WO2008039351A2

WO2008039351A2 - Method of manufacturing tablets containing pharmacologically active agents

Info

Publication number: WO2008039351A2
Application number: PCT/US2007/020406
Authority: WO
Inventors: Anasuya Ashok Ghosh; Yatindra Joshi; Shoufeng Li; Alan Edward Royce; Colleen Ruegger
Original assignee: Novartis Ag
Priority date: 2006-09-22
Filing date: 2007-09-20
Publication date: 2008-04-03
Also published as: CL2007002724A1; AR062925A1; PE20080845A1; TW200820993A; WO2008039351A3

Abstract

A method of improving the physical properties of an solid oral dosage form, especially a tablet, uses an external lubricant during the compaction process. The solid oral dosage form comprises a pharmacologically active agent, for example a protein or polypeptide, and a delivery agent. Tablet properties, such as hardness, disintegration time and dissolution, are improved using the method.

Description

Method of Manufacturing Tablets Containing Pharmacologically Active Agents

Field of the Invention

The present invention relates to a method of delivering a pharmacologically active agent(s) with a delivery agent(s) in a solid oral pharmaceutical composition made by a process using external lubrication.

Background of the Invention

Oral delivery of pharmacologically active agents is generally the delivery route of choice since it is convenient, relatively easy and generally painless, resulting in greater patient compliance relative to other modes of delivery. However, biological, chemical and physical barriers such as varying pH in the gastrointestinal tract, powerful digestive enzymes, and active agent impermeable gastrointestinal membranes, makes oral delivery of some pharmacologically active agents to mammals problematic, especially proteins and/or peptides.

Peptides particularly difficult to orally deliver are calcitonins, which are long-chain polypeptide hormones secreted by the parafollicular cells of the thyroid gland in mammals and by the ultimobranchial gland of birds and fish, has proven difficult due, at least in part, to the insufficient stability of calcitonin in the gastrointestinal tract as well as the inability of calcitonin to be readily transported through the intestinal walls into the blood stream.

Various attempts have been made in the art to improve the delivery such pharmacologically active agents. For example, proteins and peptides have been formulated with delivery agents. U.S. Patent Nos. 5,773,647; 5,866,536; and 7,049,283 describe compositions for the oral delivery of pharmacologically active agents, such as heparin and/or calcitonin, with modified amino acids, such as, Λ/-(5-chlorosalicyloyl)-8-aminocaprylic acid (5- CNAC), Λ/-(10-[2-hydroxybenzoyl] aminodecanoic acid (SNAD) and Λ/-(8-[2- hydroxybenzoyl]amino)caprylic acid (SNAC). In addition, U.S. Patent No. 6,399,798 discloses the disodium salts of formula (I)

wherein R¹, R², R³ and R⁴ are independently hydrogen, -OH₁ -NR⁶R⁷, halogen, d-C₄alkyl or Ci-C₄alkoxy;

R⁵ is a substituted or unsubstituted C₂-C,₆alkylene, substituted or unsubstituted

C₂-C₁₆alkenylene, substituted or unsubstituted d-C^alkyKarylene), or substituted or unsubstituted aryl(d-Ci₂alkylene); and

R⁶ and R⁷ are independently hydrogen, oxygen or d-C₄alkyl; and hydrates and solvates thereof as particularly efficacious for the oral delivery of pharmacologically active agents.

To prepare pharmaceutical formulations described above, powder compactions, for example direct compression or compaction after granulation may be used. The process of compaction includes filling a die cavity with tableting material (i.e., a powder or granulate blend); using a punch to apply pressure onto the tableting material to form a compact; and ejecting the compact from the die. Lubrication, often in the form of magnesium stearate, is used in the tableting material to reduce friction that may occur during the compacting process (e.g., during the punching or ejecting steps). When blended with the tableting material directly, the magnesium stearate may be considered as an internal lubricant.

When a delivery agent is incorporated in the tableting material, it has been found that the delivery agent may stick to the punch causing difficulty during tableting despite the use of an internal lubricant. Such sticking may compromise the acceptability of the resulting tablets. Thus, there is a need for a manufacturing process that improves on existing processes such that any sticking of a delivery agent to the punch is reduced.

The invention process of the present invention addressed this need by reducing any sticking of the delivery agent to the punch. The inventive process of the present invention calls for the use of an external lubricant during the compacting process. It has been found that the use of an external lubricant not only reduces the sticking problem but also surprisingly enhances the resulting tablets' physical properties, such as hardness and dissolution time.

Summary of the Invention

The present invention features a manufacturing process that improves the physical properties of solid oral dosage forms, especially tablets resulting therefrom. Manufacturing equipment, for example roller compactors and tableting presses, that uses compaction are particularly suited for use in the inventive process. In the process, an external lubricant (e.g., magnesium stearate) is applied to the contacting surfaces of the manufacturing apparatus. The manufacturing apparatus is used to compact a tableting material that comprises a pharmacologically active agent and a delivery agent. Particularly suited pharmacologically active agents include, but are not limited to proteins, polypeptides, hormones, polysaccharides, carbohydrates, lipids and combinations thereof. Particularly suited delivery agents include, but are not limited to, Λ/-(5-chlorosalicyloyl)-8-aminocaprylic acid (5-CNAC), Λ/-(10-[2-hydroxybenzoyl]amino)decanoic acid (SNAD), Λ/-(8-[2- hydroxybenzoyl]amino)caprylic acid (SNAC), salts thereof and combinations thereof.

Brief Description of the Drawings

The accompanying drawings, which are incorporated in and constitute a part of the specification, illustrate an exemplary embodiment of the present invention.

FIG. 1 shows a chart depicting the compression profiles for tablets manufactured with an internal lubricant versus that with an external lubricant;

FIG 2. shows a chart depicting the hardness versus disintegration time of tablets manufactured with an internal lubricant versus that with an external lubricant;

FIG 3. shows a chart depicting the dissolution profile of tablets made with an internal lubricant; and

FIG. 4 shows a chart depicting the dissolution profiles of exemplary tablets made with an external lubricant process of the present invention.

Detailed Description of the Invention

The present invention feature a manufacturing process for compacting tablet material used in solid oral dosage forms. Typically a lubricant is directly blended with the tablet material prior to compaction. In an exemplary process, a lubricant is also spray dried into the dies and onto the punches of a tableting equipment prior to the introduction of the tableting material. It has been surprisingly found that the incorporation of an external lubricant in the tablet process enhances the physical properties of the resulting tablets.

As used herein, "pharmaceutically acceptable" refers to those compounds, materials, compositions and/or dosage forms, which are, within the scope of sound medical judgment, suitable for contact with the tissues of mammals, especially humans, without excessive toxicity, irritation, allergic response and other problem complications commensurate with a reasonable benefit/risk.

As used herein, the term "pharmacologically active agent" means both therapeutic as well as preventative agents and is directed particularly to agents which by themselves do not pass or which pass only a small amount of the administered dose through the gastrointestinal mucosa and/or are susceptible to cleavage by acids and enzymes in the gastrointestinal tract. Examples of pharmacologically active agents include, but are not limited to, proteins, polypeptides, hormones, polysaccharides including mixtures of mucopolysaccharides, carbohydrates, lipids and combinations thereof.

Specific examples of pharmacologically active agents include, but are not limited to, the following, including synthetic, natural or recombinant sources thereof: growth hormone, including human growth hormones (hGH), recombinant human growth hormones (rhGH), bovine growth hormones, and porcine growth hormones; growth hormone-releasing hormones; interferons, including α-, β- and γ-interferon; interleukin-1; interleukin-2; insulin, including porcine, bovine, human and human recombinant, optionally having counterions including sodium, zinc, calcium and ammonium; insulin-like growth factor, including IGF-1; heparin, including unfractionated heparin, heparinoids, dermatans, chondroitins, low, very low and ultra low molecular weight heparins; calcitonin, including salmon, porcine, eel, chicken and human; erythopoietein; atrial naturetic factor; antigens; monoclonal antibodies; somatostatin; protease inhibitors; adrenocorticotropin, gonadotropin releasing hormone; oxytocin; leutilizing-hormone-releasing hormone; follicle stimulating hormone; glucocerebrosidase; thrombopoietin; filgrastim; prostaglandins; cyclosporin; vasopressin; cromolyn sodium (sodium or disodium chromoglycate); vancomycin; desferrioxamine (DFO); parathyroid hormone (PTH), including its fragments; antimicrobials, including anti-fungal agents; vitamins; analogs, fragments, mimetics or polyethylene glycol (PEG)-modified derivatives of these compounds; or any combination thereof.

A particularly useful pharmacologically active agent is a pharmacologically active peptide, particularly calcitonin. A known class of pharmacologically active agents, calcitonins have varying pharmaceutical utility and are commonly employed in the treatment of e.g. Paget's disease, hypercalcemia and postmenopausal osteoporosis. Various calcitonins, including salmon, pig and eel calcitonin are commercially available and commonly employed for the treatment of e.g. Pagefs disease, hypercalcemia of malignancy and osteoporosis. The calcitonin can be any calcitonin, including natural, synthetic or recombinant sources thereof, as well as calcitonin derivatives such as 1,7-Asu-eel calcitonin. The compositions can comprise a single calcitonin or any combination of two or more calcitonins. Particularly useful is synthetic salmon calcitonin. The calcitonins are commercially available or may be synthesized by known methods.

As used herein, the term "effective amount" refers to generally an amount effective to accomplish the intended purpose, e.g., a therapeutically effective amount. However, the amount can be less than that amount when a plurality of the compositions are to be administered, i.e., the total effective amount can be administered in cumulative dosage units. The amount of active agent can also be more than the effective amount when the composition provides sustained release of the pharmacologically active agent. The total amount of a pharmacologically active agent to be used can be determined by methods known to those skilled in the art. However, because the compositions may deliver the pharmacologically active agent more efficiently than prior compositions, less amounts of active agent than those used in prior dosage unit forms or delivery systems can be administered to a subject while still achieving the same blood levels and/or therapeutic effects.

When the pharmacologically active agent is salmon calcitonin, the appropriate dosage will, of course, vary depending upon, for example, the host and the nature and severity of the condition being treated. However, in general, satisfactory results will be obtained systemically at daily dosages of from about 0.5 Dg/kg to about 10 Dg/kg animal body weight, preferably 1 Dg/kg to about 6 Dg/kg g/kg body weight.

The pharmacologically active agent generally comprises from 0.05 to 70 percent by weight relative to the total weight of the overall pharmaceutical composition, preferably an amount of from 0.01 to 50 percent by weight, more preferably 0.3 to 30 percent by weight relative to the total weight of the overall pharmaceutical composition.

As used herein, the term "delivery agent" refers to any agent useful for delivering the particular or desired pharmacologically active agent. Suitable delivery agents are anyone of the 123 modified amino acids disclosed in aforementioned U.S. Patent No. 5,866,536 or anyone of the 193 modified amino acids described in the aforementioned U.S. Patent No. 5,773,647 or any combination thereof. The contents of the aforementioned U.S. Patent Nos. 5,773,647 and 5,866,536 are hereby incorporated by reference in their entirety. In addition, the delivery agent can be the disodium salt of any of the aforementioned modified amino acids, as well as ethanol solvates and hydrates thereof. Suitable compounds include compounds of the following formula (I),

wherein

R¹, R², R³ and R⁴ are independently hydrogen, -OH, -NR⁶R⁷, halogen, d-C₄alkyl or

C₁-C₄BIkOXy; R⁵ is a substituted or unsubstituted C₂-C₁₆alkylene, substituted or unsubstituted

C₂-C_1salkenylene, substituted or unsubstituted d-C^alky^arylene), or substituted or unsubstituted aryl(d-Ci₂alkylene); and

R⁶ and R⁷ are independently hydrogen, oxygen or d-C₄alkyl; and hydrates and alcohol solvates thereof. The compounds of formula (I), as well as their disodium salts and alcohol solvates and hydrates thereof are described in WO 00/059863, along with methods for preparing them.

The disodium salt may be prepared from the ethanol solvate by evaporating or drying the ethanol solvate by methods known in the art to form the anhydrous disodium salt. Drying is generally carried out at a temperature of from about 8O⁰C to about 12O⁰C, preferably from about 85⁰C to about 90°C and most preferably at about 85⁰C. The drying step is generally performed at a pressure of 26" Hg or greater. The anhydrous disodium salt generally contains less than about 5% by weight of ethanol and preferably less than about 2% by weight of ethanol, based on 100% total weight of anhydrous disodium salt.

The disodium salt of the delivery agent can also be prepared by making a slurry of the delivery agent in water and adding two molar equivalents of aqueous sodium hydroxide, sodium alkoxide or the like. Suitable sodium alkoxides include, but are not limited to, sodium methoxide, sodium ethoxide and combinations thereof.

A still further method of preparing the disodium salt is by reacting the delivery agent with one molar equivalent of sodium hydroxide to yield the disodium salt.

The disodium salt can be isolated as a solid by concentrating the solution containing the disodium salt to a thick paste by vacuum distillation. This paste may be dried in a vacuum oven to obtain the disodium salt of the delivery agent as a solid. The solid can also be isolated by spray drying an aqueous solution of the disodium salt.

The delivery agents may be prepared by methods known in the art, e.g., as mentioned above, by methods described in U.S. Patent Nos. 5,773,647 and 5,866,536.

The ethanol solvates, as described in the aforementioned U.S. Patent No. 6,399,798 which is also hereby incorporated by reference in its entirety, include, but are not limited to, a molecular or ionic complex of molecules or ions of ethanol solvent with molecules or ions of the disodium salt of the delivery agent. Typically, the ethanol solvate contains about one ethanol molecule or ion for every molecule of disodium salt of the delivery agent.

The ethanol solvate of the disodium salt of the delivery agent can be prepared by dissolving the delivery agent in ethanol. Typically, each gram of delivery agent is dissolved in from about 1 mL to about 50 mL of ethanol and generally, from about 2 mL to about 10 mL of ethanol. The delivery agent/ethanol solution is then reacted with a molar excess of a sodium containing salt, such as a monosodium containing salt, relative to delivery agent, i.e., for every mole of delivery agent there is more than one mole of sodium cations, yielding the ethanol solvate. Suitable monosodium salts include, but are not limited to, sodium hydroxide; sodium alkoxides, such as sodium methoxide and sodium ethoxide; and any combination of the foregoing. Preferably, at least about two molar equivalents of the monosodium containing salt are added to the ethanol solution, i.e., for every mole of delivery agent there is at least about two moles of sodium cations. Generally, the reaction is performed at or below the reflux temperature of the mixture, such as at ambient temperature. The ethanol solvate is then recovered by methods known is the art, such as, concentration of the resulting slurry at atmospheric distillation, cooling the concentrated slurry and filtering the solid. The recovered solid can then be vacuum dried to obtain the ethanol solvate.

The hydrates of the disodium salts of the delivery agents may be prepared by drying the ethanol solvate to from an anhydrous disodium salt, as described above, and hydrating the anhydrous disodium salt. Preferably, the monohydrate of the disodium salt is formed. Since the anhydrous disodium salt is very hydroscopic, the hydrate forms upon exposure to atmospheric moisture. Generally, the hydrating step is performed at from about ambient temperature to about 50⁰C, preferably ambient temperature to about 30°C and in an environment having at least 50% relative humidity. Alternatively, the anhydrous disodium salt may be hydrated with steam.

Particularly useful delivery agents are Λ/-(5-chlorosalicyloyl)-8-aminocaprylic acid (5-CNAC), Λ/-(10-[2-hydroxybenzoyl]amino)decanoic acid (SNAD), Λ/-(8-[2- hydroxybenzoyl]amino)caprylic acid (SNAC)and their monosodium and disodium salts, ethanol solvates ct their sodium salts and the monohydrates of their sodium salts and any combinations thereof. A preferred delivery agent is the disodium salt of 5-CNAC and the monohydrate thereof.

The pharmaceutical compositions of the present invention typically contain a delivery effective amount of one or more of the delivery agents, i.e., an amount sufficient to deliver the active agent for the desired effect. Generally, the delivery agent is present in an amount of 2.5-99.4% by weight, more preferably 25-50% by weight.

As used herein, the term "tableting material" refers to a blend of pharmaceutical ingredients that includes, but is not limited to, a pharmacologically active agent, a delivery agent, and a pharmaceutically acceptable excipients. This tableting material will be compacted in a tableting equipment such as a press. If the tableting material can be compressed into a solid oral dosage form, e.g., tablet, without a prior granulation step, then it is "directly compressible." The tableting material should flow freely and be cohesive. Prior to being compacted the tableting material may also have been granulated.

One particularly excipient that may be incorporated in the tableting material is a lubricant, as mentioned above. Lubricants serve to prevent the adhesion of the tableting material to the contacting surfaces (i.e., surfaces of the die and/or punches that come in contact with the tableting material) of the dies and/or punches. Additionally, they reduce friction from manufacturing and improve ejection of the compact. Examples of pharmaceutically acceptable lubricants include, but are not limited to, talc, magnesium stearate, calcium stearate, zinc stearate, glyceryl behenate, polyethylene oxide polymers, sodium lauryl sulfate, magnesium lauryl sulfate, sodium oleate, sodium stearyl fumarate, stearic acid, hydrogenated vegetable oils, and polyethylene glycol.

When incorporated with the tableting material prior to compaction in the tableting equipment, the lubricant is deemed to be an "internal lubricant" or "used internally" in the pharmaceutical composition. In contrast, if the lubricant is applied directly to the contacting surfaces of the dies and punches of the tableting equipment or the contacting surfaces of any other type of manufacturing equipment (e.g., roller of a roll compactor), the lubricant is deemed to be an "external lubricant" or "used externally." The external lubricant can comprise a lubricant alone or in combination with another pharmaceutically acceptable excipient, for example, microcrystalline cellulose. In the inventive processes of the present invention, at least one external lubricant Is used; however, use of the external lubricant does not necessarily preclude the additional use of an internal lubricant in the tableting material. Thus, in an exemplary process of the present invention both internal and external lubricants are used. Alternatively, in another exemplary process of the present invention, only an external lubricant is used, and there is no lubricant in the tableting material prior to compaction. Yet in another exemplary embodiment of the present invention, the final solid oral dosage form contains from 0% to about 0.5% (w%/w%) of lubricant.

For example, in an exemplary embodiment of the present invention, the lubricant may only be present in the solid oral dosage form due to the compacted tableting material coming into contact with the external lubricant that is applied to the contacting surface of the tableting equipment. In such an embodiment, no lubricant is initially included in the tableting material that is to be compacted. If this is the case, then in the final tablet, the lubricant, resides on the outer surface of the tablet.

Particularly useful as an external lubricant is magnesium stearate. As used herein the term "magnesium stearate" refers to that with a magnesium content of about 3.8% to 5%. The magnesium stearate comprises materials of vegetable origin. As used in the pharmaceutical industry, magnesium stearate is often included as a component of the granulate. Alternatively, it used as dusting of the contacting surfaces (i.e., external lubricant) of the equipment (e.g., tablet process or roll compactor) that come in contact with the pharmaceutical composition.

Examples of other pharmaceutically acceptable excipients include, but are not limited to, disintegrants, binders, glidants, stabilizers, fillers, diluents, coloring agents and flavoring agents. One of ordinary skill in the art may select one or more of the aforementioned excipients with respect to the particular desired properties of the solid oral dosage form by routine experimentation and without any undue burden. The amount of each excipient used may vary within ranges conventional in the art. The following references which are all hereby incorporated by reference discloses techniques and excipients used to formulate oral dosage forms. See The Handbook of Pharmaceutical Excipients, 4^th edition, Rowe et al., Eds., American Pharmaceuticals Association (2003); and Remington: the Science and Practice of Pharmacy, 20^th edition, Gennaro, Ed., Lippincott Williams & Wilkins (2003).

Examples of pharmaceutically acceptable disintegrants include, but are not limited to, starches; clays; celluloses; alginates; gums; cross-linked polymers, e.g., cross-linked polyvinyl pyrrolidone or crospovidone, e.g., POLYPLASDONE XL from International Specialty Products (Wayne, NJ); cross-linked sodium carboxymethylcellulose or croscarmellose sodium, e.g., AC-DI-SOL from FMC; and cross-linked calcium carboxymethylcellulose; soy polysaccharides; and guar gum. The disintegrant, e.g., may be present in an amount from about 1% to about 20%, e.g., from about 5% to about 10%, e.g., about 5% about by weight of the composition.

Examples of pharmaceutically acceptable binders include, but are not limited to, starches; celluloses and derivatives thereof, for example, microcrystalline cellulose, e.g., AVICEL PH from FMC (Philadelphia, PA), hydroxypropyl cellulose hydroxylethyl cellulose and hydroxylpropylmethyl cellulose METHOCEL from Dow Chemical Corp. (Midland, Ml); sucrose; dextrose; corn syrup; polysaccharides; and gelatin. The binder, for example, may be present in an amount from about 5% to about 50%, e.g., 10% to 40% by weight of the composition.

Examples of pharmaceutically acceptable glidants include, but are not limited to, colloidal silicon dioxide and talc. The glidant may be present in an amount from about 0.1% to about 10% by weight.

Examples of pharmaceutically acceptable fillers and pharmaceutically acceptable diluents include, but are not limited to, confectioner's sugar, compressible sugar, dextrates, dextrin, dextrose, lactose, mannitol, microcrystalline cellulose, powdered cellulose, sorbitol, sucrose and talc. The filler and/or diluent, e.g., may be present in an amount from about 15% to about 40% by weight of the composition.

To prepare a dry blend of tableting material, the various components (and optionally an internal lubricant) are weighed, delumped and combined. The mixing of the components may be carried out until a homogeneous blend is obtained. Alternatively, the various components without the internal lubricant may be weighed, delumped and combined until homogenous. The internal lubricant, an optional component, is subsequently added, and additional mixing occurs. If granules are to be used in the tableting material, granules may be produced in a manner known to one of ordinary skill in the art, for example using wet granulation methods known for the production of "built-up" granules or "broken-down" granules.

Methods for the formation of built-up granules may operate continuously and comprise, for example simultaneously spraying the granulation mass with granulation solution and drying, for example in a drum granulator, in pan granulators, on disc granulators, in a fluidized bed, by spray-drying or spray-solidifying, or operate discontinuously, for example in a fluidized bed, in a batch mixer or in a spray-drying drum.

Methods for the production of broken-down granules, which may be carried out discontinuously and in which the granulation mass first forms a wet aggregate with the granulation solution, which aggregate is then comminuted or formed into granules of the desired particle size and the granules then being dried. Suitable equipment for the granulation step are planetary mixers, low and high shear mixers, wet granulation equipment including extruders and spheronizers include, for example, apparatus from the companies Loedige, Glatt, Diosna, Fielder, Collette, Aeschbach, Alexanderwerk, Ytron, Wyss & Probst, Werner & Pfleiderer, HKD, Loser, Fuji, Nica, Caleva and Gabler.

Granules may be also formed by dry granulation techniques in which the pharmaceutically active agent is compressed with the excipients to form relatively large moldings, for example slugs or ribbons, which are comminuted by grinding, and the ground material serves as the tableting material to be later compacted.

To compact the tableting material into a solid oral dosage form, for example, a tablet, a tablet press may be used. In a tableting press, the tableting material is filled (e.g. force fed or gravity fed) into a die cavity. The tableting material is then compacted by a punch with pressure. Subsequently, the resulting compact, or tablet is ejected from the tableting press. Particularly useful as a tablet press is a gravity fed tableting press which allows gravity to cause the tableting blend to flow into the die. The above mentioned compaction process is subsequently referred to herein as the "compaction process."

Tablet presses include, but are not limited to, rotary tablet presses and eccentric tablet presses. Examples of tablet presses include, but are not limited to, the Korsch EK-O eccentric tableting press (Korsch AG₁ Germany) and the Manesty F-Press (Manesty Machines Ltd., United Kingdom).

The compaction process of the present invention incorporates the use of an external lubricant. The external lubricant is sprayed or applied onto the inner contact surface of the die cavity and onto the contact surface of the punch. The external lubricant can be applied to the tablet press by means known by one of ordinary skill in the art. For example, the external lubricant may be applied by dispersing the lubricant into an air flow at a constant air flow rate and spraying it onto the surfaces of the tablet press. Constant air flow rates for application range from about 5 U minute (Normal) to 30 L/minute (Normal), for example, from 8 L/minute (Normal)to 15 L/minute (Normal). "L/minute(Normal)° is a unit for expressing an amount of air, and expresses the gas flow amount reduced under the conditions of one atmosphere at 0⁰C.

In the present invention, the spray rate of the external lubricant, e.g., magnesium stearate, may be controlled either volumetrically or gravimetrically. In volumetric operation, the dosage is maintained at a constant level through the controllable rotation speed of a motor. In gravimetric operation, a high -precision scale is used to check the rate of supply; if the level is too high or too low, the speed of the application screw used to supply the external lubricant is corrected to maintain the predetermined feeding rate. Compressed air is used to carry the magnesium stearate powder to the surfaces of the equipment, for example, the upper and lower punches and press die wall of a tablet press. An exemplary method of applying external lubricants for a high speed rotary tablet press can be found in T. Jahn and K.-J. Steffens, "Press Chamber Coating as External Lubrication for High Speed Rotary Presses: Lubricant Spray Rate Optimization", 31 DRUG DEVELOPMENT AND INDUSTRIAL PHARMACY 951-57 (2005), which is hereby incorporated by reference in its entirety.

The utility of all the pharmaceutical compositions of the present invention may be observed in standard clinical tests in, e.g., known indications of drug dosages giving therapeutically effective blood levels of drug, e.g., using dosages in the range of 2.5-1000 mg of drug per day for a 75 kg mammal, e.g., adult and in standard animal models. The increased bioavailability of the drug provided by the compositions may be observed in standard animal tests and in clinical trials, e.g., as described above.

The following examples are illustrative, but do not serve to limit the scope of the invention described herein. The examples are meant only to suggest a method of practicing the present invention. Quantities of ingredients, represented by percentage by weight of the pharmaceutical composition, used in each example are set forth in the respective tables located after the respective descriptions.

In Table 1 , below, two formulations are made. Example 1 uses magnesium stearate (at a 1 w%/w%) internally, i.e., within the tableting material.

Table 1

The manufacturing process for each of the Examples 1 and 2 is as follows. A portion of the delivery agent is blended with the pharmaceutically active agent in a bin blender for fifty revolutions. The blended material is screened in an oscillator with a size of 0.25 mm (60 mesh) screen. The combined material along with remaining delivery agent is returned to the bin blender for blending. Crospovidone is then added and blended in the bin blender. Silicon dioxide and a portion of the microcrystalline cellulose are screened through a 0.85mm (20 mesh) screen and added to another portion of microcrystalline cellulose. The combination is then added to the bin blender and blended. Only in Example 1 is magnesium stearate added directly to the tableting material. The tableting material is then compacted.

For example 2, the magnesium stearate that is used as the external lubricant is first sieved through a size 0.85 mm (20 mesh) screen. Nine milligrams of the sieved magnesium stearate is blended with one mg of microcrystalline cellulose. An external lubrication unit, for example the PKB 3 magnesium stearate spraying system from Fette America (Rockaway, New Jersey), is used to coat the surfaces of a tablet press that come in contact with the tableting material with the magnesium stearate and microcrystalline cellulose blend. The tableting material is subsequently compacted.

The tablet properties of Examples 1 and 2 can be compared via physical testing, such as hardness and dissolution. For example, the hardness of the tablets made from Example 2 is better than that of Example 1. FIG. 1 shows the compression profiles for one batch of Example 1 (i.e., Example 1a) and three batches of Example 2 (Examples 2a, 2b and 2c). The compression profile measures the hardness of the tablets as a function of compression force. The batches of Example 2 have a surprisingly higher and better compression profile than that of Example 1.

FIG. 2 shows the hardness versus disintegration time of the resulting tablets of Examples 1 and 2. In addition to batches 2a, 2b, and 2c, onemore batch 2d is also shown in the plot. FIG 2. shows that the batches made with external lubrication have a much shorter disintegration time compared with Example 1a made from internal lubrication. Typically, tablets that are harder have a longer disintegration time. However, the present invention allows for harder tablets to manufactured with no detriment to the disintegration time (i.e., better hardness yet still with a disintegration time less than approximately two minutes).

Most surprising is that tablets made with external lubrication have a dissolution profile that is less sensitive to the hardness of the tablet. FIG. 3 illustrates the dissolution profiles (using baskets at 100 rpm in 0.1 N HCI at 37°C) of tablets made using internal lubrication and having varying degrees of hardness. FIG 4. illustrates the dissolution profiles (using baskets at 100 rpm in 0.1 N HCI at 37°C )of exemplary tablets made using external lubrication and having varying degrees of hardness. It can be seen that the external lubrication tablets have a dissolution profile that is not sensitive to the hardness of the tablet. In contrast, those tablets with internal lubrication have dissolution profiles that are more sensitive to the hardness of the tablets. Thus, external lubrication is preferred. From a pharmaceutical processing perspective, a dissolution profile less sensitive to hardness results in a more robust pharmaceutical manufacturing process and product.

Claims

What is claimed:

1. A method of manufacturing a tablet having improved properties comprising the steps of:

applying an external lubricant to the contacting surfaces of a manufacturing apparatus; and

compacting a tableting material comprising a pharmacologically active agent and a delivery agent in the manufacturing apparatus; wherein the pharmacologically active agent is selected from the group consisting of a protein, a polypeptide, a hormone, a polysaccharide, a carbohydrate, a lipid and combination thereof.

2. The method of Claim 1 , wherein the delivery agent is selected from the group consisting of Λ/-(5-chlorosalicyloyl)-8-aminocaprylic acid (5-CNAC), Λ/-(10-[2- hydroxybenzoyl]amino)decanoic acid (SNAD), Λ/-(8-[2-hydroxybenzoyl]amino)caprylic acid (SNAC), a salt thereof and a combination thereof.

3. The method of Claim 1 , wherein the pharmacologically active agent is a calcitonin.

4. The method of Claim 1 , wherein the external lubricant is selected from the group consisting of magnesium stearate, calcium stearate, sodium fumarate, sodium lauryl sulfate, and mixtures thereof.

5. The method of Claim 4, wherein the external lubricant further comprises microcrystalline cellulose.

6. The method of Claim 1 , wherein the manufacturing equipment is a tablet press.

7. The method of Claim 1 , wherein the improved physical properties includes one of hardness, disintegration time or dissolution.

8. The method of Claim 1 , wherein the tableting material comprises no lubricant.

9. The method of Claim 8, wherein the external lubricant resides on the outer surface of the tablet.

10. The method of Claim 9, wherein the external lubricant is present in a concentration no greater than 0.5% by weight of the tablet.