compositions according the present invention can also include other inert material or additives known as a pharmaceutically acceptable excipient.
• Pharmaceutically acceptable excipients are generally present to facilitate manufacturing, packaging and handling of the drug. These well known and art recognized excipients include, for example, fillers or diluents, binders or granulators, lubricants, glidants, disintegrants and coloring, flavoring and sweetening agents. Other excipients will be apparent to those of skill in the art.
• compositions of the present invention are preferably in solid dosage form. Any well known tabletting procedure, encapsulating procedure or other procedure to prepare a solid dosage form can be employed herein.
• paroxetine hydrochloride The following procedure was used to prepare a solid amorphous form of paroxetine hydrochloride. To begin, 10 grams of anhydrous paroxetine hydrochloride were added to 120 grams of ethanol. The sample was stirred and heated to 45 °C. Stirring was continued until the paroxetine hydrochloride was fully dissolved. Crospovidone, 30 grams of Polyplasdone XL (BASF; Mount Olive, NJ), was added to the paroxetine hydrochloride solution to form a slurry. The slurry was stirred and heated at 45 °C for 24 hours. Polyethylene glycol, 10 grams of PEG 300 (Dow Chemicals; Midland, Michigan), was added to the slurry and the sample was mixed well.
• Crospovidone 30 grams of Polyplasdone XL (BASF; Mount Olive, NJ)
• a solid paroxetine hydrochloride containing drug complex, wherein the paroxetine hydrochloride is maintained in an amorphous form is as follows:
• a solid spironolatone containing drug complex, wherein the spironolactone is maintained in an amorphous form is as follows:
• the above drug complexes can be prepared using the following steps.
• the ethanol (solvent) and the active agent are placed in a bowl of a high-shear mixer (Collette Gral), equipped with a heating jacket and connected to the source of heat.
• the set-point temperature of the heating medium is set to 50 °C.
• the content of the bowl is heated, while the material is stirred, until all of the active agent is completely dissolved.
• the povidone is added to the bowl and stirred until it is completely dissolved.
• the crospovidone is then added and the bowl's content is stirred for two hours.
• the polyethylene glycol is added next and the stirring continues for 30 minutes.
• the set-point temperature of the heating medium is set to 80°C (in the event that the solvent is water the set-point temperature of the heating medium would be set for 100°C) and the removal of the solvent is commenced under slight negative pressure, until the consistency of the material is such as to be suitable for transfer to the drying equipment (the solvent content is approximately 15% to 25%).
• the material is then placed in the drying equipment (a tray oven or a fluid-bed drier) and dried at the inlet air temperature set at 50 °C, until the residual solvent content is less than 5 % .
• the semi-dried material is milled using a comminuting mill (Fitzpatrick) equipped with a perforated plate with 0.093" diameter holes and set at 2,450 rpm (medium speed).
• the milled material is then returned back to the drying equipment and dried at 50 °C until the residual moisture content is below 2% .
• the dried material is milled again through a perforated plate with 0.020" diameter holes with the mill being set at 4,600 rpm (high speed).
• the complex can be spray dried or vacuum microwave dried. Other methods will be readily recognized by those skilled in the art.
• the milled granules are placed in a jacketed bowl of a Gral, PEG 8000 (Carbowax) is added and the content of the bowl is heated at 80°C, while mixing, until all of the particles are coated with PEG.
• PEG 8000 Carbowax
• the material is then discharged from the bowl, spread on ss trays and allowed to cool to room temperature.
• the cooled material is milled again through a perforated plate with 0.020" diameter holes with the mill being set at at 4,600 rpm (high speed).
• a final blend can be prepared which can either be compressed into tablets or filled into empty gelatin capsules.
• Final blends containing the paroxetine hydrochloride-containing drug complex as well as the spironolactone-containing drug complex are as follows:
• the above tabletting ingredients are combined in a blender and mixed together to form a final blend.
• the blend is compressed into tablets which can be optionally color coated with an aqueous dispersion such as Opadry ® (Colorcon).
• the final blend can be filled into empty gelatin capsules.
• DSC differential scanning calorimetry
• Sample 5 is simply a 1:3 ratio of anhydrous paroxetine hydrochloride: crospovidone that was mixed with a spatula.
• Figures 2- 6 and 9-10 The results of the DSC runs, as described above, are set forth in Figures 2- 6 and 9-10.
• Figures 1 and 8 demonstrate what the scans of DSC runs look like for the crystalline form of paroxetine hydrochloride and spironolactone.
• Figures 2, 4 and 6 where the co-solvent is absent, small peaks are present which indicate re-crystallization.
• Figures 3 and 5 no peaks are shown on the scan.
• the absence of peaks at the melting temperature of the drug crystals indicates the absence of drug crystals in the sample.
• the samples containing both the co-solvent and the complexing agent are maintained in a solid amorphous form.
• EXAMPLE X A solid etodolac-containing drug complex (a 1: 1:3: 1 ratio of etodolac:povidone:crospovidone:PEG 300), was prepared in the following manner.
• 800 g of micronized etodolac and 8,000 g of ethanol were places in a 25 L Collette Gral bowl and mixed while warming to 50 °C, until all of the drug was dissolved.
• 800 g of Povidone USP K 29-32 was added and mixed until completely dissolved.
• 1,600 g of Crospovidone NF was added and mixed for 2 hours while maintaining the termperature at 50°C.
• 800 g of PEG 300 was added and mixed for 30 minutes. The heating temperature was increased to 80 °C and the bulk of alcohol was evaporated. Semi-dry material was placed in a tray oven and dried at 40°C for approximately 18 hours.
• the material was then milled through a perforated plate with 0.065" diameter holes using a Fitzpatrick comminuting mill. This material was then placed back in the oven for an additional drying, until the residual solvent content is below 2 % . This material is then milled through a perforated plate with 0.020" diameter holes.
• a solid diclofenac sodium-containing drug complex (a 1: 1:3: 1 ratio of diclofenac sodium:povidone:crospovidone:PEG 300), was prepared in the following manner .
• the material was then milled through a perforated plate with 0.065" diameter holes using a Fitzpatrick comminuting mill. This material was then placed back in the oven for an additional drying, until the residual solvent content is below 2% . This material is then milled through a perforated plate with 0.020" diameter holes.

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