DESC:Field of the Invention
[001] The present invention relates to delayed release formulations of poorly water soluble azole antifungal drugs and methods of preparing them.
Background of the Invention
[002] The solubility of the hydrophobic active drug substances for efficient oral delivery still remains an area for development. At the minimum, an efficient drug delivery system should function to deliver a therapeutically effective dosage of any given compound to achieve the desired therapeutic concentration. Maximum strength formulations provide higher doses of active drug substances and therapeutic efficacy while minimizing the number of doses required. These formulations can increase patient satisfaction and compliance; however, they can be challenging to formulate for poorly soluble active drug substances often because of precipitation of the active, and often these drugs are formulated as tablets or as a suspension.
[003] Many chemical compounds, particular chemical compounds that are useful in pharmacologic applications, are poorly soluble in water. Such drugs may be classified according to USP-NF as being sparingly soluble, slightly soluble, very slightly soluble, or insoluble in water. Many of these compounds are also poorly soluble in oils. An example of such a chemical compound includes the azole family of drugs, which family includes metronidazole, fluconazole, ketoconazole, itraconazole, miconazole, dimetridazole, secnidazole, ornidazole, tinidazole, carnidazole, panidazole, saperconazole and posaconazole.
[004] In many situations, such drugs may be formulated as a suspension, in which case the lack of solubility of the drug in water and in pharmaceutical oils does not typically have a negative impact on bioavailability. However, in situations where an oral solid composition of the drug is desired, the lack of solubility of the drug, in water and oils provides a significant obstacle to obtaining desired concentrations of the drug.
[005] There have been many attempts to improve the bioavailability of poorly soluble drugs. Example of such attempts are illustrated in PCT/EP1993/002327 and PCT/EP98/01773, which relate to dosage forms of azole antifungals, such as itraconazole and saperconazole, which are said to be only very sparingly soluble in water, and both describe the incorporation of the drug with water-soluble polymers and the subsequent coating of the mixture on small beads. In PCT/EP93/02327 the beads are 600 to 700 micrometre in diameter, whereas in PCT/EP98/01773 the beads are 250 to 355 micrometre in diameter.
[006] US10/461503 discloses a solid dispersion composition comprising an azole antifungal drug itraconazole and at least one polymer having acidic functional group which provides an improved Cmax after administration in the fasted state.
[007] US14/551903 discloses a pharmaceutical composition comprising posaconazole dissolved or molecularly dispersed in HPMC derivative polymer through a hot melt extrusion technique. Hot melt extrusion (HME) is the process of applying heat and pressure to melt a polymer and force it though an orifice in a continuous process. HME is used to disperse the actives in a matrix at the molecular level, thus forming solid solutions. However, one has to consider the difficulties faced in HME i.e. the risk associated with chemical stability in thermolabile compounds and most importantly, lack of miscibility between the drug and polymer. An important requirement of HME is that it mandates the need for high flow properties of polymers and excipients, which limits the flexibility for choosing the polymers.
[008] CN 201310498619 also discloses a solid dispersion composition comprising posaconazole and hydroxypropylmethyl cellulose and an absorption enhancer such as cholic acid, tartric acid, citric acid, mannitol, or salicylic acid. According to the solid dispersion for posaconazole provided by the invention, the solubility of the posaconazole at the small intestine part can be obviously increased, and the absorption for the small intestine part is increased.
[009] Accordingly, there remains a need for new ways to produce delayed release compositions of poorly soluble drugs which utilizes different manufacturing steps and involves lesser complexity to provide acceptable dissolution profile. A process that can be industrially applicable and preferably does not use high temperatures that are needed for making solid dispersions. A process that provides a stable composition with lower bio-variability and higher bioavailability is needed, as compared to the compositions disclosed in the prior art.
Summary of the Invention
[0010] In the current invention, an attempt has been made to limit the dissolution of posaconazole in acidic environment, thereby eliminating its uncontrolled precipitation in the intestine. This is done by utilizing a specific sequence of manufacturing steps with a number of enteric polymers, without using complex manufacturing process. A new solid oral tablet composition of posaconazole has been developed that is designed to release the entire dose of solubilized posaconazole in the small intestine, maximizing the systemic absorption irrespective of fasted or fed state.
[0011] In one aspect of the present invention, there is provided a delayed release pharmaceutical composition for oral administration comprising:
i. a core comprising a therapeutically effective amount of drug or pharmaceutically acceptable salts thereof, one or more enteric polymers, one or more pharmaceutically acceptable carrier and
ii. one or more enteric polymer surrounding the core,
wherein the pharmaceutical composition exhibits improved solubility of drug in intestinal pH.

[0012] In one aspect of the present invention, there is provided a delayed release pharmaceutical composition for oral administration comprising:
i. a core comprising a therapeutically effective amount of drug or pharmaceutically acceptable salts thereof, one or more enteric polymers, one or more pharmaceutically acceptable carrier and
ii. one or more enteric polymer surrounding the cores,
wherein the pharmaceutical composition exhibits improved solubility of drug in intestinal pH, and wherein the total drug: total polymer ratio is from about 1:1 weight by weight to about 1:5 weight by weight.

[0013] In another aspect of the invention, there is provided a method for preparing a delayed release pharmaceutical composition wherein the method involves:
i. preparing granules of pharmaceutically acceptable drugs and one or more enteric polymers with a suitable solvent system using top spray fluidization;
ii. coating the granules of step i with enteric polymers using bottom spray fluidization; and
iii. formulating the coated granules obtained in step ii into a suitable solid oral composition.
Brief description of the drawing
[0014] FIG. 01 is a graph that depicts the dissolution profile in 50 mM phosphate buffer at pH 6.8 with 0.37% polysorbate.
Detailed Description of the invention
[0015] The term "formulation" or "composition" as used herein refers to the drug in combination with pharmaceutically acceptable excipients. This includes orally administrable formulations as well as formulations administrable by other means.
[0016] The term “delayed release composition”, as referred to herein, is defined to mean an oral pharmaceutical composition which does not release a substantial portion of the active content for dissolution and absorption until it passes through the stomach and reaches the small intestine and encompasses “modified release” and “enteric” compositions.
[0017] The Food and Drug Administration (FDA) defines drug dosage forms that are enteric coated as “delayed-release” dosage forms. Delayed-release (enteric coated) dosage forms are differentiated from controlled-release or sustained-release dosage forms, which are intended to provide drug input over an extended period of time, thereby reducing administration frequency. FDA guidelines for enteric-coated dosage forms state: “In vitro dissolution tests for these products should document that they are stable under acidic conditions and that they release the drug only in a neutral medium (e.g., pH 6.8).”
[0018] The term “pharmaceutically acceptable” means that which is generally safe, non-toxic and neither biologically nor otherwise undesirable and includes that which is acceptable for veterinary use as well as human pharmaceutical use.
[0019] In some embodiments, reference to an "effective" amount or a "therapeutically effective amount" of therapeutic agents referenced herein, it is meant a nontoxic but sufficient amount of the same to provide the desired effect. The amount that is "effective" will vary from subject to subject, depending on the age and general condition of the individual, the particular active agent or agents, and the like. Thus, it is not always possible to specify an exact "effective amount" However, an appropriate "effective" amount in any individual case may be determined by one of ordinary skill in the art using routine experimentation.
[0020] The term "relative bioavailability" herein denotes AUC for a specific orally administered composition expressed as a percentage of AUC for an orally administered dosage form of the active ingredient at the same dosage rate.
[0021] The terms "AUC0-144" herein mean the area under the curve relating blood plasma concentration to time after administration from 0 to 144 hours, as determined using the linear trapezoidal rule, and are expressed in units of (ngh/ml).
[0022] The term "AUC0-inf" herein means the area under the curve relating blood plasma concentration to time from time 0 hours to infinity, and is expressed in units of (ng/ml).
[0023] The term "AUC0-tau" herein means area under the blood plasma concentration to time curve from time zero to time tau over a dosing interval at steady state, where tau is the length of the dosing interval, and is expressed in units of (ng/ml).
[0024] The term "Cmax" herein means the maximum observed blood plasma concentration or the maximum blood plasma concentration calculated or estimated from a concentration to time curve, and is expressed in units of ng/ml.
[0025] The term "Cmin" herein means the minimum observed blood plasma concentration or the maximum blood plasma concentration calculated or estimated from a concentration to time curve, and is expressed in units of ng/ml.
[0026] The term "Cavg" as used herein, means the plasma concentration of the drug within the dosing interval, and is calculated as AUC/dosing interval, and is expressed in units of ng/ml.
[0027] The term "Tmax" herein means the time after administration at which Cmax occurs, and is expressed in units of hours (h).
[0028] The term "steady state" means that the blood plasma concentration curve for a given drug does not substantially fluctuate after repeated doses to dose of the formulation.
[0029] The term "Degree of Fluctuation" is expressed as (Cmax-Cmin)/Cavg.
[0030] The term "bioequivalence" means the absence of a significant difference in the rate and extent to which the active ingredient or active moiety in pharmaceutical equivalents or pharmaceutical alternatives becomes available at the site of drug action when administered at the same molar dose under similar conditions in an appropriately designed study.
[0031] The term "intestinal pH" means a pH in the range of about 5.0 to about 7.7. In one embodiment, the intestinal pH means a pH in the range of about 5.5 to about 7.2. In another embodiment, the intestinal pH means a pH in the range of about 6.2 to about 7.0.
[0032] The delayed release composition includes tablets, coated tablets, layered tablets, granules, powders, microparticles, capsules which may be hard gelatin or soft gelatin, caplets, sachets, pellets, spheroids, mini-tablets, beads, microcapsules and pills.
[0033] One embodiment discloses the delayed release dosage form comprising an azole antifungal drug and an enteric polymer.
[0034] Another embodiment discloses a delayed release composition of an azole antifungal drug and enteric release polymer which provides therapeutically effective concentration of the drug for a period of at least 8 hours preferably 24 hours or more.
[0035] As used herein, the term "poorly soluble" when referring to a chemical compound in relation to its solubility in water or an oil means a chemical compound that is sparingly soluble, slightly soluble, very slightly soluble, or insoluble in water or an oil, as defined in U.S. Pharmacopeia and National Formulary (USP-NF). According to this definition, solubility is stated in terms of the parts of the solvent needed to dissolve one part of the solute. A compound that is sparingly soluble in a particular solvent, such as water, requires 30-100 parts of the solvent to dissolve one part of the compound. A compound that is slightly soluble requires 100-1000 parts of the solvent. A compound that is very slightly soluble requires 1000-10,000 parts of the solvent. A compound that is insoluble requires more than 10,000 parts of the solvent to dissolve one part of the solute.
[0036] The term “pharmaceutical dosage form” means a dosage form of a drug (e.g., tablet, powder, capsule, and the like) which is pharmaceutically acceptable, as defined above, and which possesses the necessary and desirable characteristics of a dosage form acceptable for administration to a patient (e.g., a tablet of acceptable hardness, dissolution, stability, and a size and weight practical for oral administration).
[0037] As used herein, "core" refers to a material that is at least partially enveloped or surrounded by another material. The core may be any suitable dosage form, for example, a tablet, a mini-tablet, a pellet, a granule, a microparticle, a hard or soft capsule, or a microcapsule. In preferred embodiments, the core is a granule, spheroids, mini-tablet, tablet or a capsule. The core comprises the drug(s), which may be contained within the body of the core, for example within the matrix of a tablet or pellet, or within the contents encapsulated within a capsule. Alternatively, the drug may be in a coating applied to the core, for example where the core is a bead of edible material such as sugar, e.g. where the core is in the form of a nonpareil bead or dragee.
[0038] The core may consist of the drug(s) alone, or more usually may consist of the drug(s) and at least one pharmacologically acceptable excipient. In this connection, the core is typically a tablet or pellet and consists of a mixture of the drug(s) with a filler or diluent material, e.g. lactose or cellulose material such as microcrystalline cellulose; a binder, e.g. polyvinylpyrrolidone ("PVP") or hydroxypropyl methylcellulose (HPMC); a disintegrant, e.g. croscarmellose sodium (e.g. Ac-Di-SolTM) and sodium starch glycolate (e.g. ExplotabTM); and/or a lubricant, e.g. magnesium stearate and talc. The core may also be a compressed granulate comprising at least some of these materials.
[0039] The core may be uncoated or, as indicated above, the core may itself comprise a coating such as an isolation layer on to which the inner layer is applied.
[0040] The formulation of the present invention may be manufactured by various methods known in the art such as by dry granulation, wet granulation, melt granulation, direct compression, double compression, extrusion spheronization, layering and the like. Compaction of the blend may be carried out using a slugging technique or roller compaction. The milling of the granules may be carried out according to conventional milling methods.
[0041] Fluid bed technology is commonly used for drying and granulating pharmaceutical dosage forms. In fluid bed drying, a wet, granulated mixture of drug and excipients, produced by a high shear mixing, is fluidized with warm air to afford a dried granulation for further processing. In fluid bed granulation, a binder solution is sprayed into a heated and fluidized bed of drug-excipients blend to afford a dried granulation.
[0042] In general applications of the technology, powders are suspended in an upwardly moving column of air while at the same time a controlled and defined amount of liquid is injected into the powder stream to produce a moistened state or agglomeration of the powder; mild heat is then used to dry the agglomerated powder. Following this agglomeration, the powder has altered physical characteristics from the starting powder. For example, non-processed powder often produces significant dust when used, and dissolves poorly or slowly in various solvents, while agglomerated powder is substantially dust-free and dissolves rapidly.
[0043] In a spray drying process, an aqueous solution of core material and hot solution of polymer is atomized into hot air, the water then evaporates, and the dry solid is separated in the form of pellets, for example by air suspension. A spray-drying process can produce hollow pellets when the liquid evaporates at a rate that is faster than the diffusion of the dissolved substances back into the droplet interior, or if due to capillary action the dissolved substance migrates out with the liquid to the droplet surface, leaving behind a void. Another example is a spray congealing process, where a slurry of drug material that is insoluble in a molten mass is spray congealed to obtain discrete particles of the insoluble materials coated with the congealed substance. A further example is a fluidized bed based granulation/pelletization process, where a drug is suspended in a stream of hot air to form a constantly agitated fluidized bed. An amount of binder or granulating liquid is then introduced in a finely dispersed form to cause pelletization.
[0044] The process of the present invention can be practiced with commercially available fluid-bed apparatuses that are equipped with an insert for top spray or bottom spray (using a Wurster-type column) or tangential spray (using a rotor disk). The design and operation of the sprayer can vary many characteristics of the final product, such as particle size and size distribution, bulk and particle densities, porosity, moisture content, flowability and friability.
[0045] In top spray coating, the spray liquid is sprayed from above onto the fluidized particles. This involves suspending particles in an air stream and spraying a liquid from the top of the system down onto the fluidized bed (top-down spray). Particles in the path of the spray get slightly wet and become sticky. The sticky particles collide with other particles in the bed of material and adhere to them to form granules. There are two different modes of fluid bed granulating i.e. wet stage and dry stage. In wet stage granulation, the particles require a significant amount of moisture or granulating solution before they become tacky enough to stick to each other. The granulating solution is applied at a rate higher than the evaporation rate until the particles build up enough moisture to granulate. In dry stage granulation, the particles only require a slight wetting to become tacky and stick to each other. The granulating solution is applied at a rate less than or equal to its evaporation rate. Thus, the particles remain “dry” through the entire process.
[0046] In bottom spray coating, a coating solution is sprayed from the bottom of the bed up onto the particles while they are suspended. The basic concept in bottom spray coating is to separate the particles in the fluid bed from one another in an air (gas) stream. This process takes place inside a specially modified fluid bed that is divided into two zones by a partition. The inner area is a high velocity zone that separates the particles and pneumatically transports them past the spray nozzle. After passing the nozzle, the particles enter the expanded area of the chamber, slow down and fall back into the outer section of the fluid bed product bowl. The coating dries while the particles are suspended to prevent agglomeration from occurring when they enter the tranquil part of the bed. The coated particles in the tranquil storage area remain fluidized just enough to allow them to continue moving towards the bottom of the bowl. When the particles reach the bottom, they are drawn back into the high velocity air stream and the cycle is repeated. This process continues until the desired level of coating has been achieved.
[0047] Another fluid-bed technique for wet granulation is the tangential-spray process, available since the early 1980s which depicts a tangential-spray processor. The nozzle is introduced at the side of a product container and is imbedded in the substrate during processing.
[0048] The present invention claims a combination of top spray as well as bottom spray for the coating of enteric polymers on the granules to provide an effective and acceptable dissolution profile. The enteric coating by either one of the solvent evaporation approaches i.e. top spray or spray drying or bottom spray coating does not provide the release profile as provided by the combination of the manufacturing steps.
[0049] In one general aspect of the present invention, the compositions of the present invention are especially useful for delivering poorly water soluble drugs having solubility of less than 10 mg/mL. The present poorly-soluble drug may have any dosage form of an oral preparation for internal application, an injection, a preparation for local administration, etc. Examples of such a poorly-soluble drug include an antitumor agent, an antibiotic, an antipyretic analgesic, an anti-hyperlipidemic agent, an antibacterial agent, a sedative hypnotic, a tranquilizer, an antiepileptic agent, an antidepressant, a gastrointestinal agent, an allergic disease therapeutic agent, an antihypertensive agent, a drug for arteriosclerosis, a blood circulation promoting agent, an antidiabetic agent, a hormonal agent, a fat-soluble vitamin, an antiandrogen agent, a cardiotonic drug, a drug for arrhythmia, a drug for diuresis, a local anesthetic, an anthelminthic, an antiarrhythmic agent, an anticoagulant, an antihistamic agent, an antimuscarinic agent, an antimycobacterial agent, an immunosuppressive agent, an antithyroid agent, an antiviral agent, an anxiolytic agent, an astringent, a .beta.-adrenoreceptor blocker, an agent exerting inotropic action on cardiac muscle, a contrast medium, corticosteroid, a cough suppressing agent, a diagnostic agent, a diagnostic imaging agent, a diuretic, a dopamine agonist, a hemostatic agent, a lipid adjuster, a muscle relaxer, a parasympathetic drug, thyrocalcitonin and biphosphonate, prostaglandin, a radiopharmaceutical agent, sex hormone, a stimulant, an appetite suppressing agent, a sympathetic agent, a thyroid drug, a vasodilator, an antifungal agent and xanthene.
[0050] Specific examples of anti-fungal include clotrimazole, econazole nitrate, miconazole, terbinafine, fluconazole, ketoconazole, amphotericin, itraconazole, miconazole, saperconazole, and posaconazole.
[0051] In another general aspect of the invention, the drug is selected from an anti-fungal drug. In yet another general aspect, the anti-fungal drug is selected from itraconazole, ketoconazole, fluconazole, miconazole, saperconazole, and posaconazole.
[0052] The invention provides methods of prophylactically or therapeutically treating fungal infections by administering a quantity of a composition of the invention or dosage form comprising a composition of the invention, which provides about 50 mg to about 650 mg of posaconazole per day, either in a single or divided dose. In some embodiments, it is preferred to administer daily, in either a single or divided dose an amount of a composition of the invention or dosage form comprising a composition of the invention which provides from about 100 mg to about 600 mg of posaconazole, preferably at least about 300 mg of posaconazole. In some embodiments, wherein it is preferred to provide treatment by administering from about 100 mg of posaconazole to about 300 mg of posaconazole per day, it is preferred to supply a medicament comprising an amount of a composition of the invention providing from about 80% to about 125% of the amount of posaconazole desired for providing treatment.
[0053] Posaconazole is an extended spectrum triazole antifungal agent. It is soluble at low pH. For example, in the environment of the stomach (approximately pH 1) posaconazole free base has a solubility of approximately 0.8 mg/mL. However, when posaconazole dissolved in the stomach fluids reaches the environment of the intestine (typically less acidic than about pH 6.4) a substantial amount of the dissolved posaconazole precipitates, hindering absorption in the intestine. It has been determined that in environments where the pH is about 6.4 or more, the solubility of posaconazole free base is less than about 1 mg/mL. The provision of a solid composition comprising posaconazole suitable for preparing a solid dosage form for oral administration has heretofore been hampered by the poor solubility and weak basicity of the posaconazole free-base compound.
[0054] The method according to the invention consists in using specific steps in the process for preparing the delayed release composition, in order to arrive at an improved dissolution profile in the alkaline media (simulated intestinal fluid) with limited or no dissolution in the acidic media.
[0055] The percentage of the antifungal agent may vary between 5 and 70% of the total tablet weight. More preferably, it may range between 7 and 50%. In another embodiment, it is preferred that the percentage of antifungal agent may vary between 10 and 30%.
[0056] The modified release formulation may further contain pharmaceutically acceptable excipients such as binders; diluents; lubricants; disintegrating agents; glidants; stabilizers; and surface active agents.
[0057] The binders may be selected from potato starch; modified starch; gelatin; wheat starch; corn starch; microcrystalline cellulose; celluloses such as hydroxypropyl cellulose, hydroxyethyl cellulose, hydroxypropylmethyl cellulose (Hypromellose), ethyl cellulose and sodium carboxy methyl cellulose; natural gums such as acacia, alginic acid and guar gum; liquid glucose; dextrin; povidone; syrup; polyethylene oxide; polyvinyl pyrrolidone; poly vinyl alcohol; poly-N-vinyl amide; polyethylene glycol; gelatin; poly propylene glycol; tragacanth; hydrogenated vegetable oil; castor oil; paraffin; higher aliphatic alcohols; higher alphatic acids; long chain fatty acids; fatty acid esters; and wax-like materials such as fatty alcohols, fatty acid esters, fatty acid glycerides, hydrogenated fats, hydrocarbons, normal waxes, stearic acid and stearyl alcohol. The amount of binder present can vary from about 0.1% to about 25% by weight of the tablet dry weight, preferably about 0.5% to about 10%.
[0058] The diluent may be selected from pharmaceutically acceptable inert fillers such as microcrystalline cellulose; lactose; dibasic or tribasic calcium phosphate; saccharides confectioner's sugar; compressible sugar; dextrates; dextrin; dextrose; fructose; lactitol; mannitol; sucrose; starch xylitol; sorbitol; talc; calcium carbonate; or calcium sulphate. The diluent is preferably used in an amount of about 10 to 90% by weight.
[0059] The disintegrating agent may be selected from cross-linked polymers such as crospovidone; starch or modified starch such as sodium starch glycolate; clays such as bentonite or veegum; celluloses or cellulose derivatives or crosslinked cellulose such as croscarmellose sodium; or resins such as polacrillin potassium.
[0060] The lubricant may be selected from Mg, Al or Ca or Zn stearate; polyethylene glycol; glyceryl behenate; glyceryl monosterate; mineral oil; sodium stearyl fumarate; stearic acid; hydrogenated vegetable oil; talc; hydrogenated soybean oil; stearyl alcohol; leucine; polyethylene glycol; ethylene oxide polymers; or colloidal silica.
[0061] The glidant may be selected from magnesium trisilicate; powdered cellulose; starch; talc and tribasic calcium phosphate; calcium silicate; magnesium silicate; colloidal silicon dioxide; or silicon hydrogel.
[0062] In one of the embodiment the delayed release formulation comprises an azole anti-fungal drug and an enteric release polymer which may be optionally coated with a functional or non-functional coating.
[0063] Enteric coatings include any barrier known in the art that is applied to oral medications, food supplements, or the like that prevents the release of the active agent before it reaches the small intestine. Enteric coatings prevent the destruction of the active agent by the acidic environment of the stomach.
[0064] Suitable enteric polymers used for enteric coating include shellac, methacrylic acid copolymers and their derivatives, cellulose acetate, styrol maleic acid copolymers, polymethacrylic acid/acrylic acid copolymer, hydroxylpropyl methyl cellulose phthalate, methylcellulose phthalate, ethylhydroxycellulose phthalate, polyvinyl acetate phthalate, hydroxyethyl ethyl cellulose phthalate, hydroxypropyl methyl cellulose acetate succinate, cellulose acetate tetrahydrophthalate, polyvinylbutyrate acetate, vinyl acetate-maleic anhydride copolymer, styrene-maleic mono-ester copolymer, methyl acrylate-methacrylic acid copolymer or methacrylate-methacrylic acid-octyl acrylate copolymer, acrylic resin, timellitate, zein, calcium alginate, fatty acids, fats, and combinations thereof, among others. Examples of suitable commercially available enteric coatings include, but are not limited to, MARCOAT® 125 from Emerson Resources, Inc. (Norristown, Pa.), EUDRAGIT® from Degussa, or Cellulose Acetate Phthalate, NF (“CAP”) from Eastman Chemical Co. (Kingston, Tenn.), or the like.
[0065] The target weight gain after enteric coating may vary between about 1 to about 100% by weight of uncoated composition. More preferably the target weight gain after enteric coating may vary between about 5 to 80% by weight of the uncoated composition. In one preferred embodiment, the target weight gain after enteric coating may vary between 10% to about 50% by weight of the uncoated composition.
[0066] The drug is coated with same or two different enteric polymers in two steps i.e. in top spray as well as in bottom spray. This helps in adequate coating of the drug with the polymer and helps in the appropriate dissolution of the drug in the alkaline media and also prevents the degradation/dissolution or both of the drug in acidic media. The use of bottom spray coating ensures that the drug is coated evenly and results in an optimal film quality.
[0067] Accordingly, the total polymer content in the formulation varies with respect to the drug. The ratio of the drug: total polymer ranges from about 1:0.1 to about 1:5. More preferably, the ratio ranges from 1:2 to 1:4. More preferably, the ratio ranges from 1:3 to 1:3.5.
[0068] The polymer content and the type of polymer in the top spray process has also been varied. The drug: top spray polymer ratio is from about 1:1.5 to about 1:5. More preferably, the ratio ranges from 1:2.5 to 1:3.5. The different polymers used for the top spray are illustrated in the examples.
[0069] A similar consideration has been made to diversify the ratio of the bottom spray process and the type of polymer to be used. The drug: extragranular polymer ratio is from about 1:0.1 to about 1:1.5. More preferably, the ratio ranges from 1:0.5 to 1:1. The different polymers used for the bottom spray are illustrated in the examples.
[0070] Commercially available, ready-to-coat preparations, sold under various brand names such as various grades of Opadry®. Opadry® is a film coating system comprising hypromellose, polyethylene glycol and titanium dioxide which does not alter the release of drug.
[0071] In one of the embodiment of the invention, there is provided a process for preparing a delayed release pharmaceutical composition, wherein the method involves:
i. Preparing granules of pharmaceutically acceptable drugs and one or more enteric polymers with a suitable solvent system using top spray fluidization;
ii. coating the granules of step i with enteric polymers using bottom spray fluidization; and
iii. formulating the coated granules obtained in step ii into a suitable solid oral composition.

[0072] In another embodiment of the invention, there is provided a process for preparing a delayed release pharmaceutical composition, wherein the method involves:
i. Preparing granules of posaconazole and hydroxyl propyl methyl cellulose – acetate succinate with a suitable solvent system using top spray fluidization;
ii. coating the granules of step i with hydroxyl propyl methyl cellulose – acetate succinate using bottom spray fluidization; and
iii. formulating the coated granules obtained in step ii into a suitable solid oral composition.

[0073] In another embodiment of the invention, there is provided a process for preparing a delayed release pharmaceutical composition, wherein the method involves:
i. Preparing granules of posaconazole and hydroxyl propyl methyl cellulose – acetate succinate with a suitable solvent system using top spray fluidization;
ii. coating the granules of step i with hydroxyl propyl methyl cellulose –phthalate using bottom spray fluidization; and
iii. formulating the coated granules obtained in step ii into a suitable solid oral composition.

[0074] In yet another embodiment of the invention, there is provided a process for preparing a delayed release pharmaceutical composition, wherein the method involves:
i. Preparing granules of posaconazole and hydroxyl propyl methyl cellulose – acetate succinate with a suitable solvent system using top spray fluidization;
ii. coating the granules of step i with methacrylic acid and methymethacrylate co-polymer (Eudragit L100) using bottom spray fluidization; and
iii. formulating the coated granules obtained in step ii into a suitable solid oral composition.

[0075] In one embodiment of the invention, there is provided a process for preparing a delayed release pharmaceutical composition, wherein the method involves:
i. Preparing granules of posaconazole and hydroxyl propyl methyl cellulose – phthalate with a suitable solvent system using top spray fluidization;
ii. coating the granules of step i with methacrylic acid and methymethacrylate co-polymer (Eudragit L100) using bottom spray fluidization; and
iii. formulating the coated granules obtained in step ii into a suitable solid oral composition.

[0076] In another embodiment of the invention, there is provided a process for preparing a delayed release pharmaceutical composition, wherein the method involves:
i. Preparing granules of posaconazole and methacrylic acid and methylmethacrylate copolymer (Eudragil-L100) with a suitable solvent system using top spray fluidization;
ii. coating the granules of step i with methacrylic acid and methymethacrylate co-polymer (Eudragit L100) using bottom spray fluidization; and
iii. formulating the coated granules obtained in step ii into a suitable solid oral composition.

[0077] In yet another embodiment of the invention, there is provided a process for preparing a delayed release pharmaceutical composition, wherein the method involves:
i. Preparing granules of posaconazole and a with a suitable solvent system using spray drying technique;
ii. coating the granules of step i with hydroxyl propyl methyl cellulose – acetate succinate using bottom spray fluidization; and
iii. formulating the coated granules obtained in step ii into a suitable solid oral composition.

[0078] In one of the embodiments of the invention, the delayed release composition exhibits not more than 10% drug release in 0.01N hydrochloric acid within 2 hours and not less than 80% drug release in 50mM phosphate buffer having a pH of 6.8 with 0.37% polysorbate 80 for 45 minutes, wherein the method for preparing the composition involves:
i. Preparing granules of posaconazole and enteric polymer with a suitable solvent system using top spray fluidization;
ii. coating the granules of step i with same or different enteric polymer using bottom spray fluidization; and
iii. formulating the coated granules obtained in step ii into a suitable solid oral composition.

[0079] In one of the embodiments of the invention, the delayed release composition exhibits not more than 10% drug release in 0.01N hydrochloric acid within 2 hours and not less than 80% drug release in 50mM phosphate buffer having a pH of 6.8 with 0.37% polysorbate 80 for 45 minutes, wherein the method for preparing the composition involves:
i. Preparing granules of posaconazole and enteric polymer with a suitable solvent system using spray drying technique;
ii. coating the granules of step i with same or different enteric polymer using bottom spray fluidization; and
iii. formulating the coated granules obtained in step ii into a suitable solid oral composition.

[0080] An important aspect of the manufacture (and also the regulatory review and approval) of all modified release preparations, including delayed release preparations, concerns their stability over extended periods of time, particularly their ability to provide a dissolution profile that is largely unaffected during the intended shelf life of the preparation.

[0081] The invention is not to be limited in scope by the specific embodiments described herein. The different modifications of the invention in addition to those described herein will become apparent to those skilled in the art from the foregoing description. Such modifications are intended to fall within the scope of the appended claims.

Table 01(A): Following are the compositions (Examples 01-08) of the present invention with %w/w ingredients:
Ingredients Examples
01 02 03 04 05 06 07 08
Intra-Granular
FBP Top Spray/ Spray Drying
Posaconazole 16.67 16.67 13.89 16.67 16.67 16.67 16.67 16.67
HPMC-AS 50 50 55.56 50 50 - - 50
Hypromellose Phthalate - - - - - 50 - -
Methacrylic acid and methylmethacrylate copolymer - - - - - 50 -
Crosscarmellose sodium 1 1 18.26 1 1 1 1 -
Microcrystalline Cellulose 21.12 21.67 - 21.12 21.12 21.12 21.12 19.54
Hydroxy propyl cellulose - - - - - - - 1.5
Dichloromethane* qs qs qs qs qs qs qs qs
Methanol* qs qs qs qs qs qs qs qs
Pre-compaction Lubrication
Magnesium stearate 0.25 0.25 0.25 0.25 0.25 0.25 0.25 0.25
Bottom Spray Coating of compacted Granules
HPMC-AS 11.88 7.17 8.8 - - - - 8.8
Hypromellose Phthalate - - - 11.88 - - - -
Methacrylic acid and methylmethacrylate copolymer - - - - 11.88 11.88 11.88 -
Dichloromethane* qs qs qs qs qs qs qs qs
Methanol* qs qs qs qs qs qs qs qs
Extra-Granular
Crosscarmellose sodium 1 1 1.5 1 1 1 1 1
Hydroxypropyl cellulose 1.5 1.5 1 1.5 1.5 1.5 1.5 1.5
Colloidal silicon dioxide 0.5 0.5 0.5 0.5 0.5 0.5 0.5 0.5
Magnesium stearate 0.25 0.25 0.25 0.25 0.25 0.25 0.25 0.25
Film Coating (coat buildup on core)
Opadry 3%

[0082] Procedure for preparing formulations of examples 01-07:
1. All ingredients were sifted through suitable sieve. Posaconazole and Hypromellose Acetate Succinate/ Hypromellose Phthalate/ Methacrylic acid and methylmethacrylate co-polymer were dissolved in a mixture of dichloromethane and methanol.
2. Crosscarmellose sodium and MCC were blended together and the solution of step I was sprayed on this blend using top spray method to obtain the granules.
3. A solution of Hypromellose Acetate Succinate/ Hypromellose Phthalate/ Methacrylic acid and methylmethacrylate co-polymer was sprayed by Bottom spray coating on the granules of step 2 followed by lubrication, compression to a tablet dosage form and film coating.

[0083] Procedure for preparing formulations of example 08:
1. All ingredients were sifted through suitable sieve. Posaconazole and Hypromellose Acetate Succinate were dissolved in a mixture of dichloromethane and methanol and spray dried.
2. Hydroxypropyl cellulose and microcrystalline cellulose were sifted, blended together and thereafter lubricated with magnesium stearate followed by compaction.
3. A solution of hydroxylpropylmethylcellulose acetate succinate was sprayed on the granules of step 2 followed by lubrication, compression to a tablet dosage form and film coating.
Table 01(B): Following are the compositions (Examples 09-13) prepared by either Top Spray or Bottom Spray or Spray drying with %w/w ingredients:
Ingredients Examples
09 10 11 12 13
Posaconazole 16.39 13.47 16.67 16.39 16.67
HPMC-AS 40.98 60.64 50.00 40.98 50.00
Dichloromethane NA NA NA NA NA
Methanol NA NA NA NA NA
Diluent 32.79
(MCC) - - 32.79
(MCC Sphere) 32.79
(Sugar sphere)
Process Parameters
Drug: Polymer Ratio 1 : 4 1 : 4.5 1 : 3 1 : 2.5 1 : 3
Process Type FBP Top Spray Spray Drying Spray Drying FBP Bottom spray FBP Bottom spray

[0084] Procedure for preparing formulations of examples 09, 12 &13:
1. Dissolve Posaconazole and polymer Hypromellose acetate succinate in DCM: Methanol solvent mixture to obtain clear viscous solution.
2. Sift MCC and load into the bowl of FBP top spray equipment.
3. Spray the solution of Step-1 over materials of Step-2 in FBP at suitable process parameters using FBP top spray process.

[0085] Procedure for preparing formulations of examples 10 & 11:
1. Dissolve Posaconazole and polymer HPMC-AS in DCM: Methanol solvent mixture to obtain clear viscous solution.
2. Spray dry the solution of Step-1 over solution at suitable process parameters using spray dryer.

[0086] The dissolution for the formulations of the present invention have been carried out in accordance with the USFDA dissolution criteria for Posaconazole Delayed Release tablets, which comprises of the following:
i. USP Apparatus: Type II (Paddle)
ii. Speed: 75 rpm
iii. Medium: Acid Stage: 0.01 N HCl: Buffer Stage: 50 mM phosphate buffer, pH 6.8 with 0.37 % Polysorbate 80 (after 120 minutes, to the acid stage, add 250 mL of 0.2M Phosphate Buffer, 1.46% Polysorbate 80)
iv. Volume (mL): Acid Stage: 750 mL; Buffer Stage 1000 mL
v. Recommended Sampling Times (min): Acid Stage: 120 min; Buffer Stage: 10, 15, 20, 30 and 45 min
vi. Drug Release (%): Acid Stage: Not more than 10%; Buffer Stage: Not less than 80%.

Table 02: Results of the in vitro dissolution profile are as follows:
Time (Min) Examples
01 02 03 08 09 10 11 12 13
Acid stage
120 3
(3-3) 6
(5-6) 4
(4-5) 6
(4-7) 13 39 39 2 -
Buffer stage
10 89
(87-91) 90
(88-91) 96
(95-98) 76
(70-81) 98 - - 44 13
15 99
(98-100) 101
(100-102) 97
(95-98) 87
(82-92) 98 - - 50 17
20 101
(100-101) 102
(101-103) 100
(99-103) 96
(93-99) 99 96 97 52 22
30 101
(100-102) 103
(102-104) 101
(99-102) 102
(99-104) 100 - - 54 31
45 101
(99-101) 104
(103-105) 102
(100-103) 108
(107-109) 100 - - 54 44

[0087] Dissolution study: Under acidic condition, all the tablets of examples 01-03 & 08 released less than 10% of Posaconazole. Under alkaline environment, all the tablets of example 01-03 and 08 released no less than about 80% to about 90% of posaconazole in initial 10 minutes and complete drug released within 45 minutes in an alkaline environment.

Figure 01: Dissolution profile of Examples 01, 02, 03 & 08 in Buffer stage (50 mM phosphate buffer at pH 6.8 with 0.37% polysorbate).

[0088] The formulations were found to be bioequivalent to the Marketed formulation, Noxafil Delayed Release Formulation
,CLAIMS:1. A delayed release composition of poorly water soluble drug for oral administration comprising:
(i) a core comprising a therapeutically effective amount of drug or pharmaceutically acceptable salts thereof, one or more enteric polymers, one or more pharmaceutically acceptable carrier and
(ii) one or more enteric polymer surrounding the core, wherein the pharmaceutical composition exhibits improved solubility of drug in intestinal pH.

2. A delayed release composition of poorly water soluble drug for oral administration comprising:
(i) a core comprising a therapeutically effective amount of drug or pharmaceutically acceptable salts thereof, one or more enteric polymers, one or more pharmaceutically acceptable carrier and
(ii) one or more enteric polymer surrounding the core,
wherein the pharmaceutical composition exhibits improved solubility of drug in intestinal pH, and
wherein the total drug: total polymer ratio is from about 1:1 weight by weight to about 1:5 weight by weight.

3. The composition according to claim 1 and 2, wherein the core is a tablet, a mini-tablet, a pellet, a granule, a microparticle, a hard or soft capsule, or a microcapsule.

4. The composition according to claim 1 and 2, wherein the enteric polymer is selected from shellac, methacrylic acid copolymers and their derivatives, cellulose acetate, styrol maleic acid copolymers, polymethacrylic acid/acrylic acid copolymer, hydroxylpropyl methyl cellulose phthalate, methylcellulose phthalate, ethylhydroxycellulose phthalate, polyvinyl acetate phthalate, hydroxyethyl ethyl cellulose phthalate, hydroxypropyl methyl cellulose acetate succinate, cellulose acetate tetrahydrophthalate, polyvinylbutyrate acetate, vinyl acetate-maleic anhydride copolymer, styrene-maleic mono-ester copolymer, methyl acrylatemethacrylic acid copolymer or methacrylate-methacrylic acid-octyl acrylate copolymer, acrylic resin, timellitate, zein, calcium alginate, fatty acids, fats or combinations thereof.

5. The method of preparing a delayed release composition of claim 1 and 2 involves:
(i) preparing granules of pharmaceutically acceptable drugs and one or more enteric polymers with a suitable solvent system using top spray fluidization;
(ii) coating the granules of step i with enteric polymers using bottom spray fluidization and
(iii) formulating the coated granules obtained in step ii into a suitable solid oral composition.