WO2014161131A1 - Préparation d'un complexe d'inclusion de méloxicam-β-cyclodextrine amorphe par l'intermédiaire d'un procédé de séchage par atomisation - Google Patents

Préparation d'un complexe d'inclusion de méloxicam-β-cyclodextrine amorphe par l'intermédiaire d'un procédé de séchage par atomisation Download PDF

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WO2014161131A1
WO2014161131A1 PCT/CN2013/073547 CN2013073547W WO2014161131A1 WO 2014161131 A1 WO2014161131 A1 WO 2014161131A1 CN 2013073547 W CN2013073547 W CN 2013073547W WO 2014161131 A1 WO2014161131 A1 WO 2014161131A1
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meloxicam
inclusion complex
βcd
spray
process according
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PCT/CN2013/073547
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English (en)
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Luwei ZHAO
Hong Sun
Yan Hu
Yansheng CHEN
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Arissa Pharma
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Priority to PCT/CN2013/073547 priority Critical patent/WO2014161131A1/fr
Publication of WO2014161131A1 publication Critical patent/WO2014161131A1/fr

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    • 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
    • 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
    • A61K47/30—Macromolecular organic or inorganic compounds, e.g. inorganic polyphosphates
    • A61K47/36—Polysaccharides; Derivatives thereof, e.g. gums, starch, alginate, dextrin, hyaluronic acid, chitosan, inulin, agar or pectin
    • A61K47/40—Cyclodextrins; Derivatives thereof
    • 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
    • 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
    • A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
    • A61K9/4841—Filling excipients; Inactive ingredients
    • A61K9/4866—Organic macromolecular compounds

Definitions

  • the present invention relates to a spray drying process for preparing meloxicam- ⁇ - cyclodextrin inclusion complex where the drug meloxicam remains stable amorphous.
  • the process is applicable to pilot and commercial manufacturing which is advantageous compared to other technological methods.
  • the inclusion complex obtained has desired physical chemical and biopharmaceutical properties, and can be made into product that shows superior oral absorption to the present meloxicam commercial product.
  • US 6,284,269 Bl discloses pharmaceutical compositions comprising meloxicam, a cyclodextrin, a facultative oligosaccharide, one or more pharmaceutically acceptable additives selected from the group consisting of: surfactants, hydrotropic agents, alkalizing agents, hydrocolloids, and polymers.
  • the above composition of this application is obtained by co-milling, co-grinding, or co-kneading meloxicam in the presence of cyclodextrin.
  • US 6,284,269 Bl does not disclose the preparation of meloxicam ⁇ -cyclodextrin inclusion complex via the specific spray drying process of the present invention.
  • US2004/0229038 Al (Cooper ER et al.) relates to nanoparticulate composition comprising meloxicam and at least one surface stabilizer adsorbed to or associated with the surface of the drug.
  • the nanoparticulate meloxicam particles have an effective average particle size of less than about 200nm.
  • composition prepared surprisingly exhibited superior T max profiles as compared to meloxicam's commercial product Mobic made by Boehringer Ingelheim Pharmaceuticals, Inc.
  • US2004/0229038 Al does not disclose the preparation of meloxicam ⁇ -cyclodextrin inclusion complex via the specific spray drying process of the present invention.
  • Characterization of ternary complexes of meloxicam-l- ⁇ CD and PVP or L-arginine prepared by the spray-drying technique (El-Maradny et al. Acta Pharm.
  • El-Maradny discloses ternary complexes of meloxicam with hydroxypropyl ⁇ -cyclodextrin (l- ⁇ CD) and either hydrophilic polymer (polyvinyl pyrrolidone, or PVP) or a basic amino acid such as L-arginine, were prepared by the spray drying technique, and the dissolution profiles of these formulations were compared with those of the corresponding binary system of meloxicam-l- ⁇ CD.
  • the spray drying technique disclosed in this publication is totally different form that of the present invention. For example, "El-Maradny” uses l- ⁇ CD instead of ⁇ CD.
  • l- ⁇ CD has much higher aqueous solubility, but is also much more expensive than ⁇ CD (lOOx more).
  • the substance concentration of "El-Maradny" is about 1.5% (w/v), which means that the method has very low manufacturing efficiency, and is limited to the lab production only.
  • the substance concentration is up to 20% (w/v), and the method can be scaled up for pilot or commercial manufacturing.
  • the method produced an inclusion complex, it did not mention or verify whether the complexation has been taken to completion.
  • meloxicam ⁇ CD inclusion complex was reported both in the published papers and in patents. There are a few different methods to prepare for it, including solution saturation method, freeze-drying method, milling method, etc.
  • the inlet temperature of the spray dryer, the heating temperature of the spray solution - both are keys to ensure the physical and chemical stability of the end product (amorphous meloxicam ⁇ CD inclusion complex, also referred to as "intermediate"), and the spray drying processability (the powder collected from the process not to be sticky to the wall or to accumulate at the mouth of the atomizer)
  • an amorphous meloxicam- ⁇ CD inclusion complex (also referred to as "intermediate") can be prepared and can be processed with other pharmaceutical excipients to produce conventional oral dosage formulations such as capsules or tablets, in order to achieve the intended purpose of fast onset in vivo once administered via oral route.
  • the intermediate needs to have the complexation to the full extent.
  • the drug meloxicam must be complexed with the ⁇ CD at molecular level, and that meloxicam must remain in amorphous state and not in crystalline state.
  • the present invention discloses a spray drying process for the preparation of amorphous meloxicam ⁇ CD inclusion complex (the "intermediate”).
  • the process comprises the following steps: a. dissolve meloxicam and ⁇ CD in a heated aqueous solution (also referred to as “spray solution”) in the presence of ammonium hydroxide; b. feed the spray solution into the drying chamber of a spray-dryer through a pump and an atomizing device to form droplets; c. introduce a stream of hot and drying gas into the drying chamber and through the cyclone to form powder particles; d. further dry and separate the collected powder particles to rid of the moisture (or so-called “secondary drying”).
  • the molar ratio of meloxicam and ⁇ CD is maintained at 1:1.5 to 1:3.
  • the spray solution is heated at a temperature 65-85 ° C .
  • the pH of the spray solution is kept at pH 8.5-11 with ammonium hydroxide concentration at 0.5% to 3% (w/v).
  • the substance concentration of combined weight of meloxicam and ⁇ CD is kept at 5% to 25% (w/v).
  • the inlet temperature of the spray-dryer is maintained between 110-160 ° C .
  • the powder particles that collected from the spray drying process are further dried. This is secondary drying process is set at 60-90 ° C and 1-12 hrs.
  • the present invention relates to the inclusion complex of meloxicam- ⁇ CD obtained through the process described above, wherein the complexation between meloxicam and ⁇ CD is taken to the full extent, and where meloxicam remains amorphous characterized by X-ray powder diffraction (XRPD) and differential scanning calorimetry (DSC) instrumentation.
  • XRPD X-ray powder diffraction
  • DSC differential scanning calorimetry
  • the present invention relates to a formulation comprising of the intermediate prepared according to the present process together with pharmaceutical acceptable excipients.
  • FIG. 1 shows results of the differential scanning calorimetry (DSC). From top to bottom: DSC profiles for meloxicam, ⁇ CD, PM (meloxicam- ⁇ CD physical mixture, molar ratio: 1:2), and intermediate (meloxicam- ⁇ CD inclusion complex, molar ratio 1:2).
  • the DSC was conducted using TA Q.50. Temperature control was regulated in both ovens with a nitrogen flux at 50ml/min; heating rate is 5°C/min from 25 °C to 300°C.
  • the indium was used for instrument calibration. The amount of material used for analysis: 2-5mg; the sample was placed in aluminum perforated pans.
  • FIG. 2 shows results of the X-ray powder diffraction (XRPD). From top to bottom: XRPD diffractogram for meloxicam, ⁇ CD, PM (meloxicam- ⁇ CD physical mixture, molar ratio: 1:2), and intermediate (meloxicam ⁇ CD inclusion complex, molar ratio 1:2).
  • the XRPD was conducted using Bruker AXS D8 Advance diffractometer. The experimental conditions: Cu-LKa radiation, voltage: 40kV, current: 60mA, 2 ⁇ range: 5-45°; diffractograms run: 4°/min. A chart of a series of peaks collected at different scattering angles was presented as below (graph of scattering intensity vs. 2 ⁇ ).
  • Figure 3 shows results of the Raman spectroscopy.
  • meloxicam Spectra from top to bottom: meloxicam, ⁇ CD, PM (meloxicam- ⁇ CD physical mixture, molar ratio: 1:2), and intermediate (meloxicam- ⁇ CD inclusion complex, molar ratio 1:2).
  • Raman spectra were recorded by using DXR Raman Spectrometer (manufacturer: Thermo Scientific). Laser excitation wavelength: 780nm.
  • Figure 4 shows results of the scanning electron microscope (SEM). Photos from top left clockwise to bottom left: meloxicam, ⁇ CD, PM (meloxicam- ⁇ CD physical mixture, molar ratio: 1:2), and intermediate (meloxicam ⁇ CD inclusion complex, molar ratio 1:2).
  • Figure 5 shows the mean plasma concentration in non-na ' ive male and female beagle dogs after oral administration with meloxicam new formulation (meloxicam ⁇ CD inclusion complex, capsule), Mobic (Tablet) and meloxicam new formulation (meloxicam ⁇ CD inclusion complex, suspension) at 7.5 mg per dosing per dog.
  • Meloxicam is a non-steroidal anti-inflammatory drug (NSAID) that exhibits antiinflammatory, analgesic, and antipyretic activities.
  • NSAID non-steroidal anti-inflammatory drug
  • the prescription products are widely prescribed across the globe for the treatment of osteoarthritis, rheumatoid arthritis as well as many types of pains such as back pain, post-surgical pain, migraine headaches, etc.
  • the primary mechanism of action is for the drug to selectively inhibit the cyclooxygenase (COX) enzyme system which results in decreased prostaglandin synthesis.
  • COX enzyme system is comprised of a few isoenzymes including COX-1 and COX-2.
  • the COX-1 is expressed in the gastrointestinal tract, kidneys, etc., and is involved in the production of prostaglandins required for gastric mucosal production and proper renal blood flow.
  • the COX-2 is not expressed in healthy tissue. Rather, it is present in certain inflammatory disease states such as rheumatoid arthritis or osteoarthritis.
  • meloxicam has a COX-2/COX-1 inhibition ratio of 0.09, and hence, the preferential inhibition of COX-2, which makes the drug superior to traditional non- selective NSAIDs, as it causes fewer gastrointestinal side-effects such as bleeding, heartburn, abdominal pain, etc.
  • Meloxicam has been shown to be useful in the symptomatic treatment of painful osteoarthritis (arthrosis, degenerative joint disease), symptomatic treatment of rheumatoid arthritis, symptomatic treatment of ankylosing spondylitis, and symptomatic treatment of the signs and symptoms of osteoarthritis, including pain, stiffness, and inflammation.
  • meloxicam product Mobic was initially launched in United States by Boehringer Ingelheim Pharmaceuticals, which is an oral tablets providing 7.5 and 15 mg strengths. The drug was introduced into the US market in 2000, and has been in the generic market since 2006, and is now widely available across the globe. Some of the trade names under which meloxicam has or is marketed include Mobic, Mobec, Mobicox, Movalis, and Movatec. Chemically, meloxicam is designated as 4-hydroxy-2-methyl-N-(5-methyl-2-thiazolyl)-2H- l,2-benzothiazine-3-carboxamide-l,l-dioxide. The molecular weight is 351.41. Its empirical formula is Ci 4 Hi 3 N 3 0 4 S 2 , and it has the following structural formula:
  • Meloxicam is a pastel yellow solid, practically insoluble in water, with higher solubility observed in strong bases.
  • Some of the physicochemical properties are listed as follows: melting point: 254 ° C, pK a : 4.2, log P app : 0.1 in n-octanol/buffer (pH 7.4), solubility in water: 7.5-12.5 ⁇ g/ml (various sources).
  • meloxicam in its present commercial product (such as Mobic or generic products) is unable to effectively manage the acute pain treatment. Also, it is of note that traditional narcotics have their limits: with a fast onset of action, these drugs generally have a short duration in plasma. Hence, there exists a need for medications that provide both fast onset and long duration for pain relief.
  • amorphous meloxicam- ⁇ CD inclusion complex prepared by the spray drying process disclosed in the present invention demonstrates that the drug has a much faster dissolution in vitro and has a much faster absorption in vivo in animal pharmacokinetics study, as compared with the performance of its commercial product Mobic.
  • meloxicam has a long half-life (Ti/ 2 : 15-20 hrs in humans). This would make the drug in an advantageous position that meets the demand of a desired drug product for managing the acute pain and with significantly improved patient compliance
  • cyclodextrins provides an attractive option: meloxicam, due to its structure, can be complexed with cyclodextrins, especially with ⁇ -cyclodextrin or its derivatives.
  • Literature search indicates that the inclusion complex with cyclodextrins can be formed via different approaches including solution saturation, spray drying, milling, freeze-drying, etc. Years of research in literatures has demonstrated that the meloxicam-cyclodextrin complex significantly improves the drug dissolution.
  • Cyclodextrins are doughnut-shaped molecules with a lipophilic surface on the inside ring and hydrophilic surface on the outer surface of the ring.
  • the principle behind this strategy is that the poorly soluble drug molecule fits into the inner ring and the outer hydrophilic surface of the cyclodextrin holds the complex in solution.
  • cyclodextrins are cyclic oligosaccharides which are obtained by enzymatic degradation of starch.
  • ⁇ CD or its derivatives is the most useful for complexing the drug meloxicam. It is of note that naturally occurring CDs including ⁇ CD have limited aqueous solubility, while many of its modified derivatives have shown significantly enhanced aqueous solubility.
  • ⁇ CD due to its well-established safety profile (as a GRAS, or generally-regarded-as-safe, pharmaceutical excipient), easy accessibility and significant less cost as compared to its derivatices, are broadly used in a variety of pharmaceutical products as well as food and cosmetic products across the globe.
  • Drug products that use ⁇ CD and have made to the commercial market include: piroxicam, nimesulide, dexamethasone, nitroglycerine, omeprazole, nicotine, cetirizine, etc.
  • the meloxicam ⁇ CD inclusion complex is expected to exhibit anti-inflammatory, analgesic and antipyretic properties, much the same way as piroxicam in the inclusion complex.
  • analgesic drug meloxicam is indicated for the treatment of diseases such as dental pain, post-traumatic pain, headache and dysmenorrhoea. It can be administered by oral route in the form of tablets, capsules, sachets or others.
  • the meloxicam ⁇ CD inclusion complex can also be prepared into dosage forms for other routes of administration such as suppository, trans-dermal, trans-mucosal, etc.
  • the drug meloxicam indeed remains as in amorphous state, as opposed to the crystalline state. It is expected that the formulation product containing the amorphous meloxicam ⁇ CD inclusion complex (e.g. molar ratio 1:2) will have a fast absorption, and hence a fast onset, making the drug meloxicam effective as an analgesic far more so than its generic version for pain relief and in pa rticular for acute pain relief.
  • the formulation product containing the amorphous meloxicam ⁇ CD inclusion complex e.g. molar ratio 1:2
  • the amorphous meloxicam-BCD inclusion complex (intermediate) prepared above ca n be manufactured into conventional dosage forms via blending and granulating with GRAS (generally-regarded-as-safe) pharmaceutical excipients, followed by encapsulating or tableting.
  • GRAS generally-regarded-as-safe
  • the ratio for the intermediate to pha rmaceutical excipients has a broad range from 10%: 90% to 90%: 10%.
  • a series of formulation products were made by blending, granulating and encapsulating the intermediate with other com mon pha rmaceutica l excipients including lactose monohydrate, crospovidone, magnesium stearate, etc. M uch like the intermediate itself, the formulation product demonstrates a significantly improved dissolution rate of meloxicam as compa red to that of meloxicam commercia l product Mobic in a variety of pH buffered solutions including pH 1, 2, 4.5, 6.1, 6.7, and 7.4.
  • One of the above formulations in capsule and in suspension, also referred to as "New Formulation" was tested in non-na ' ive beagle dogs, male and female, via ora l dosing.
  • the formulation prepared by the present invention shows a superior performance in vivo as compared with meloxicam commercial product Mobic.
  • the dog pharmacokinetics study indicates that the formulation containing the intermediate has a significantly improved in vivo profile : meloxicam's C max and AUC increased approx. 10-15%, as compared to those of Mobic product, and the drug's T max is reduced to approx. 1.5 hours, as compared to 4 hours of Mobic product.
  • spray-drying is usually referred to a process involving breaking up liquid mixture into small droplets (atomization) and rapidly removing solvent from the mixture in a spray-drying chamber (or a pparatus) where there is a strong driving force for evaporation of solvent from the droplets.
  • the strong driving force for solvent evaporation is generally provided by maintaining the partial pressure of solvent in the spray-drying apparatus well below the vapor pressure of the solvent at the temperature of the drying droplets.
  • the present invention discloses a special spray-drying process to prepare amorphous meloxicam ⁇ CD inclusion complex where the drug meloxicam remains in stable amorphous.
  • the present process comprising the following steps: First, meloxicam and ⁇ CD were dissolved in a heated aqueous solution in the presence of ammonium hydroxide. Then, the above spray solution was fed into the drying chamber of a spray- dryer through an atomizing device to form droplets. After a stream of drying gas was introduced into the drying chamber to form powder particles, the droplets were dried and separated to form powder particles.
  • the intermediate prepared by the present invention has a complexation to the full extent. This can be seen through DSC and XRPD as well as other instrumentations. DSC can be used to monitor the heat release or absorption during the drug phase transition, while XRPD can be used to detect if any trace of crystalline material is still existed. Both are important in interpreting if the drug exists in crystalline or amorphous state. In our investigation, DSC and XRPD are used to monitor the amorphous meloxicam inclusion complex during initial preparation and follow-up stability evaluation.
  • the molar ratio of meloxicam and ⁇ CD when dissolving in the heated aqueous solution in the presence of ammonium hydroxide is maintained at 1:1 to 1:5. In another embodiment of the invention, the molar ratio of meloxicam and ⁇ CD is maintained at 1:1.5 to 1:3. In preferred embodiment of the invention, the molar ratio of meloxicam and ⁇ CD is maintained at 1:2 to 1:2.5. In most preferred embodiment of the invention, the molar ratio of meloxicam and ⁇ CD is maintained at 1:2.
  • the alkaline solution is heated at a temperature of 65-85 ° C . In another embodiment of the invention, the alkaline solution is heated at a temperature of 65-75 ° C . In one embodiment of the invention, the pH of the spray solution is kept at pH 8.5-11 with ammonium hydroxide concentration at 0.5% to 3%. In another embodiment of the invention, the pH of the spray solution is kept at pH 8.5-10 with ammonium hydroxide concentration at 1-2%. Although the present invention utilizes high pH and high temperature in the spray solution preparation, such conditions do not compromise the chemical stability of the resultant product, as shown in the stability studies.
  • the substance concentration (combined weight of meloxicam and ⁇ CD) is kept at 5% to 30% (w/v). I n preferred embodiment of the present invention, the substance concentration is kept at 5-25% (w/v). In preferred embodiment of the present invention, the substance concentration is kept at 13-20% (w/v).
  • the substance concentration in the spray solution is about 1-3% (w/v).
  • the substance concentration in the spray solution is up to 15-25% (w/v) in the spray solution.
  • the spray drying process requires high inlet temperature, so that the spray solution can be evaporated immediately, and the dry powder can be collected accordingly.
  • the inlet temperature is too high, meloxicam may run the risk of chemical degradation or even decomposition during the spray-drying process, and the resultant particles are not suitable for medicament.
  • the inlet temperature is low, the spray solution may not be fully evaporated or get sticky in the drying chabmer, and it is difficult to complete the spray-drying process. Therefore, suitable inlet temperature plays a key part in the preparation of meloxicam ⁇ CD inclusion complex of the present invention.
  • the inlet temperature of the spray-dryer is maintained between 110-180 ° C . In preferred embodiment of the invention, the inlet temperature of the spray-dryer is maintained between 120-170 ° C . In preferred embodiment of the invention, the inlet temperature of the spray-dryer is maintained between 130 160 ° C . In more preferred embodiment or more preferably, the inlet temperature of the spray-dryer is maintained between 120-140 ° C . In more preferred embodiment or more preferably, the inlet temperature of the spray-dryer is maintained between 110-130 ° C .
  • the resultant powder particles can be further dried.
  • the powder can be dried via oven drying, tray drying, or fluid bed drying, etc.
  • the drying condition is kept at 60-120 ° Cfor 1 to 12 hours.
  • the amorphous meloxicam ⁇ CD inclusion complex is further processed with other pharmaceutical excipients to manufacture a conventional oral dosage formulation, in order to achieve the intended purpose of fast absorption and fast onset of meloxicam once administered via oral route.
  • the meloxicam ⁇ CD inclusion complex prepared by the present invention displays characteristic amorphous properties.
  • the inclusion complex of meloxicam ⁇ CD prepared by the present invention is substantially free of crystals.
  • substantially free is less than 5%, such as less than 1%, such as less than 0.1%, such as completely free (e.g., 0%). This can be verified through instrumentation analysis such as DSC and XRPD.
  • DSC the drug meloxicam has no showing of any endothermic peaks around 250 ° C .
  • XRPD there is no showing of any characteristic peaks of crystalline meloxicam including major peaks at 13.1, 14.9, 18.6, 25.9 ° at 2 ⁇ scale.
  • the amorphous property is a very important feature for the inclusion complex of meloxicam ⁇ CD. If there exists a small amount of crystal of the drug in the product, as time goes by, these remaining crystals may act as the crystal seed to induce the formation of more crystals. As a result, the stability (or the shelf-life) of the formulation product may be seriously compromised. An acceptable shelf-life is a must for the drug product to be registered with governmental regulatory body such as FDA in USA.
  • DSC Differential scanning calorimetrv
  • DSC measures the heat transition of a given compound. As such, it is frequently used in pharmaceutical research to assess the crystalline/amorphous state of the drug substance.
  • the principle behind DSC is that two cups, placed in an oven, one containing the sample and the other nothing (empty or an inert material), are heated and kept at the same temperature. Once an endothermic or an exothermic phase transition occurs within the sample, the heat flow provided to keep the two cups at the same temperature needs to be respectively increased or decreased giving thus rise to an endothem or an exotherm.
  • the X-ray powder diffraction is another powerful and widely used tool for substance crystalline/amorphous state evaluation.
  • the XRPD pattern is part of the electromagnetic spectrum lying between ultraviolet and gamma rays (wavelength expressed in Angstrom units - 0.01 to lOOA).
  • gamma rays wavelength expressed in Angstrom units - 0.01 to lOOA.
  • the XRPD pattern also called the diffractogram, consists of a series of peaks collected at different scattering angles (graph of scattering intensity vs. 2 ⁇ ). If the sample is amorphous (no long range order), then X-rays are not coherently scattered and no peaks can be observed.
  • Example 1 Preparation of amorphous meloxicam-BCD inclusion complex (or intermediate)
  • Table 1 lists a series of experiments designed to optimize the spray drying process.
  • Experiments 1-3 were designed to evaluate the molar ratio of meloxicam and ⁇ CD in the spray solution.
  • the molar ratio (meloxicam : ⁇ CD) ranges from 1: 1.5, 1:2 to 1:2.5.
  • the key measurement is the physical property evaluation by using DSC and XRPD, related substance (by HPLC), and processability.
  • Experiments 4-8 were conducted to evaluate the effect of inlet temperature, the single most important parameter in the spray drying process. Inlet temperature testing ranges from 110°C to 160°C. Table 1 presents all the major evaluation data.
  • dissolution of the intermediate all show significantly improvement at a number of experimental conditions (e.g.: pH 6.1 and pH 7.4), and are not substantially different from each other. Hence, the data are not listed here, though a representative set of dissolution data for the intermediate is listed in the Table 3 along with dissolution data of other testing samples.
  • intermediate i.e., meloxicam ⁇ CD inclusion complex with a molar ratio of 1:2.
  • intermediate i.e., meloxicam ⁇ CD inclusion complex with a molar ratio of 1:2.
  • the intermediate was subject to oven drying at 75°C for 1 hour. It was then analyzed for physical and chemical properties including: DSC, XRPD, Raman spectroscopy, SEM (scanning electron microscopy), assay, related substance, dissolution, water content, etc.
  • the SEM pictures in Figure 4 also shows that the morphology of meloxicam and ⁇ -CD are large crystalline particles with diameters in the range of 10-20 ⁇ , while the intermediate are showing smooth porous ball-like particles with diameters in the range of l-5um. All of the above indicate that meloxicam, once complexed with ⁇ CD to the full extent, shows the properties of a total amorphous, which is very different from its original state as a crystalline material. The solubility testing results are also listed (see Table 2).
  • a series of capsule form ulations were manufactured by blending, granulating and encapsulating the meloxicam ⁇ CD inclusion complex (or intermediate) with other common pha rmaceutica l excipients including lactose monohydrate, crospovidone, magnesium stearate, etc.
  • the formulation product demonstrates a significa ntly improved dissolution rate of meloxicam as compared to that of meloxicam commercial product Mobic in a variety of pH buffered solutions including pH 1, 6.1, water, and 7.4. I n fact, the dissolution rate was even faster in the capsule formulations due to the use of disintegrant (crospovidone) a nd subsequent dry granulation process.
  • the fina l composition for the formulation product (w/w) is listed as follows (see Table 3).
  • the dissolution data is listed in Ta ble 4.
  • the test condition is set at pH 6.1, as it is more sensitive in differentiating meloxicam in varying forms: meloxicam in the intermediate, meloxicam in physical mixture, meloxicam in the intermediate but formulated in capsule product (composition shown in Table 3), meloxicam in commercial product Mobic.
  • Dissolution test condition medium: pH 6.1 (0.05 M phosphate buffer), basket method, 100 rpm, 900ml,
  • Example 3 Comparative pharmacokinetic study of meloxicam new formulations and Mobic following single oral administrations to non-naive beagle dogs
  • Example 2 One of the formulation batches prepared from the Example 2 was used for comparative pharmacokinetic evaluation as compa red to the meloxicam commercial product Mobic (Lot No. 184637; manufactured by Boehringer Ingelheim Pharmaceuticals). The procedure is as follows: amorphous meloxicam ⁇ CD inclusion complex (intermediate) was blended with pha rmaceutica l excipients, and was then granulated and encapsulated into Size 3 opaque capsules with strength as 7.5mg. The formulation composition and the fill weight are shown in Table 3. This formulation was referred to as "Meloxicam New Formulation (capsule)" in the following pharmacokinetics study, and was administered to non-na ' ive beagle dogs, male and female, via oral dosing.
  • meloxicam commercial product Mobic Tablet, and Meloxicam New Formulation (suspension).
  • the "suspension” was essentially the Meloxicam New Formulation (capsule), except that the capsule shell was opened, and the powder content was poured into a vial containing 5 ml water. The suspension as such was made in situ and was dosed into animals right after preparation.
  • Test system and study design is listed in Table 5: two male and two female beagle dogs with body weight over the range of 8.62-9.40 kg were assigned to this study. The nominal dosage for all of the dogs was 7.5mg/ dog. The dosing is arranged in the sequence as shown in Table 5.
  • Phase 1 Meloxicam New Formulation (capsule); Phase 2, Mobic (tablet); Phase 3: Meloxicam New Formulation (suspension). There was one week washout period between each phase. The test article was monitored in plasma for up to 48 hrs. Blood samples were harvested according to each sampling time. Table 6 lists all major pharmacokinetic data analysis by HPLC.
  • Plasma concentration data of Meloxicam were subjected to a non-compartmental pharmacokinetic analysis using WinNonlinTM Version 6.2.1 (Pharsight, Mountain View, CA). Peak plasma concentrations (C max ) and the corresponding peak times (T max ) were taken directly from the plasma concentration vs. time profiles. Terminal half-life (t 1/2 ), mean residence time (MRT) from time zero to infinity (MRT 0 .
  • Figure 5 shows that the pharmacokinetics of the new formulations (in capsule or in suspension) demonstrates a rapid absorption with a time to peak plasma concentration (Tmax) 1.5-2 hrs (2 hrs for capsule, and 1.5 hrs for suspension), as compared to Mobic (4 hrs). It is also noted that the C max was slightly increased for new formulations, as opposed to the Mobic, while the AUC remained largely unchanged between new formulations and Mobic. The relative oral bioavailability of new formulations (capsule, suspension) to Mobic was 112% and 116%, respectively. The study indicates that the meloxicam in new Formulations (capsule or suspension) has an enhanced absorption as compared to meloxicam from the commercial product Mobic.
  • Tmax time to peak plasma concentration

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Abstract

La présente invention concerne un procédé de séchage par atomisation pour la préparation d'un complexe d'inclusion de méloxicam-β-cyclodextrine, où le médicament méloxicam reste amorphe stable. Le procédé peut être appliqué à une fabrication pilote et commerciale qui est avantageuse en comparaison à d'autres procédés technologiques. Le complexe d'inclusion obtenu a des propriétés physicochimiques et biopharmaceutiques souhaitées et peut être façonné en un produit qui présente une absorption orale supérieure au produit commercial actuel de méloxicam.
PCT/CN2013/073547 2013-04-01 2013-04-01 Préparation d'un complexe d'inclusion de méloxicam-β-cyclodextrine amorphe par l'intermédiaire d'un procédé de séchage par atomisation WO2014161131A1 (fr)

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US11944683B2 (en) 2017-06-29 2024-04-02 Axsome Therapeutics, Inc. Pharmaceutical compositions comprising meloxicam
US11135295B2 (en) 2017-06-29 2021-10-05 Axsome Therapeutics, Inc. Pharmaceutical compositions comprising meloxicam
US10688185B2 (en) 2017-06-29 2020-06-23 Axsome Therapeutics, Inc. Pharmaceutical compositions comprising meloxicam
US10758617B2 (en) 2017-06-29 2020-09-01 Axsome Therapeutics, Inc. Pharmaceutical compositions comprising meloxicam
US11759522B2 (en) 2017-06-29 2023-09-19 Axsome Therapeutics, Inc. Pharmaceutical compositions comprising meloxicam
US11020483B2 (en) 2017-06-29 2021-06-01 Axsome Therapeutics, Inc. Pharmaceutical compositions comprising meloxicam
US10512693B2 (en) 2017-06-29 2019-12-24 Axsome Therapeutics, Inc. Pharmaceutical compositions comprising meloxicam
US10918722B2 (en) 2017-06-29 2021-02-16 Axsome Therapeutics, Inc. Pharmaceutical compositions comprising meloxicam
US11826370B2 (en) 2017-06-29 2023-11-28 Axsome Therapeutics, Inc. Pharmaceutical compositions comprising meloxicam
US11865117B2 (en) 2017-06-29 2024-01-09 Axsome Therapeutics, Inc Pharmaceutical compositions comprising meloxicam
WO2021207253A1 (fr) * 2020-04-06 2021-10-14 Axsome Therapeutics, Inc. Compositions pharmaceutiques comprenant du méloxicam
US11998552B2 (en) 2020-12-31 2024-06-04 Axsome Therapeutics, Inc. Pharmaceutical compositions comprising meloxicam
US12005118B2 (en) 2022-05-19 2024-06-11 Axsome Therapeutics, Inc. Pharmaceutical compositions comprising meloxicam

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