WO2014161131A1

WO2014161131A1 - PREPARING AMORPHOUS MELOXICAM-β-CYCLODEXTRIN INCLUSION COMPLEX VIA SPRAY DRYING PROCESS

Info

Publication number: WO2014161131A1
Application number: PCT/CN2013/073547
Authority: WO
Inventors: Luwei ZHAO; Hong Sun; Yan Hu; Yansheng CHEN
Original assignee: Arissa Pharma
Priority date: 2013-04-01
Filing date: 2013-04-01
Publication date: 2014-10-09

Abstract

The present invention relates to a spray drying process for preparing meloxicam‐β‐ 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.

Description

PREPARING AMORPHOUS MELOXICAM^-CYCLODEXTRIN

INCLUSION COMPLEX VIA SPRAY DRYING PROCESS

The present invention relates to a spray drying process for preparing meloxicam-β- 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.

Background of the Invention

US 6,284,269 Bl (Struengmann et al.) 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. Methods of making nanoparticulate active agent compositions are described in US Pat. No. 5,518,187 and No. 5,862,999, both for "Method of Grinding Pharmaceutical Substances"; US Pat. No. 5,718,388 for "Continuous Method of Grinding Pharmaceutical Substances", and US Pat. No 5,510,118 for "Process of Preparing Therapeutic Compositions Containing Nanoparticles". The composition prepared surprisingly exhibited superior T_max profiles as compared to meloxicam's commercial product Mobic made by Boehringer Ingelheim Pharmaceuticals, Inc. Similarly, 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. 455-466, 58, 2008) (referred to as "El-Maradny" in the following contents) 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 βCD. l-^CD has much higher aqueous solubility, but is also much more expensive than βCD (lOOx more). Also, 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. As a comparison, in the present invention, the substance concentration is up to 20% (w/v), and the method can be scaled up for pilot or commercial manufacturing. In addition, though the method produced an inclusion complex, it did not mention or verify whether the complexation has been taken to completion. The authors used IR (infrared spectroscopy) and DSC (differential scanning calorimeter) to characterize the inclusion complex— neither of which is definitive to show if there still exists small percentage of crystalline meloxicam (e.g.: <5%). It is of note that residual meloxicam crystal can be a source for product instability and hence a potential threat to product shelf-life. In viewing the prior art, it is found that 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. However, it is also found that none of the meloxicam^CD or meloxicam with βCD derivatives such as l-^CD discusses or discloses the process for preparing amorphous meloxicam^-cyclodextrin inclusion complex. In fact it is quite unexpected to find out that the drug meloxicam in the inclusion complex disclosed in this invention demonstrates a total and stable amorphous. It is also of note that none of the prior art discloses or discusses the spray drying process as specified in this invention that can be applicable to both pilot and commercial manufacturing.

Summary of the Invention

For spray drying process, a few technical parameters are critical:

a) the molar ratio of meloxicam vs. βCD - key to ensure the formation of the inclusion complex to be complete, and the drug remains as amorphous

b) meloxicam concentration in the spray solution - key to raise the manufacturing efficiency

c) 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)

For meloxicam and βCD to be fully complexed and the process to be efficient, one must have sufficient amount of meloxicam and sufficient amount of βCD dissolved in the spray solution. It was found that raising solution pH increases the solubility of meloxicam, while raising the solution temperature increases the solubility of βCD. For βCD, its aqueous solubility at room temperature is low, approx. 2% (w/v). As the solution temperature increases, so does the βCD solubility. At 65-80°C, βCD solubility can be raised to approx. 10-20% (w/v). In addition, the presence of meloxicam in the solution promotes the β-CD solubilization in the solution. As for complexation, there exists equilibrium among the drug, the βCD, and the inclusion complex. Sufficient amount of the βCD pushes the equilibrium to the right to form the inclusion complex. However, there also exists a technical hurdle: more βCD raises the difficulty in spray drying processability. It is generally accepted that the substance concentration in the spray solution should be below 20% (w/v), or no more than 25% (w/v). Preliminary studies found that an experimental condition can be reached balancing all factors: solution pH 8.5-11 adjusted by ammonium hydroxide, and the spray solution temperature: 65-85°C. With such condition in the present invention, an amorphous meloxicam- βCD 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. For this purpose, the intermediate needs to have the complexation to the full extent. In other words, the drug meloxicam must be complexed with the βCD at molecular level, and that meloxicam must remain in amorphous state and not in crystalline state.

In one aspect, 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 βCD 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").

In one embodiment of the present invention, the molar ratio of meloxicam and βCD is maintained at 1:1.5 to 1:3.

In one embodiment of the present invention, the spray solution is heated at a temperature 65-85 ^°C .

In one embodiment of the present invention, the pH of the spray solution is kept at pH 8.5-11 with ammonium hydroxide concentration at 0.5% to 3% (w/v). In one embodiment of the present invention, the substance concentration of combined weight of meloxicam and βCD is kept at 5% to 25% (w/v).

In one embodiment of the present invention, the inlet temperature of the spray-dryer is maintained between 110-160 ^°C .

In one embodiment of the present invention, 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. In another aspect, the present invention relates to the inclusion complex of meloxicam- βCD obtained through the process described above, wherein the complexation between meloxicam and βCD is taken to the full extent, and where meloxicam remains amorphous characterized by X-ray powder diffraction (XRPD) and differential scanning calorimetry (DSC) instrumentation. In another aspect, the present invention relates to a formulation comprising of the intermediate prepared according to the present process together with pharmaceutical acceptable excipients.

Other features and advantages of the present invention will be apparent from the detailed description of the invention and from the claims.

Brief Description of the Figures

Figure 1 shows results of the differential scanning calorimetry (DSC). From top to bottom: DSC profiles for meloxicam, βCD, PM (meloxicam- βCD physical mixture, molar ratio: 1:2), and intermediate (meloxicam- βCD 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.

Figure 2 shows results of the X-ray powder diffraction (XRPD). From top to bottom: XRPD diffractogram for meloxicam, βCD, PM (meloxicam- βCD 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, 2Θ 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. 2Θ). Figure 3 shows results of the Raman spectroscopy. Spectra from top to bottom: meloxicam, βCD, PM (meloxicam- βCD physical mixture, molar ratio: 1:2), and intermediate (meloxicam- βCD 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, βCD, PM (meloxicam- βCD physical mixture, molar ratio: 1:2), and intermediate (meloxicam^CD inclusion complex, molar ratio 1:2). Scanning electron microscopy (SEM): FEI Ouanta 250 SEM (Manufactured by FEI). Accelerating voltage: 200v-30 kV; magnification: 3000X.

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. Detailed Description of the Invention

It is believed that one skilled in the art can, based upon the description herein, utilize the present invention to its fullest extent. The following specific embodiments can be construed as merely illustrative, and not limitative of the remainder of the disclosure in any way whatsoever.

Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which the invention belongs. Also, all publications, patent applications, patents, and other references mentioned herein are incorporated by reference. As used herein, all percentages are by weight unless otherwise specified.

Meloxicam

Meloxicam is a non-steroidal anti-inflammatory drug (NSAID) that exhibits antiinflammatory, analgesic, and antipyretic activities. The prescription products (Mobic and many generics) 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. The 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, on the other hand, is not expressed in healthy tissue. Rather, it is present in certain inflammatory disease states such as rheumatoid arthritis or osteoarthritis. It is worth noting that 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.

The 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 Ci₄Hi₃N₃0₄S₂ , 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 μg/ml (various sources).

Meloxicam's good permeability and poor water solubility places the drug in Biopharmaceutical Classification System (BCS) Class II, which is responsible for some of its dissatisfactory performance in vivo, in particular the slow onset in vivo: the T_max is reported 4-5 hours, and is extended to 5-6 hours in fast state. The drug is subject to significant food effect.

Due to the delayed onset of action, 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.

The amorphous meloxicam- βCD 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. In addition, 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

Meloxicam-Cvclodextrin Inclusion Complex

There are a variety of methods available that can be used to make the drug soluble, with faster dissolution, and potentially, make the drug more readily bioavailable once administered via oral route. These include: addition of cosolvents, addition of surfactants, addition of cyclodextrins, salt formation, solid dispersion, formation of co-crystals, nanoparticles, etc. While all other approaches have issues one way or another, the use of cyclodextrins provides an attractive option: meloxicam, due to its structure, can be complexed with cyclodextrins, especially with β-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.

Structurally, cyclodextrins (CD) are cyclic oligosaccharides which are obtained by enzymatic degradation of starch. There are three major categories: α-, β- and γ-CD consist of 6-, 7-, and 8-glucopyranose units, respectively. Among them, βCD or its derivatives is the most useful for complexing the drug meloxicam. It is of note that naturally occurring CDs including βCD have limited aqueous solubility, while many of its modified derivatives have shown significantly enhanced aqueous solubility. It is also noted that βCD, 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 βCD 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. As 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.

It is found that the drug meloxicam, once the inclusion complex is formed with βCD to the full extent, demonstrates a significantly improved dissolution rate as compared to meloxicam drug substance.

The fast dissolution results achieved with the use of βCD in our study rely on the fact that, through complexation, the drug meloxicam acquires a stable amorphous state, and as such, it displays a higher apparent solubility and faster dissolution than its crystalline counterpart. As the drug meloxicam is a Biopharmaceutical Classification System (BCS) Class II compound (low solubility, high permeability), increasing dissolution is the key for meloxicam to be absorbed through Gl (gastrointestinal) track membrane, which makes it critical for the drug to be readily bioavailable once administered via oral route.

Moreover, it has also been demonstrated by DSC and XRPD techniques that 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.

Formulations Comprising Amorphous Meloxicam-BCD Inclusion Complex

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. The ratio for the intermediate to pha rmaceutical excipients has a broad range from 10%: 90% to 90%: 10%.

A series of formulation products (capsules) 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. Along with the testing is meloxicam commercial product Mobic. The dose is 0.75 mg/kg. It was found that the pharmacokinetics of the New Formulations demonstrated a rapid absorption with a time to peak plasma concentration (T_max) 1.5-2 hrs - 2 hrs for ca psule, and 1.5 hrs for in situ suspension (prepared by ta king the content out of the capsule, and making an in situ suspension right before dosing), 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 bioavaila bility of New Formulations (capsule, suspension) to Mobic was 112% and 116%, respectively. This demonstrates that the meloxicam in the New Formulations (capsule or suspension) has a faster absorption as compared to meloxicam from the commercia l product Mobic.

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

The term "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 βCD 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.

In one embodiment of the invention, the molar ratio of meloxicam and βCD 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 βCD is maintained at 1:1.5 to 1:3. In preferred embodiment of the invention, the molar ratio of meloxicam and βCD is maintained at 1:2 to 1:2.5. In most preferred embodiment of the invention, the molar ratio of meloxicam and βCD is maintained at 1:2.

In one embodiment of the invention, 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. A sensitive HPLC (high performance liquid chromatography) method was developed to monitor the chemical degradation generated during the process and upon storage in the accelerated stability conditions, i.e., 40°C 75% RH (relative humidity). In one embodiment of the invention, the substance concentration (combined weight of meloxicam and βCD) 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).

Maintaining a high substance concentration in the spray solution is very important for potential large scale manufacturing. In most cases reported, the substance concentration in the spray solution is about 1-3% (w/v). On the contrary, in the spray drying process of the present invention, the substance concentration is up to 15-25% (w/v) in the spray solution. As is known to all, the higher the substance concentration the spray solution is, the higher the yield will be. This is especially beneficial for product pilot and industrial scale manufacture.

Usually, 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. However, if 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. On the other hand, if 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.

In one embodiment of the 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 .

In one embodiment of the invention, the resultant powder particles can be further dried. For example, the powder can be dried via oven drying, tray drying, or fluid bed drying, etc. In one embodiment of the invention, the drying condition is kept at 60-120 ^°Cfor 1 to 12 hours.

In one embodiment of the invention, 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. As used herein, what is meant by "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. On DSC, the drug meloxicam has no showing of any endothermic peaks around 250^°C . On 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 2Θ 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.

However, all of the previous mentioned patent documents did not fully appreciate the importance of maintaining an amorphous state of the drug substance in the inclusion complex as well as in the final product. The present inventor, however, deems that DSC is not sufficient to prove the amorphous property, and rather, uses both DSC and XRPD to verify amorphous state of the power particles, as XRPD is a more sensitive analytical means when evaluating the amorphous status. As shown in Figure 2, the powder particles prepared by the present invention is in total amorphous state, and not in crystalline state.

Differential scanning calorimetrv (DSC)

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.

X-rav powder diffraction (XRPD)

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). When X-rays are incident on a crystalline sample, they are scattered in all directions (scattering occurs due to the radiation wavelength being of the same order of magnitude as the interatomic distances within the crystal structure) and in some of the these directions, the scattered beams are completely in phase and reinforce one another to form the diffracted beams. The XRPD pattern, also called the diffractogram, consists of a series of peaks collected at different scattering angles (graph of scattering intensity vs. 2Θ). If the sample is amorphous (no long range order), then X-rays are not coherently scattered and no peaks can be observed.

Examples Specific embodiments of the present invention are illustrated by way of the following examples. This invention is not confined to the specific limitations set forth in these examples. 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 βCD in the spray solution. The molar ratio (meloxicam : βCD) 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. After the molar ratio was finalized as 1: 2 (meloxicam : βCD), 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. It is of note that the 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.

Table 1 Preparation of various intermediates through varying intermediate composition (molar ratio) and experimental conditions (inlet temperature of the spray dryer)

8 160 None None 0.64% Good: no powder stickiness

*: detailed preparation see below text description

For illustration purpose, the following lists a detailed description of the preparation procedure for the intermediate (Exp. 6, from Table 1), and its extensive evaluation using various instrumentation techniques:

1. Heated a solution of 500 ml water to 75°C and maintained the temperature all through; then added 68.8 g βCD to the solution (approx. 13.8% w/v), stirred till it was dissolved. Added 10ml ammonium hydroxide (cone. 28%); then added 10.64 g meloxicam (approx. 2.1% w/v), stirred till all drug particles were dissolved. This made a solid concentration approx. 16%; the molar ratio of meloxicam : βCD was 1: 2.

2. Fed the above spray solution into the drying chamber of a spray-dryer (equipment model: SprayDryer YC-015, Shanghai Yacheng Company) through a pump and an atomizing device to form droplets. The feed flow rate was at 5ml/min; the drying gas (compressed air) was introduced into the drying chamber to dry the droplets to form powder particles with the gas flow at 2.5M³/min; the inlet temperature was set at 130°C; the outlet temperature was not set, but was usually around 65- 75°C; the atomizing device was pressure regulated; the separation of powder particles was carried out in a cyclone by centrifugal action. The yield was approx. 70%.

3. The material obtained above is referred to as "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.

4. Evaluation using different instrumentation on physical property of meloxicam^CD inclusion complex (intermediate) as well as meloxicam, βCD, and physical mixture (PM) reveals that the drug meloxicam is indeed entirely complexed and is in a total amorphous state: from DSC, we observed that the meloxicam's characteristic endothermic peak (254°C) was absent (see Figure 1). From XRPD, we observed that all diffraction peaks of meloxicam crystalline characteristics were absent including peaks at 13.1, 14.9, 18.6, 25.9° at 2Θ scale (see Figure 2). The Raman spectroscopy shows that the peaks are also different between the meloxicam and the intermediate (see Figure 3). The SEM pictures in Figure 4 also shows that the morphology of meloxicam and β-CD are large crystalline particles with diameters in the range of 10-20μιη, 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 βCD 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).

Table 2 Solubility data for meloxicam and the intermediate in various vehicles*

*: Solubility testing: excess amount of meloxicam, or intermediate was added to the vials containing approx. 10 ml vehicle. The vials were placed on the rotary shaker at room temperature for 48 hours. Afterwards, samples were filtered through polycarbonate membrane (0.45um) and suitably diluted and analyzed via HPLC under 270 nm (Shimazu LC-20AT, Japan) Example 2 Prepa ration of the capsule formulation comprising the intermediate

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. M uch like the meloxicam^CD inclusion complex, 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). Product analysis: assay: 98.8%, related substances: 0.28%; water content: 8.12%. 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.

Table 3 Composition of capsule formulation containing intermediate

Crosspovidone 4.09 4.50

Magnesium stearate 1.00 1.10

Total 100.00 110.00

Table 4 Dissolution* testing on meloxicam in various forms - all testing samples containing 7.5mg meloxicam or equivalent

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

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. Along with the testing is 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.

Table 5 Pharmacokinetic test system and study design

Table 6 Pharmacokinetic data analysis*

* : Plasma concentration data of Meloxicam were subjected to a non-compartmental pharmacokinetic analysis using WinNonlin™ 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 (MRT₀._inf), mean residence time (MRT) from time zero to the last quantifiable concentration (MRT₀.|_ast), the area under the plasma concentration-time curve (AUC) from time zero to the last quantifiable concentration (AUC₀.|_ast) and AUC from time zero extrapolated to infinity (AUC₀._inf) were calculated using the model of linear log trapezoidal.

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.

It is understood that while the invention has been described in conjunction with the detailed description thereof, that the foregoing description is intended to illustrate and not limit the scope of the invention, which is defined by the scope of the appended Claims. Other aspects, advantages, and modifications are within the Claims.

Claims

Claims 1. A spray drying process for the preparation of amorphous meloxicam^CD inclusion complex, comprising the following steps:

a. dissolve meloxicam and βCD in a heated aqueous solution in the presence of ammonium hydroxide to form a spray solution;

b. feed the spray solution into the drying chamber through a pump and an atomizing device to form droplets;

c. introduce a stream of drying gas into the drying chamber to dry the droplets in order to form powder particles;

d. further dry the powder particles to rid of the moisture; the resultant particles are the amorphous meloxicam^CD inclusion complex.

2. A process according to Claim 1 wherein the molar ratio of meloxicam and βCD is maintained at 1:1.5 to 1:3.

3. A process according to claim 1 wherein the spray solution in step a) is heated at temperature 65-85 ^°C .

4. A process according to Claim 1 wherein the ammonium hydroxide concentration in Step a) is at 0.5% to 3% (w/v).

5. A process according to Claim 1 wherein the substance concentration of combined weight of meloxicam and βCD in Step a) is kept at 5% to 25% (w/v).

6. A process according to Claim 1 wherein the substance concentration of combined weight of meloxicam and βCD in Step a) is kept at 13% to 20% (w/v).

7. A process according to Claim 1, wherein the inlet temperature of the spray chamber in step c) is maintained between 110-160 ^°C .

8. A process according to Claim 1, wherein the inlet temperature of the spray chamber in step c) is maintained between 110-130 ^°C .

9. The meloxicam^CD inclusion complex obtained through the process of Claim 1 shows an amorphous state where it displays no characteristic peaks of crystalline meloxicam at 13.1, 14.9, 18.6, 25.9° at 2Θ scales on X-ray powder diffraction spectrum, and no characteristic endothermic peak of crystalline meloxicam at 254°C via differential scanning calorimetry.

10. Formulations comprising of meloxicam^CD inclusion complex prepared according to any one of Claims 1-8 together with pharmaceutically acceptable excipients.