(19)
(11)EP 2 968 578 B1

(12)EUROPEAN PATENT SPECIFICATION

(45)Mention of the grant of the patent:
26.06.2019 Bulletin 2019/26

(21)Application number: 14778989.5

(22)Date of filing:  12.03.2014
(51)International Patent Classification (IPC): 
A61K 47/02(2006.01)
A61K 47/32(2006.01)
C09D 139/06(2006.01)
A61K 9/20(2006.01)
A61J 3/10(2006.01)
A61K 31/522(2006.01)
C09J 139/06(2006.01)
(86)International application number:
PCT/US2014/024956
(87)International publication number:
WO 2014/165246 (09.10.2014 Gazette  2014/41)

(54)

COPROCESSED SILICA COATED POLYMER COMPOSITION

COVERARBEITETE SILICABESCHICHTETE POLYMERZUSAMMENSETZUNG

COMPOSITION DE POLYMÈRE REVÊTU DE SILICE CO-TRAITÉE


(84)Designated Contracting States:
AL AT BE BG CH CY CZ DE DK EE ES FI FR GB GR HR HU IE IS IT LI LT LU LV MC MK MT NL NO PL PT RO RS SE SI SK SM TR

(30)Priority: 12.03.2013 US 201361777604 P

(43)Date of publication of application:
20.01.2016 Bulletin 2016/03

(73)Proprietor: Hercules LLC
Wilmington, DE 19808 (US)

(72)Inventors:
  • TEWARI, Divya
    West Chester, Pennsylvania 19382 (US)
  • TITOVA, Yevgeniya A.
    Wilmington, Delaware 19808 (US)
  • BEISSNER, Brad
    Wilmington, Delaware 19808 (US)
  • DURIG, Thomas
    Chadds Ford, Pennsylvania 19317 (US)

(74)Representative: Kutzenberger Wolff & Partner 
Waidmarkt 11
50676 Köln
50676 Köln (DE)


(56)References cited: : 
WO-A1-2010/126828
WO-A2-2004/022601
US-A1- 2012 178 822
WO-A1-2011/133956
US-A1- 2001 001 664
  
  • CAMILA BRAGA DORNELAS ET AL: "Preparation and Evaluation of a New Nano Pharmaceutical Excipients and drug Delivery System Based in Polyvinylpyrrolidone and Silicates", JOURNAL OF PHARMACY AND PHARMACEUTICAL SCIENCES, vol. 14, no. 1, 29 March 2011 (2011-03-29) , pages 17-35, XP55300737, CA ISSN: 1482-1826, DOI: 10.18433/J3HC72
  • Dr M C Gohel ET AL: "Corresponding Author: A review of co-processed directly compressible excipients", J Pharm Pharmaceut Sci (www.cspscanada.org), 1 January 2005 (2005-01-01), pages 76-93, XP55109525, Retrieved from the Internet: URL:http://www.ualberta.ca/~csps/JPPS8(1)/ P.Jogani/excipients.pdf [retrieved on 2014-03-24]
  • Laila J. Jallo ET AL: "Improvement of flow and bulk density of pharmaceutical powders using surface modification", INTERNATIONAL JOURNAL OF PHARMACEUTICS, vol. 423, no. 2, 1 February 2012 (2012-02-01), pages 213-225, XP55404560, AMSTERDAM, NL ISSN: 0378-5173, DOI: 10.1016/j.ijpharm.2011.12.012
  
Note: Within nine months from the publication of the mention of the grant of the European patent, any person may give notice to the European Patent Office of opposition to the European patent granted. Notice of opposition shall be filed in a written reasoned statement. It shall not be deemed to have been filed until the opposition fee has been paid. (Art. 99(1) European Patent Convention).


Description

FIELD OF THE INVENTION



[0001] The present invention relates to a coprocessed excipient composition and to a method of producing the same. The present invention particularly relates to a coprocessed excipient comprising vinyl lactam derived polymer and a deagglomerated coprocessing agent.

BACKGROUND OF THE INVENTION



[0002] Excipient powders frequently exhibit poor flow and compaction behavior. Various techniques such as wet granulation, spray drying, mechanofusion, and grinding have been employed to improve the flow and compaction behavior.

[0003] U.S. Patent No. 4,734,285 assigned to Dow Chemical Company discloses delayed release solid tablets of a therapeutically active composition and a process to prepare such a composition. Fine particles, which can pass through a 100 mesh screen (149 micrometer mesh size) and preferably 140 mesh screen (105 micrometer mesh size), of hydroxypropyl methylcellulose ether are present as an excipient in the tablet composition. These fine particles are very small in size and shows poor flow properties. Poor particle flow can lead to consolidation of the powder bed in processing equipment, such as storage bins and tablet press feed hoppers. Problems can include increased inconsistency in tablet weight or tablet crushing strength from tablet-to-tablet as well as inconsistency in the amount of active ingredient incorporated into each dosage form.

[0004] WO2004/022601 assigned to JRS Pharma LP and U.S. Patent No. 5,585,115 assigned to Edward H. Mendell Co., Inc. disclose an agglomerated microcrystalline cellulose blend containing silicon dioxide, purported to have improved compressibility. The disclosure states that silicon dioxide is a critical component to improve compressibility. The two step process described includes spray granulation followed by wet granulation. The prepared granules in this process are further dried using heat, which is not advantageous. However, granulation is a time consuming and adds cost to the process, due to the time lost, additional labor, energy consumption and additional equipment required.

[0005] Several processes for drying-grinding moist cellulose derivatives are known in the art, such as described in the patent applications GB 2262527A; EP 0 824 107 A2; EP-B 0 370 447 (equivalent to U.S. Patent No. 4,979,681); EP 1 127 895 A1 (equivalent to U.S. Patent No. 6,509,461); EP 0 954 536 A1 (equivalent to U.S. Patent No. 6,320,043); WO96/00748 A1; WO2011/046679 (equivalent to US 2012/187225) and WO2012/138532.

[0006] US2012/160944A1 assigned to ICEUTICA PTY LTD discloses a method to produce nano and micro-particle powders of a biologically active material which have improved powder handling properties using dry milling process.

[0007] WO2012/116402A1 assigned to University of Monash discloses binder powders for use in powder material processing and processes for their preparation by using techniques such as spray drying and mechanofusion. These processes lead to reduction in particle size of the polymer. Moreover, these processes are costly and time consuming.

[0008] US2012/0178822A assigned to ISP INVESTMENTS INC discloses coprocessing of PVP and calcium silicate by using ball milling, spray drying or freeze drying.

[0009] The increase in flow of cellulose polymers by co-milling microcrystalline cellulose with nano-silica is described in J. Pharm. Sci. 2011 Nov; 100(11):4943-52, Chattoraj S, Shi L, Sun CC.

[0010] Moreover, spray drying, mechanofusion, magnetic assisted impaction, hybridizer, and grinding require specialized instruments that are commonly not available at manufacturing units.

[0011] Surprisingly, it has been found that bulk density and flowability of vinyl lactam derived polymers can be increased by a novel continuous process comprising coprocessing the polymer and a coprocessing agent using high shear.

[0012] Thus, the present invention relates to a coprocessed excipient composition comprising vinyl lactam derived polymer and a deagglomerated coprocessing agent. The coprocessed excipient is prepared in a continuous process and has excellent compactability and improved flow property as measured by Johanson flow rate number increase from 1.1 to 5.0 fold, is characterized by a Brookfield cohesion of less than 0.12 kPa and a bulk density of at least 0.249 g/ml. The coprocessing agent is fumed silica, colloidal silica, silicon dioxide, calcium silicate or a combination thereof.

SUMMARY OF THE INVENTION



[0013] The present invention provides a coprocessed excipient comprising vinyl lactam derived polymer or a blend and a deagglomerated coprocessing agent according to the claims. The coprocessed excipient is prepared in a continuous process and has a Brookfield cohesion of less than 0.12 kPa and a bulk density of at least 0.249 gram/milliliter and a flow property as measured by Johanson flow rate number increase from 1.1 to 5.0 fold.

[0014] The vinyl lactam derived polymer used in the present invention is selected from the group comprising N-vinyl-2-pyrrolidone, poly(vinyl pyrrolidone), polyvinyl poly pyrrolidone, N-vinyl-2-caprolactam, N-vinyl-3-methyl-2-pyrrolidone, N-vinyl-3-methyl-2-caprolactam, N-vinyl-4-methyl-2-pyrrolidone, N-vinyl-4-methyl-2-caprolactam, N-vinyl-5-methyl-2-pyrrolidone, N-vinyl-5,5-dimethyl-2-pyrrolidone, N-vinyl-3,3,5-trimethyl-2-pyrrolidone, N-vinyl-5-methyl-5-ethyl-2-pyrrolidone, N-vinyl-3,4,5-trimethyl-3-ethyl-2-pyrrolidone, N-vinyl-7-methyl-2-caprolactam, N-vinyl-7-ethyl-2-caprolactam, N-vinyl-3,5-dimethyl-2-caprolactam, N-vinyl-4,6-dimethyl-2-caprolactam, N-vinyl-3,5,7-trimethyl-2-caprolactam, and/or combinations thereof.

[0015] The coprocessing agent is selected from fumed silica, colloidal silica, silicon dioxide, calcium silicate or a combination thereof.

[0016] The lactam derived polymer is present in an amount of about 90.0% to about 99.9%. The coprocessing agent is present in an amount of about 0.1% w/w to about 10.0% w/w of the total coprocessed excipient composition.

[0017] In one of the particular embodiment, the weight ratio of the lactam derived polymer to coprocessing agent is about 90:10, 95:5, 98:2, 99:1 or even 99.9 to 0.1.

[0018] The coprocessed excipient of the present invention is further combined with an active or functional ingredient selected from paints and coatings, personal care, detergents, pharmaceuticals, neutraceuticals, ceramics, insulators, pet food, animal food and human food, agricultural products, adhesives, electroplating, inks, dyes, paper, catalytic convertors and electronics.

[0019] Yet another aspect of the present invention provides a process to prepare coprocessed excipient comprising the steps of:
  1. i. deagglomerating coprocessing agent using shear in magnitude of at least 0.01kW-hr/kg;
  2. ii. passing the lactam derived polymer blend thereof and deagglomerated coprocessing agent through a blender with an average particle residence time of >1 second;
  3. iii. subjecting the above two components to pass through a universal mill;
  4. iv. maintaining an average particle residence time within the universal mill system to be >1 seconds completed by a continuous recycle process; and
  5. v. obtaining the coprocessed excipient having a Brookfield cohesion of less than 0.12 kPa, a bulk density of at least 0.249 gram/milliliter and a flow property as measured by Johanson flow rate number increased from 1.1 to 5.0 fold.


[0020] In a preferred embodiment, the universal mill consists of a rotor with tip speed for about 15 meters/second to about 150 meters/second and screen size of about 0.2 millimeter to about 0.9 millimeter.

[0021] The composition can be used in various industrial applications including paints and coatings, personal care, detergents, pharmaceuticals, neutraceuticals, ceramics, insulators, pet food, animal food and human food, agricultural products, adhesives, electroplating, inks, dyes, paper, catalytic convertors and electronics.

[0022] In a preferred embodiment, the composition is used in pharmaceuticals.

[0023] In a preferred embodiment, the composition is formulated into an oral dosage form, such as a tablet, by dry granulation, direct compression or hot melt extrusion processing.

[0024] The present invention provides a directly compressible pharmaceutical composition compising an active pharmaceutical ingredient and coprocessed excipient.

[0025] Yet another aspect of the present invention provides a direct compression process comprising the steps of
  1. i) blending an active pharmaceutical ingredient, the above-described coprocessed excipient, and optionally one or more pharmaceutically acceptable adjuvants to produce a blend with improved flow property and
  2. ii) compressing the resulting composition to get a product with improved drug content uniformity and improved compactability.


[0026] In a preferred embodiment, the directly compressible pharmaceutical composition is formulated into modified release, controlled release, sustained release, immediate release, extended release dosage forms.

[0027] The present invention provides a process to prepare a directly compressible pharmaceutical composition comprising blending the active pharmaceutical ingredient, the coprocessed excipient having a Brookfield cohesion of less than 0.12 kPa, a bulk density of at least 0.249 grain/milliliter and a flow property as measured by Johanson flow rate number increased from 1.1 to 5.0 fold, and optionally one or more adjuvants and compressing the resulting components to obtain directly compressible pharmaceutical composition.

BRIEF DESCRIPTION OF THE DRAWING



[0028] 

FIG 1 represents a diagram of a universal mill and its various parts

FIG 2 represents a diagram of a STYLCAM 200R, a single-punch rotary tablet press

FIG 3 represents enhanced flow as a result of low Interparticle Brookfield Cohesion


DETAILED DESCRIPTION OF THE INVENTION



[0029] Typical polymers used for the direct compression formulations have a fibrous nature. small particle size, strong inter-particle cohesion and surface charge, which lead to a poor flow in pharmaceutical unit process. Formulators often have to use a granulation step to overcome these challenges to powder flow. The powder flow is affected by gravitational forces (influenced by bulk density) and the interparticle cohesion and a balance is needed between the two to improve the flow (as shown in Figure 3). Not to be bound by any theories, the inventors of the present invention discovered the increased flowability is observed when an additive is coprocessed with the polymeric powder whose flowability is to be increased. Enhanced flow rate of almost 5 fold was achieved as a result of very low interparticle cohesion and higher bulk density.

[0030] There are several advantages for using the coprocessed excipient of the present invention: (i) reduced processing time and production costs, no additional capital investment is necessary for adopting this flow-improvement technique; (ii) improved powder flow; (iii) improved content uniformity (iv) dissolution profiles comparable with other commercial polymeric grade available in the market; (v) the present process is fast, continuous, and scalable. Hence, it can be readily adopted during both development and manufacturing of pharmaceutical products.

[0031] Throughout this specification and the claims which follow, unless the context requires otherwise, the word "comprise" and variations such as "comprises" and "comprising", will be understood to imply the inclusion of a stated integer or step or group or integers or steps but not the exclusion of any other integer or step or group or integers or steps.

[0032] The singular forms "a", "an" and "the" include plural aspects unless the context clearly dictates otherwise.

[0033] All aspects, embodiments and examples described herein are encompassed by the term "invention".

[0034] As used herein, the term "m/sec" refers to the units of rotor speed in meters per second.

[0035] As used herein, the term "mm" refers to the units of mesh size in millimeters.

[0036] As used herein, the term "bulk density" refers to Bulk density (BD) is defined as the ratio of apparent volume to mass of the material taken, called untapped bulk density, and also the ratio of tapped volume to mass of material taken, called tapped bulk density. A useful procedure for measuring these bulk densities is described in United States Pharmacopeia 24. Test 616 "Bulk Density and Tapped Density," United States Pharmacopeia Convention, Inc., Rockville, Maryland, 1999.

[0037] As used herein, the term "Flow Rate Indicizer" refers to an instrument manufactured by Johanson that was used to characterize properties such as FRI (flow rate index), FDI (Flow density index), BDI (Bin density index), and SBI (Spring back index).

[0038] As used herein, the term "Johanson flow rate number" refers to Flow Rate Index (FRI), which is a measure of a powder's limiting flow rate through a container after deaeration. The negative direction for the FRI is a decrease. The FRI is also useful for correlating particle sizes and size distribution if the mean particle size remains constant. A lower FRI indicates a smaller particle size or a wider size distribution if the mean size remains unchanged.

[0039] As used herein, the term "deagglomeration" refers to a process of breaking up or dispersing that which has agglomerated, aggregated, or clustered together.

[0040] The term "coprocessed excipient composition" as used herein, refers to a coprocessed excipient that is a combination of two or more compendial or non-compendial excipients designed to physically modify their properties in a manner not achievable by simple physical mixing and without significant chemical change.

[0041] As used herein, the term "Universal Mill" refers to a high speed fine impact mill for the dry grinding or deagglomerating of various products. In particular the mill is utilized as a rotor impact mill, which is characterized by an impact process between the rotor and a stator (such as a screen). Material and air enter the mill and are subject to centrifugal forces from the rotor; subsequently the impact beater forces the material through the milling gap provided by the stator (grinding track and screen). Various configurations of the rotor/impact beater include the wing beater and blast rotor.

[0042] As used herein, the term "Blender" refers to a continuous single or double helix ribbon blender with a residence time of at least one second; or a blender with similar capability that allows for mixing in a continuous process, a residence time of at least one second, and shaft speed of 10-30 rotations per minute.

[0043] The term "Brookfield Cohesion" as used herein, refers to failure strength measured at an applied compression force in time consolidation test of Brookfield powder flow tester (ASTM D6128). In preferred embodiments, the Brookfield cohesion of the composition of this invention is less than 0.10 kPa and more preferably less than 0.08 kPa.

[0044] The term "compaction" as used herein, is a simultaneous process of compression and consolidation of a two phase system (solid-air) due to the applied force.

[0045] As used herein, the term "Direct compression" or "DC" refers to obtaining a formulation by directly compressing and molding a raw material powder. This process is described in publications such as The Theory and Practice of Industrial Pharmacy (Third Edition) (Leon Lachman, et al.: LEA & FEBIGER 1986) and Pharmaceutical Dosage Forms: Tablets Volume 1 (Second Edition) (Herbert A. Lieberman, et al.: MARCEL DEKKER INC. 1989).

[0046] As used herein, the term "continuous process" refers to production that is not executed batch wise but steadily, such as production on a continuous blend. In non-continuous processes, i.e, batch production processes, insertion of the raw materials into the machine/mill and subsequent unloading of the newly produced composition from the machine/mill occupies too much time to make low-cost production possible. The significance of the term "continuous production" here is the implication of the advantages gained by an assembly line with each step characterized by an average residence time.

[0047] The present invention provides a coprocessed excipient comprising a vinyl lactam derived polymer or a blend and a deagglomerated coprocessing agent.

[0048] The coprocessed excipient is prepared in a continuous process and has a bulk density of at least 0.249 gram/milliliter and improved flow property as measured by Johanson flow rate number increased from 1.1 to 5.0 fold. The coprocessing agent is fumed silica, colloidal silica, silicon dioxide, calcium silicate or a combination thereof.

[0049] Vinyl lactam derived polymers useful in the practice of the present invention are selected from the group comprising N-vinyl-2-pyrrolidone, poly(vinyl pyrrolidone)(PVP), polyvinyl poly pyrrolidone (PVPP), N-vinyl-2-caprolactam, N-vinyl-3-methyl-2-pyrrolidone, N-vinyl-3-methyl-2-caprolactam, N-vinyl-4-methyl-2-pyrrolidone, N-vinyl-4-methyl-2-caprolactam, N-vinyl-5-methyl-2-pyrrolidone, N-vinyl-5,5-dimethyl-2-pyrrolidone, N-vinyl-3,3,5-trimethyl-2-pyrrolidone, N-vinyl-5-methyl-5-ethyl-2-pyrrolidone, N-vinyl-3,4,5-trimethyl-3-ethyl-2-pyrrolidone, N-vinyl-7-methyl-2-caprolactam, N-vinyl-7-ethyl-2-caprolactam, N-vinyl-3,5-dimethyl-2-caprolactam, N-vinyl-4,6-dimethyl-2-caprolactam, N-vinyl-3,5,7-trimethyl-2-caprolactam, and/or combinations thereof.

[0050] The tenn "Polyvinyl pyrrolidone (PVP)" as used herein, including the claims, refers to a polymer available in different pharmaceutical grades. A particularly preferred source of polyvinyl pyrrolidone is Ashland Specialty Ingredients (Wilmington, Delaware), which markets "PVP" under the trade name of Plasdone™ Povidone.

[0051] The terms "Polyvinyl polypyrrolidone" or "Crospovidone" as used herein, including the claims, refers to a polymer available in different pharmaceutical grades. A particularly preferred source of crosslinked polyvinyl pyrrolidone is Ashland Specialty Ingredients (Wilmington, Delaware), which markets "PVPP" under the trade name of Polyplasdone XL®, Polyplasdone XL-10®, Polyplasdone INF-10, Polyplasdone ultra, and Polyplasdone ultra 10.

[0052] The silica useful in the practice of the present invention is selected from the group comprising fumed silica, colloidal silica, silicon dioxide, calcium silicate and/or combinations thereof.

[0053] Silica useful in the practice of the present invention is silicon dioxide, particularly colloidal silicon dioxide that has particles size particularly less than 500nm, more particularly less than 400nm. Those skilled in the art will appreciate that the name and/or method of preparation of the silicon dioxide utilized in the present invention is not determinative of the usefulness of the product. Rather, it has been surprisingly discovered that it is the physical characteristics of the silicon dioxide which are critical. In particular, it has been discovered that silicon dioxide having a relatively large particle size (and correspondingly small surface area), such as silica gel, is not useful in the current invention. Silica itself is a submicron, fluffy, light, loose, bluish-white, odorless and tasteless amorphous powder which is commercially available from a number of sources, including Cabot Corporation (under the tradename Cab-O-Sil); Degussa, Inc. (under the tradename Aerosil®); E.I. DuPont & Co.; and W.R. Grace & Co. Colloidal silicon dioxide is also known as colloidal silica, fumed silica, amorphous fumed silica, silicon dioxide, amorphous silica, light anhydrous silicic acid, silicic anhydride, and silicon dioxide fumed, among others. However, the amount of silicon dioxide included in pharmaceutical applications is limited and it is in the range of 0.01-1% by weight. Handbook of Pharmaceutical Excipients. COPYRGT.1986 American Pharmaceutical Association, page 255.

[0054] In further embodiments, the lactam derived polymer is present in an amount of about 90.0% to about 99.9% and coprocessing agent is present in an amount of about 0.1% w/w to about 10.0% w/w or the total coprocessed excipient composition.

[0055] In one particular embodiment, the weight ratio of the lactam derived polymer to coprocessing agent is about 90:10, 95:5, 98:2, 99:1 or even 99.9 to 0.1. Alternatively, the amount coprocessing agent may be expressed as wt/wt%, of the lactam derived polymer, for example, 0.1%, 0.25%, 0.5%, 0.75 %, 1.0 %, 2.5%, 5 %, or 10%.

[0056] The present coprocessed excipient can be further combined with an active or functional ingredient selected from paints and coatings, personal care, detergents, pharmaceuticals, neutraceuticals, ceramics, insulators, pet food, animal food and human food, agricultural products, adhesives, electroplating, inks, dyes, paper, catalytic convertors and electronics.

[0057] The present invention provides a continuous process to prepare coprocessed excipient comprising the steps of
  1. i. deagglomerating coprocessing agent using shear in magnitude of at least 0.01kW-hr/kg;
  2. ii. passing a lactam derived polymer and deagglomerated coprocessing agent through a blender with an average particle residence time of >1 second:
  3. iii. subjecting the above two components to pass through a universal mill;
  4. iv. maintaining an average particle residence time within the universal mill system to be >1 seconds completed by a continuous recycle process; and
  5. v. obtaining the coprocessed excipient having a Brookfield cohesion of less than 0.12 kPa, a bulk density of at least 0.249 gram/milliliter and a flow property as measured by Johanson flow rate number increased from 1.1 to 5.0 fold.


[0058] In further embodiments, the universal mill consists of a rotor with tip speed for about 15 meters/second to about 150 meters/second and screen size of about 0.2 millimeter to about 0.9 millimeter

[0059] The present invention provides a direct compressible pharmaceutical composition comprising an active pharmaceutical ingredient, which is not more than 1.0% of the coprocessed excipient and optionally one or more pharmaceutically acceptable additives. The direct compression process comprising the steps of
  1. i. blending the active pharmaceutical ingredient, the coprocessed excipient having a Brookfield cohesion of less than 0.12 kPa, a bulk density of at least 0.249 gram/milliliter and a flow property as measured by Johanson flow rate number increase from 1.1 to 5.0 fold, and optionally one or more adjuvants without adding a substantial amount of added solvent or heat; and
  2. ii. compressing the resulting components to obtain directly compressible pharmaceutical composition.


[0060] The present invention provides a direct compressible pharmaceutical composition comprising an active pharmaceutical ingredient, the above-described coprocessed excipient and optionally one or more pharmaceutically acceptable additives.

[0061] The present invention provides a direct compression process comprising the steps of,
  1. i. blending the active pharmaceutical ingredient, the coprocessed excipient having a Brookfield cohesion of less than 0.12 kPa bulk density of at least 0.249 gram/milliliter and improved flow property as measured by Johanson flow rate from about 1.1 to about 5.0 fold, and optionally one or more adjuvants without adding a substantial amount of added solvent or heat; and
  2. ii. compressing the resulting components to obtain directly compressible pharmaceutical composition.


[0062] The following examples further illustrate the invention.

Example 1: Coprocessing of Polyvinyl pyrrolidone ("Plasdone" or "PVP") and deagglomerated silica (Cab-O-Sil).



[0063] The coprocessing performed by co-milling powdered polyvinyl pyrrolidone (Grade: Plasdone) with silica. The silica-coating of the polyvinyl pyrrolidone (Plasdone) was accomplished by geometric dilution of the powdered polymer with silica by sieving and then passing through a blender and then through a universal mill, which is fitted with a blunt impeller. The steps include deagglomeration of silica powder and subsequently at least with a partial coating of silica on the powdered polymer. The speed of the impeller was 3000 rpm and screen size was 0.5mm and mesh size is 35 with 0.0075 inches during the process.

Example 2: Coprocessing of crosslinked Polyvinyl pyrrolidone ("Crospovidone") and Silica.



[0064] The same process described in Example 1 was repeated with crosslinked polyvinyl pyrrolidone ("PVPP") and silica by replacing the mesh size to 50.

Example 3: Flow characterization measurement of polymers by using Johanson Flow Rate Indicizer



[0065] All components of the test cell and machine pistons were cleaned. Air connections and air pressure were checked and the air pressure was kept at 25psi. Weight of the empty test cell was measured and recorded. Crosslinked polyvinyl pyrrolidone sample was fluffed up to break-up lumps and to bring material to minimum bulk density. The sample was loaded and it was distributed evenly by using a spoon. The sample was filled just above the top of the rim. The cell was held at 90° angle and excess material was skimmed off. Weight of the sample with polymer was measured. Similarly measurements for other polymers were also measured. All the measurements of sample were listed in Table 2 (Model Best-Nr: JR FLW; Serial-Nr: FLW 33S)

Example 4: Flow characterization measurement of silica coated polymers by using Johanson Flow Rate Indicizer



[0066] The same process which was described in Example 3 was repeated by replacing the polymer sample with silica coated polymer sample. All the measurements of sample were listed in Table 2.
Table 2: Flow and Cohesion characteristics of samples
ExcipientProcessing conditionsFlow Characterization (Johanson Flow Rate Index(lb/min)Brookfield Cohesion Coefficient (kPa)
RPM(Rotations per minute)Screen size
Plasdone control 221 0.221
Plasdone DC 3000 0.5 276 0.061
Crospovidone control 97 0.186
CrospovidoneDC 3000 0.3 186 0.111

Example 5: Pharmaceutical Tablet Preparation.



[0067] A pharmaceutical tablet was prepared using standard Plasdone™, and Plasdom™ DC. The tablet formula was:
Table 4: Tablet Composition
Tablet CompositionAddition level (%)
StandardInvention
Plasdone® Plasdone® DC 50
Theophyline 25
Fastflo® Lactose 24.5
Magnesium stearate 0.5
Total 100


[0068] Hardness of the tablet formulations comprising standard Plasdone® and Plasdone® DC was measured and found to be at least 20 N.

[0069] The compatibility of tablets containing the compressed excipient of this invention can he at least 20 N over tablets with comparable quantities of the same incorporated excipients.

[0070] The present invention also provides applications of the coprocessed excipient in paints and coatings, personal care, detergents, pharmaceuticals, neutraceuticals, pet food, animal food, agricultural products, adhesives, electroplating, inks, dyes, paper, catalytic convertors, ceramics, insulators, and electronics.


Claims

1. A continuous process for preparing a coprocessed excipient comprising the steps of:

i. deagglomerating coprocessing agent using shear in magnitude of at least 0.01 kW-hour/kilogram; wherein the coprocessing agent is selected from fumed silica, colloidal silica, silicon dioxide, calcium silicate and combinations thereof;

ii. passing a lactam derived polymer and the deagglomerated coprocessing agent through a blender with an average particle residence time of >1 second; wherein the vinyl lactam derived polymer is selected from the group consisting of N-vinyl-2-pyrrolidone, poly(vinyl pyrrolidone), polyvinyl poly pyrrolidone, N-vinyl-2-caprolactam, N-vinyl-3-methyl-2-pyrrolidone, N-vinyl-3-methyl-2-caprolactam, N-vinyl-4-methyl-2-pyrrolidone, N-vinyl-4-methyl-2-capro-lactam, N-vinyl-5-methyl-2-pyrrolidone, N-vinyl-5,5-dimethyl-2-pyrrolidone, N-vinyl-3,3,5-trimethyl-2-pyrrolidone, N-vinyl-5-methyl-5-ethyl-2-pyrrolidone, N-vinyl-3,4,5-trimethyl-3-ethyl-2-pyrrolidone, N-vinyl-7-methyl-2-caprolactam, N-vinyl-7-ethyl-2-caprolactam, N-vinyl-3,5-dimethyl-2-caprolactam, N-vinyl-4,6-dimethyl-2-caprolactam, N-vinyl-3,5,7-trimethyl-2-caprolactam, and combinations thereof;

iii. subjecting the above two components to pass through a universal mill; preferably wherein the universal mill consists of a rotor with tip speed of 15 meters/second to 150 meters/second and screen size of 0.2 millimeter to 0.9 millimeter;

iv. maintaining an average particle residence time within the universal mill system to be >1 seconds completed by a continuous recycle process; and

v. obtaining the coprocessed excipient having a Brookfield cohesion of less than 0.12 kPa, a bulk density of at least 0.249 gram/milliliter and a flow property as measured by Johanson flow rate number increase from 1.1 to 5.0 fold.


 
2. A coprocessed excipient obtainable by the process according to claim 1.
 
3. The coprocessed excipient of claim 2, wherein said lactam derived polymer is present in an amount of 90.0% to 99.9% and coprocessing agent is present in an amount of 0.1% w/w to 10.0% w/w of the total coprocessed excipient composition.
 
4. The coprocessed excipient of claim 2, wherein said lactam derived polymer and coprocessing agent is present in a ratio from 90:10 to 99.9 to 0.1.
 
5. The coprocessed excipient of claim 2, wherein said coprocessed excipient is further combined with an active or functional ingredient selected from paints and coatings, personal care, detergents, pharmaceuticals, neutraceuticals, ceramics, insulators, pet food, animal food, and human food, agricultural products, adhesives, electroplating, inks, dyes, paper, catalytic converters and electronics.
 
6. A composition comprising the coprocessed excipient of claim 2 for use in an industrial application selected from paints and coatings, personal care, detergents, pharmaceuticals, neutraceuticals, ceramics, insulators, pet food, animal food and human food, agricultural products, adhesives, electroplating, inks, dyes, paper, catalytic convertors and electronics.
 
7. The composition of claim 6, wherein said composition is used in pharmaceuticals.
 
8. The composition of claim 7, wherein said composition is formulated into an oral dosage form by dry granulation, direct compression, or hot melt extrusion processing.
 
9. A directly compressible pharmaceutical composition comprising:

i. an active pharmaceutical ingredient;

ii. the coprocessed excipient of claim 2; and

iii. optionally one or more pharmaceutically acceptable additives.


 
10. The directly compressible pharmaceutical composition of claim 9, wherein said composition is formulated into modified release, controlled release, sustained release, extended release dosage forms or immediate release and soluble dosage form.
 
11. The directly compressible pharmaceutical composition of claim 9, wherein the compactability of the tablet containing coprocessed excipient is at least 20 N over tablets made with the same uncoprocessed excipients.
 
12. A process of preparing the directly the compressible pharmaceutical composition of claim 11, comprising the steps of:

i. blending the active pharmaceutical ingredient, the coprocessed excipient of claim 2, and optionally one or more adjuvants, and

ii. compressing the resulting components to obtain directly compressible pharmaceutical composition.


 


Ansprüche

1. Ein kontinuierliches Verfahren zur Herstellung eines koprozessierten Hilfsstoffs, umfassend die Schritte:

i. Deagglomerieren eines Koprozessmittels unter Verwendung von Scherung in einer Größenordnung von mindestens 0,01 kWh/Kilogramm; wobei das Koprozessmittel ausgewählt wird aus pyrogener Kieselsäure, kolloidaler Kieselsäure, Siliciumdioxid, Calciumsilikat und deren Kombinationen;

ii. Durchleiten eines von Lactam-abgeleiteten Polymers und des deagglomerierten Koprozessmittels durch einen Mischer mit einer durchschnittlichen Teilchenverweilzeit von >1 Sekunde; wobei das von Vinyllactam-abgeleitete Polymer ausgewählt wird aus der Gruppe bestehend aus N-Vinyl-2-pyrrolidon, Polyvinylpyrrolidon, Polyvinylpolypyrrolidon, N-Vinyl-2-caprolactam, N-Vinyl-3-methyl-2-pyrrolidon, N-Vinyl-3-methyl-2-caprolactam, N-Vinyl-4-methyl-2-pyrrolidon, N-Vinyl-4-methyl-2-caprolactam, N-Vinyl-5-methyl-2-pyrrolidon, N-Vinyl-5,5-dimethyl-2-pyrrolidon, N-Vinyl-3,3,5-trimethyl-2-pyrrolidon, N-Vinyl-5-methyl-5-ethyl-2-pyrrolidon, N-Vinyl-3,4,5-trimethyl-3-ethyl-2-pyrrolidon, N-Vinyl-7-methyl-2-caprolactam, N-Vinyl-7-ethyl-2-caprolactam, N-Vinyl-3,5-dimethyl-2-caprolactam, N-Vinyl-4,6-dimethyl-2-caprolactam, N-Vinyl-3,5,7-trimethyl-2-caprolactam und deren Kombinationen;

iii. Aussetzen der beiden zuvor genannten Komponenten, um durch eine Universalmühle geleitet zu werden; wobei bevorzugt die Universalmühle aus einem Rotor mit einer Spitzengeschwindigkeit von 15 Metern/Sekunde bis 150 Metern/Sekunde und einer Siebgröße von 0,2 Millimeter bis 0,9 Millimeter besteht;

iv. Aufrechterhalten einer durchschnittlichen Teilchenverweilzeit innerhalb des Universalmühlsystems von >1 Sekunde, das durch einen kontinuierlichen Recyclingprozess vervollständigt wird; und

v. Erhalten des koprozessierten Hilfsstoffs mit einer Brookfield-Kohäsion von weniger als 0,12 kPa, einer Schüttdichte von mindestens 0,249 Gramm/Milliliter und einer Fließeigenschaft, gemessen durch die Johanson-Fließratenzahl, die um das 1,1- bis 5,0-fache erhöht ist.


 
2. Ein koprozessierter Hilfsstoff, der durch das Verfahren gemäß Anspruch 1 erhalten wird.
 
3. Der koprozessierte Hilfsstoff gemäß Anspruch 2, wobei das von Lactam-abgeleitete Polymer in einer Menge von 90,0% bis 99,9% und das Koprozessmittel in einer Menge von 0,1 Gew.-% bis 10,0 Gew.-% der gesamten koprozessierten Hilfsstoffzusammensetzung vorhanden ist.
 
4. Der koprozessierte Hilfsstoff gemäß Anspruch 2, wobei das von Lactam-abgeleitete Polymer und das Koprozessmittel in einem Verhältnis von 90:10 zu 99,9 bis 0,1 vorliegen.
 
5. Der koprozessierte Hilfsstoff gemäß Anspruch 2, wobei der koprozessierte Hilfsstoff ferner mit einem aktiven oder funktionalen Inhaltsstoff ausgewählt aus Farben und Beschichtungen, Körperpflegemitteln, Reinigungsmitteln, Pharmazeutika, Neutrazeutika, Keramiken, Isolatoren, Heimtiernahrung, Tiernahrung und menschlicher Nahrung, landwirtschaftlichen Produkten, Klebstoffen, Galvanik, Tinten, Farbstoffen, Papier, Katalysatoren und Elektronik kombiniert wird.
 
6. Eine Zusammensetzung umfassend den koprozessierten Hilfsstoff gemäß Anspruch 2 zur Verwendung in einer industriellen Anwendung ausgewählt aus Farben und Beschichtungen, Körperpflegemitteln, Reinigungsmitteln, Pharmazeutika, Neutrazeutika, Keramiken, Isolatoren, Heimtiernahrung, Tiernahrung und menschlicher Nahrung, landwirtschaftlichen Produkten, Klebstoffen, Galvanik, Tinten, Farbstoffen, Papier, Katalysatoren und Elektronik.
 
7. Die Zusammensetzung nach Anspruch 6, wobei die Zusammensetzung in Pharmazeutika verwendet wird.
 
8. Die Zusammensetzung gemäß Anspruch 7, wobei die Zusammensetzung in eine orale Darreichungsform durch Trockengranulation, Direktverdichtung oder Schmelzextrusionsverfahren formuliert wird.
 
9. Eine direkt komprimierbare pharmazeutische Zusammensetzung umfassend:

i. einen aktiven pharmazeutischen Inhaltsstoff;

ii. den koprozessierten Hilfsstoff nach Anspruch 2; und

iii. gegebenenfalls ein oder mehrere pharmazeutisch verträgliche Zusatzstoffe.


 
10. Die direkt komprimierbare pharmazeutische Zusammensetzung gemäß Anspruch 9, wobei die Zusammensetzung in eine Dosierungsform mit modifizierter Freisetzung, mit kontrollierter Freisetzung, mit verzögerter Freisetzung, mit verlängerter Freisetzung oder mit sofortiger Freisetzung und lösliche Dosierungsformen formuliert wird.
 
11. Die direkt komprimierbare pharmazeutische Zusammensetzung gemäß Anspruch 9, wobei die Kompaktierbarkeit der Tablette, die einen koprozessierten Hilfsstoff enthält, wenigstens 20 N über Tabletten liegt, die mit den gleichen nicht-koprozessierten Hilfsstoffen hergestellt wurden.
 
12. Ein Verfahren zur Herstellung der direkt komprimierbaren pharmazeutischen Zusammensetzung nach Anspruch 11, umfassend die Schritte:

i. Mischen des aktiven pharmazeutischen Inhaltsstoffs, des koprozessierten Hilfsstoffs gemäß Anspruch 2 und gegebenenfalls eines oder mehrerer Hilfsstoffe, und

ii. Verdichten der resultierenden Komponenten, um eine direkt komprimierbare pharmazeutische Zusammensetzung zu erhalten.


 


Revendications

1. Procédé continu de préparation d'un excipient cotraité comprenant les étapes de :

i. désagglomération d'un agent de cotraitement en utilisant un cisaillement ayant une amplitude d'au moins 0,01 kW-heure/kilogramme ; dans lequel l'agent de cotraitement est choisi parmi la silice pyrogénée, la silice colloïdale, le dioxyde de silicium, le silicate de silicium et des combinaisons de ceux-ci ;

ii. Passage d'un polymère dérivé de lactame et de l'agent de cotraitement désaggloméré à travers un mélangeur avec un temps de séjour de particule moyen > 1 seconde ; dans lequel le polymère dérivé de vinyllactame est choisi dans le groupe constitué des N vinyl-2-pyrrolidone, poly(vinylpyrrolidone), polyvinyl-polypyrrolidone, N-vinyl-2-caprolactame, N-vinnyl-3-méthyl-2-pyrrolidone, N-vinyl-3-méthyl-2-caprolactame, N-vinyl-4-méthyl-2-pyrrolidone, N-vinyl-4-méthyl-2-caprolactame, N-vinyl-5-méthyl-2-pyrrolidone, N-vinyl-5,5-diméthyl-2-pyrrolidone, N-vinyl-3,3,5-triméthyl-2-pyrrolidone, N-vinyl-5-méthyl-5-éthyl-2-pyrrolidone, N-vinyl-3,4,5-triméthyl-3-éthyl-2-pyrrolidone, N-vinyl-7-méthyl-2-caprolactame, N-vinyl-7-éthyl-2-caprolactame, N-vinyl-3,5-diméthyl-2-caprolactame, N-vinyl-4,6-diméthyl-2-caprolactame, N-vinyl-3,5,7-triméthyl-2-caprolactame, et des combinaisons de ceux-ci ;

iii. passage des deux composants ci-dessus à travers un broyeur universel ; le broyeur universel étant, de préférence, constitué d'un rotor ayant une vitesse d'extrémité de 15 mètres/seconde à 150 mètres/seconde et une taille de tamis de 0,2 millimètre à 0,9 millimètre ;

iv. Maintien d'un temps de séjour de particule moyen dans le système de broyeur universel comme étant > 1 seconde complété par un processus de recyclage continu ; et

v. Obtention de l'excipient cotraité ayant une cohésion Brookfield inférieure à 0,12 kPa, une masse volumique apparente d'au moins 0,249 gramme/millilitre et une propriété d'écoulement telle que mesurée par une augmentation de l'indice de débit de Johanson de 1,1 à 5,0 fois.


 
2. Excipient cotraité pouvant être obtenu par le procédé selon la revendication 1.
 
3. Excipient cotraité selon la revendication 2, dans lequel ledit polymère dérivé de lactame est présent en une quantité de 90,0 % à 99,9 % et l'agent de cotraitement est présent en une quantité de 0,1 % m/m à 10,0 % m/m de la composition d'excipient cotraité totale.
 
4. Excipient cotraité selon la revendication 2, dans lequel lesdits polymère dérivé de lactame et agent de cotraitement sont présents dans un rapport de 90:10 à 99,9 à 0,1.
 
5. Excipient cotraité selon la revendication 2, ledit excipient cotraité étant en outre combinée avec un composant actif ou fonctionnel choisi parmi des peintures et des revêtements, des produits de soins personnels, des détergents, des produits pharmaceutiques, des produits nutraceutiques, des céramiques, des isolants, des aliments pour animaux de compagnie, des aliments pour animaux et des aliments pour humains, des produits agricoles, des adhésifs, des revêtements électrolytiques, des encres, des colorants, du papier, des convertisseurs catalytiques et des produits électroniques.
 
6. Composition comprenant l'excipient cotraité selon la revendication 2 pour utilisation dans une application industrielle choisie parmi des peintures et des revêtements, des produits de soins personnels, des détergents, des produits pharmaceutiques, des produits nutraceutiques, des céramiques, des isolants, des aliments pour animaux de compagnie, des aliments pour animaux et des aliments pour humains, des produits agricoles, des adhésifs, des revêtements électrolytiques, des encres, des colorants, du papier, des convertisseurs catalytiques et des produits électroniques.
 
7. Composition selon la revendication 6, ladite composition étant utilisée dans des produits pharmaceutiques.
 
8. Composition selon la revendication 7, dans laquelle ladite composition est formulée dans une forme pharmaceutique orale par granulation par voie sèche, compression directe ou traitement d'extrusion à l'état fondu.
 
9. Composition pharmaceutique directement compressible comprenant :

i. un composant pharmaceutique actif ;

ii. l'excipient cotraité selon la revendication 2 ; et

iii. facultativement, un ou plusieurs additifs pharmaceutiquement acceptables.


 
10. Composition pharmaceutique directement compressible selon la revendication 9, ladite composition étant formulée dans des formes pharmaceutiques à libération modifiée, à libération contrôlée, à libération prolongée, à libération étendue ou une forme pharmaceutique à libération immédiate et soluble.
 
11. Composition pharmaceutique directement compressible selon la revendication 9, l'aptitude au compactage du comprimé contenant l'excipient cotraité étant au moins supérieure de 20 N à celle de comprimés fabriqués avec les mêmes excipients non cotraités.
 
12. Procédé de préparation de la composition pharmaceutique directement compressible selon la revendication 11, comprenant les étapes de :

i. mélange du composant pharmaceutique actif, de l'excipient cotraité selon la revendication 2, et facultativement d'un ou plusieurs adjuvants ; et

ii. compression des composants résultants pour obtenir une composition pharmaceutique directement compressible.


 




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Cited references

REFERENCES CITED IN THE DESCRIPTION



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Patent documents cited in the description




Non-patent literature cited in the description