CN102946872A

CN102946872A - Micropellet compositions comprising pancreatin containing digestive enzyme mixtures

Info

Publication number: CN102946872A
Application number: CN2011800303935A
Authority: CN
Inventors: 戈皮·M·文卡特施; 克雷格·克雷默; 弗拉维奥·法比亚尼; 路易吉·马佩利; 乔瓦尼·奥滕齐; 马西莫·拉汀诺
Original assignee: Aptalis Pharma Ltd
Current assignee: Allergan Pharmaceuticals Holdings Ireland ULC
Priority date: 2010-05-03
Filing date: 2011-05-03
Publication date: 2013-02-27
Also published as: WO2011140106A1; RU2012148776A; IL222796A0; JP2013525488A; AU2011248293A1; CO6640298A2; EP2566466A1; CA2798280A1; MX2012012794A

Abstract

The present invention relates to a small particle size composition comprising pancreatin containing digestive enzymes for use in patients in need, including pediatric, geriatric, and adult patients, particularly those patients with dysphagia or wherein enteral administration using such composition would be suitable. In addition, the invention is directed to the composition as particles, such as micropellets or microgranules having a high potency, high useable yield and at least 10% - 90% of 400-800 [mu]m. Furthermore, the composition optionally has an improved enteric coating and concomitant improved stability and enzyme activity compared to conventional prepared enterically coated pancreatic enzyme particles.

Description

The pellet composition that comprises the digestive enzyme mixture that contains pancreatin

The cross reference of related application

The application requires the priority of the U.S. Provisional Application submitted on May 3rd, 2010 number 61/330,768, for all purposes it is combined in this in full with it by reference.

Background of invention

The pancreatin enriching substance at " food, medicine and cosmetics bill " (Food, Drugand Cosmetic Act) in 1938 by being obtainable in the U.S. before.Do not had up to date to be subjected to the approval of regulations restrict, the pancreatin that has and do not have enteric coating is formulated and introduces to the market.

The exocrine pancreatic function that affects pancreas that is caused by various disease not complete (EPI) (for example pancreatitis, pancreatectomy, cystic fibrosis (CF), etc.) has become a kind of disease of having used the pancreatin enriching substance.Aspect the generation and/or secretion of the pancreatin that the nutrient in digest food is essential, can give pancreatic lipase and other pancreatin goods (PEP) are corrected enzyme deficiency disease at least in part.Do not have these enriching substances, patient's serious nutrition that becomes is impaired.If do not treat, this nutrition infringement can life-threatening, particularly in the situation that the baby.

The physiology is upper acceptablely to have that microbe-derived steatolysis, protein decompose and the digestive enzyme mixture of pancreatin mixture and/or the especially animal origin of amylolytic activity, and the catalysis fat splitting is that glycerol and fatty acid, Starch Hydrolysis are that dextrin and sugar and proteolysis are aminoacid and derived material.These pancreatin are not absorbed with appreciable amount from gastrointestinal (GI) road.About the curative effect terminal point of pancreatin mixture is the mean deviation of the CFA (CFA) between pancreatin and placebo treatment.CFA determines by 72 hours feces collections during treating, and wherein measures fat and drains and fat intake.The CFA of each patient during placebo treatment is used as not treating the CFA value.

Pancreatic lipase mainly is the combination of three fermentoids: lipase, protease and amylase together with their different cofactors and coenzyme, are used for augmenting for the loss of the digestive enzyme of many basic body processes or low-level.These enzymes are spontaneous in pancreas and are important in the digestion of fat, protein and carbohydrate.Although other sources also can be used, for example at U.S.6,051,220, U.S.2004/0057944,2001/0046493 and WO 2006044529 in describe those, pancreatic lipase is typically from the preparation of Pancreas Sus domestica gland.These enzyme catalysis fat splittings are that glycerol and fatty acid, Starch Hydrolysis are that dextrin and sugar and proteolysis are aminoacid and derived material.

Pancreatin is a kind of digestive enzyme, and it also is used to augment for the loss of the digestive enzyme of many basic body processes or low-level.Pancreatin comprises the enzyme of pancreas: lipase, amylase and protease.With regard to the activity level of three kinds of Major Enzymes, pancreatin is different from pancreatic lipase.

Can occur by the GI transportation through the digestion of pancreatin and the absorption of metabolite.But, being near neutral under the light subalkaline condition, pancreatin demonstrates optimum activity.Under the condition of stomach, namely acid and pepsic in the presence of, most of enzymes, especially lipase can irreversibly be inactivated, and cause bioactive loss.Therefore, the exogenous enzyme that gives usually at them by stomach transportation and enter and protectedly in the duodenum process avoid the deactivation of stomach and keep complete.Because enzymatic activity is retained under such condition and the absorption of metabolite mainly occurs in the epimere of intestinal, these enzymes preferentially were released in pH in 5-30 minute〉in 5.5 the duodenum.

Carry out the protection that coating has typically affected pancreatin with a kind of enteric coating polymer, this enteric coating polymer protective enzyme compositions is resisted the sour environment of stomach and then the release of enzyme in small intestinal is provided.Lipase is the most responsive pancreatin and is most important single enzyme in the treatment of malabsorption.Typically monitor lipase active and determine a kind of stability that contains the enzymatic compositions of lipase.Although protection is desirable, also can find not coated preparation in commerce.

Typically use conventional pan coating or fluidized bed coating method with pancreatin compositions coating, wherein with polymer solution or polymer suspension sufficiently high in case evaporate rapidly under the temperature of coating solvent to pancreatin granules (such as pellet, microplate, small pieces, etc.) carry out coating, and provide thus and have polymer coating relatively dry, that solidify.Yet it is difficult using conventional pan coating or fluidized bed coating method to provide uniform polymer coating at pancreatin granules (for example being suitable for those pancreatin granules of Infants'feeding via spraying).In addition, such coating conditions makes pancreatin granules stand to affect heat, moisture and the oxygen of enzyme stability, and therefore causes the enzymatic activity forfeiture.What therefore, make us wishing is the pancreatin granules that obtains coating under the more not rigorous condition of keeping enzymatic activity and stability.

Conventional pancreatin compositions also comprises the relatively large pancreatin granules that not too is fit to pediatric patient or enteral administration, and (NG), nasojejunal (NJ), the Ponsky method pipe administration (PEG) or Jejunostomy of nasogastric tube for example passed through in the enteral administration.T.Sipos is at US 4,079,125 and US 5,302, taught the preparation of the pancreatin micropill core of using subsequently a kind of enteric polymer coatings in 400, this preparation comprises granulates pancreatin mixture, binding agent, disintegrating agent, effervescent to (effervescent couple) and bile acid, extrude and round as a ball.These enteric coating balls have the granularity of 1.4-2.0mm.US 4,280,971 have taught the preparation of the long line (strands) of 1.5-1.7mm, mixture and aqueous isopropanol by alternately spray polyvidone or Polyethylene Glycol and the pancreatin and the line of drying is round as a ball of this preparation by extruding pancreatin with the isopropyl alcohol granulation, magnesium stearate.These enteric coating balls have 0.5 to 4mm, preferred 1 to 2.5mm granularity.M.Maio has disclosed in US 20040101562 by the melt granulation with any solvent not and has prepared the microsphere that comprises pancreatin and hydrophilic low melting point polymer.The magnitude range of these microspheres is used a kind of enteric polymer coatings at 10 to 1500 μ m.(for example US 5 for United States Patent (USP), 378,462, US 5,725,880) and open (for example US 20070148152 Al, the US 20070148153 Al) preparation of having taught the pancreatin micropill core of using subsequently the resistant to gastric juice polymer coating, this preparation by extrude comprise pancreatin, Polyethylene Glycol (PEG 4000) and enough lower alcohol mixture to reach extrudable denseness, then in the presence of liquid paraffin or isopropyl alcohol that extrudate is round as a ball, the ball that generates has 0.7-1.4mm or larger minimum diameter spherical in shape to elliposoidal in shape.Because pancreatin in water and/or the unstability in the presence of moisture, causes aforementionedly being suitable for melt extruding-round as a ball friendly solvent or the use of low melting point hydrophilic polymer, the preparation of pancreatin compositions is difficult.Yet these extrusion by meltings typically produce the pancreatin granules with wide particle size distribution.Consider the problem of aforesaid relatively large pancreatin granules about conventional pancreatin compositions and their manufacture method, will be made us wishing by the pancreatin compositions that the relatively little enzyme granulate with narrow size distribution forms.

Made the pancreatin compositions that substitutes.The people such as KY Weon have disclosed the preparation of pancreatin core in WO2007013752, this preparation is by carrying out in the aqueous solution that a kind of dispersion that comprises pancreatin is sprayed to a kind of polymer adhesive.The major defect of this process is to be difficult to finish the pancreatin delaminating process within 60-90 minute of preparation preparation to avoid significant loss of activity.The people such as A.Margolin have disclosed in US 20010046493, US20030017144 and WO 2006044529 and have comprised the stable amorphous amylase of microbial lipase crystal, microorganism of acid and the compositions of microbial protease, together with the method that need not being used for the treatment of of resistant to gastric juice coating and comprise the disease of EPI.The people such as Galle have disclosed a kind of preparation that is reported as the mixtures of microbial enzymes that is suitable for treating the EPI relevant with CF in US20040057944.Although said preparation can be in 4 to 8 pH scope retains biological activity, it is inactivated under the condition in patient's CF of the stomach pH with 2.5-4 body to a certain extent.U. S. application serial number 12/034A80(publication number US2008/0299185) stable digestive enzyme compositions has been described.Scharpe is at US6,051, disclosed in 220 and comprise the stable enzyme of acid or contain compositions up to the microbe-derived complex with maltase, amylase and dextrinizing activity of 75% sour stable lipase, with proteolytic enzyme and lipid lyases (lipid splitting enzyme) the combination treatment for EPI.US 20080279839(patent application serial numbers 12/092,255) taught the preparation of digestive enzyme compositions, this digestive enzyme compositions shows that the EPI that treatment is associated with CF is effective, it comprises the derivative lipase of at least a microorganism, derivative amylase and at least a preferred protease derived from plant of at least a microorganism, and all these is to tolerate deactivation in 2 to 8 pH scope.US 6,051, and 220, US20010046493, US 2003017144, US 20040057944, WO 2006044529 and US 20080279839 also described pancreatinum.US 7,658, and 918 have described

A kind of enzymatic mixture that is the treatment effective dose of HPMC capsule form.Each capsule that is used for oral administration contains enteric coating beadlet (for 5, the lipase of 000USP unit is 1.8-1.9mm, and for 10,000,15,000 and 20, the lipase of 000USP unit is 2.2-2.5mm).

Should begin to the every meal 2 of maximum from every meal 500 lipase unit/kg body weight for the people's enzyme dosage more than 4 years old, 500 lipase unit/kg body weight (or are less than or equal to every day 10,000 lipase unit/kg body weight) or less than every day 4,000 lipase unit/g take in fat.It is about 12 that the pancreatin of 500 milligrams of tablets has usually, the trypsin of 500USP unit, 12, the amylase of 500USP unit and 1, the lipase of 000USP unit.Therefore, client need is at table or is swallowed several capsules during snacks, and these capsules are so that the adhering to and/or current obtainable wherein 90% granule of dosage regimen〉pancreatinum of 900 μ m give difficult.

In addition, because the significant difference of particle size distribution between pancreatin and food article, they pass in the gastrointestinal tract transportation although to be synchronized with the movement from the viewpoint of fat and the better absorption of nutrient be important, but usually be difficult to realize, and be a subject matter, especially in child and baby.The people such as Choe prove, gastric emptying only depends on size rather than chemical composition (people such as Choe, " European pharmaceutical journal (the Euro J.Pharma Sci.) " 2001 of ball; 14,347-353), wherein used ball and the γ scintigraphy of the 0.7mm that contains APAP or caffeine.They also prove, 0.7mm and the administering drug combinations of the ball (APAP) of 3.6mm shows, the 3.6mm(APAP of the ball of the 0.7mm of reduced size (caffeine) and large-size) ball compare all more emptying and abundant absorptions (P＜0.05) morning under little liquid meal (through 35min) and standard meal (through 33min).These balls difference on the gastric emptying time under fasting state is inapparent.The people such as JH Meyer prove, when taking in 420g or 100g meals, the 1mm spheroid is than 2.4 or 3.2mm spheroid consistently quickly emptying (＜＜0.01, pairing t-check), (people such as JH Meyer, " gastroenterology " (Gastroenterology), 1988; 94:1315-1325).Based on the men's health volunteer's in 18 18-50 of non-blind, random, single dose, tripartite crossing research year result, these volunteers have at treatment (the didanosine beadlet of encapsulated enteric coating (1 * 200mg for example; The about enteric beadlet of 2mm diameter) and the didanosine small pieces (4 * 50mg of enteric coating; The eluting phase at least 1 week the ECT of about 5mm diameter)), the people such as B.Damle draw a conclusion: the timing definition of gastric emptying is the time that is greater than or less than 95% radioactivity of the didanosine dosage form under one's belt observed first, and the enteric beadlet is longer than enteric coatel tablets with regard to the time that obtains; Yet the time of the concentration of first the quantifiable didanosine in blood plasma of observing is shorter for the enteric beadlet.Therefore, be defined as time delay at gastric emptying and didanosine and absorb time between the beginning, for the enteric beadlet be significantly shorter than enteric coatel tablets (people such as B.Damle, " Britain's clinical pharmacology magazine " be .2002 (Br.J.Clin.Pharmacol.); 54 (3): 255-261).Therefore, the pharmaceutically acceptable compositions oral, delayed release (wherein 90% enteric coated article has the granularity that is not more than 800 μ m) for the digestive enzyme mixture that contains pancreatin that is used for pediatric patient, elderly patients and adult patient (for example typically protease, lipase and amylase) exists still unsatisfied needs.In addition, such preparation makes administration easier, especially in baby and child.

Have been found that now the pharmaceutically acceptable micropill that contains pancreatin that comprises (has narrow/little particle size distribution, high available output, and the diameter of these micropills of 10%-90% or microgranule is 400-800 μ m at least) the compositions of digestive enzyme mixture, these micropills or microgranule randomly carry out coating with resistant to gastric juice coating or moisture-proof coating and are suitable for pediatric patient with generation, elderly patients, and adult patient's stable digestive enzyme compositions and dosage form, be used for correcting at least in part enzyme deficiency disease, this coating for example comprises hydrophilic polymer and plasticizer, randomly comprises hydrophilic antiplastering aid (Talcum for example, magnesium stearate, colloidal silica and their combination; The low viscosity ethyl cellulose of further can choosing any one kind of them).

Brief Description Of Drawings

Fig. 1: have the Granurex GX-35-GXR processing plug-in unit of taper flap and the photo with VEC-Lab 3 of the GXR-35 plug-in unit of packing into.

Fig. 2: microphotograph: A-is from the digestive enzyme that contains pancreatin (LotS1) of science albumen laboratory (Scientific ProteinLaboratories), B – is by the micropill (LotS2) of the preparation of powder layering in Granurex GX-35, the enteric coated-pellet of C-digestive enzyme (LotS3), and the enteric coated-pellet of D-digestive enzyme (LotS4).

Fig. 3: microphotograph: A-is from the digestive enzyme that contains pancreatin and the micronized digestive enzyme that contains pancreatin of B-of Nordmark.

Fig. 4 A and B: accordingly (LotNl) and the microphotograph of the pancreatin granules of (LotN2) afterwards before the heat treatment in cyclohexane extraction.

Fig. 5 A and B: the microphotograph of pancreatin microgranule (LotN3,5% cohesion polymer).

Fig. 6 A and B: the microphotograph of pancreatin microgranule (LotN4,20% cohesion polymer).

Fig. 7 A and B: the microphotograph of pancreatin microgranule (LotN5,20% cohesion polymer).

Fig. 8 A and B: photo (〉 the 250 μ m of the pancreatin LotNl of selection).

Fig. 9 A and B: the microphotograph of pancreatin microgranule (LotN6,5% cohesion polymer).

Figure 10 A and B: the microphotograph of pancreatin microgranule (LotN7,5% cohesion polymer).

Figure 11 A and B: the photo of the pancreatin LotNl of selection (＜250 μ m).

Figure 12 A and B: the microphotograph of pancreatin microgranule (LotN8,20% cohesion polymer).

Figure 13 A and B: the cohesion polymer of the microphotograph of pancreatin microgranule (LotN9,〉20%).

Detailed description of the present invention

In different embodiments, the present invention relates to a kind of small grain size compositions that comprises the digestive enzyme that contains pancreatin, be used for that it is had the patient who needs, comprise pediatric patient, elderly patients and adult patient, particularly those have dysphagia or wherein use such compositions to be suitable for the patient of enteral administration.In other embodiments, the present invention be directed to compositions of a granular form, for example have efficient, high available output and at least micropill or the microgranule of the granule of the 400-800 micron of 10%-90%.In addition, said composition is compared with the pancreatin granules of the enteric coating of conventional preparation and is randomly had a kind of improved enteric coating and follow improved stability and enzymatic activity.

The present invention be directed to comprise mainly by a plurality of granulometric composition that contain at least a digestive enzyme or consisting of a kind of pharmaceutical composition, wherein said granule has low size.Specifically, described granule has the volume diameter d (v that is not less than 400 μ m through laser diffraction measurement, 0.1) and be not more than the volume diameter d (v, 0.9) of 800 μ m or described granule and have as by the measured granularity less than about 800 μ m of screening.In certain embodiments, as measured by screening, the particle size range that they have is: all scope and subrange from about 200 μ m to about 700 μ m, from about 200 μ m to about 600 μ m, from about 400 μ m to about 600 μ m or from about 250 μ m to about 500 μ m and therebetween.

These granules comprise the following, main these compositions or consisting of: the digestive enzyme mixture of 40%-98% percentage by weight, a kind of polymer of 2%-20% percentage by weight, randomly inert core and one or more pharmaceutically acceptable excipient randomly of 0-30% percentage by weight.They can comprise by weight at least 60% digestive enzyme mixture.They can have one or more coatings.

These granules can be that micropill and they comprise the following, main these compositions or consisting of: the digestive enzyme mixture of 40%-98% percentage by weight, a kind of water-soluble polymer of 2%-10% percentage by weight, randomly inert core and one or more pharmaceutically acceptable excipient randomly of 0-30% percentage by weight.These micropills can have one or more coatings.Polymer as the micropill component is a kind of pharmaceutically acceptable water-soluble polymer, this water-soluble polymer can be selected from lower group, and this group is comprised of the following: hydroxypropyl cellulose, polyvidone, methylcellulose, hydroxypropyl emthylcellulose, carboxyl alkyl cellulose, poly(ethylene oxide), vinylpyrrolidone-vinyl acetate copolymer, polysaccharide, and composition thereof.Described micropill can randomly comprise a kind of hydrophobic insoluble polymer, this insoluble polymer can be selected from lower group, and this group is comprised of the following: low viscosity ethyl cellulose, cellulose acetate, acetylbutyrylcellulose, polyvinyl acetate, neutral methacrylic acid esters copolymer, quaternary amine ylmethyl acrylate copolymer, and composition thereof.

These granules can also be that microgranule and they comprise the following, main these compositions or consisting of the digestive enzyme mixture of 80%-95% percentage by weight; A kind of insoluble polymer of 5%-20% percentage by weight; And one or more pharmaceutically acceptable excipient randomly.The insoluble polymer of these microgranules is a kind of cohesion polymers that are deposited on them.In certain embodiments of the invention, this insoluble polymer is selected from lower group, and this group is comprised of the following: ethyl cellulose, cellulose acetate, acetylbutyrylcellulose, polyvinyl acetate, neutral methacrylic acid esters copolymer, quaternary amine ylmethyl acrylate copolymer, and composition thereof.

Term " digestive enzyme " expression is a kind of decomposes food component so that the enzyme that these components can be absorbed by organism in digestive tract.Term " digestive enzyme of stabilisation " is illustrated in the digestive enzyme that substantive enzymatic activity is kept in long term storage afterwards.Term " pancreatic lipase " or " pancreatin " have also been used at this; Both represent a kind of mixture of the enzyme of several types, comprise amylase, lipase and protease.

The non-limiting classification that is suitable for digestive enzyme of the present invention comprises lipase, amylase and protease.The limiting examples of digestive enzyme comprises: pancreatic lipase, lipase, trypsin, chymase, chymase B, pancreas peptidase, Carboxypeptidase A, protaminase, GEH, phospholipase, phospholipase A2, sterol ester hydrolytic enzyme, ribonuclease, deoxyribonuclease, α-amylase, papain, chymopapain, bromelain, ficin, beta amylase, cellulase, beta galactosidase, and composition thereof.They can obtain, manually make or obtain from the source (for example from microorganism, plant or other animal tissues) that is different from pancreas by extracting from pancreas.

Lipase is the enzyme that the catalysis hydrolysis of lipid becomes glycerol and simple fatty acids.The example that is suitable for lipase of the present invention include but not limited to Animal fat enzyme (for example pork fat enzyme), comprising lipase of bacterial origin (for example Pseudomonas Lipases and/or burkholderia lipase), fungal lipase, plant fat enzyme, recombinant lipase (lipase that is for example produced by the host cell that is fit to by recombinant DNA technology, this host cell be selected from following any one: the antibacterial of cultivation, yeast, fungus, plant, insecticide or mammiferous host cell; Or comprise and naturally occurring sequence homology or the recombinant lipase of consistent aminoacid sequence basically; By with nucleic acid homology or the lipase of consistent nucleic acid coding basically of the naturally occurring lipase of coding, etc.), the lipase of synthctic fat enzyme, chemical modification, and composition thereof.

Amylase is diastatic glycoside hydrolase, for example α-amylase, beta amylase, acid alpha-Glucosidase (acid alfa-glucosidase), ptyalin (for example ptyalin (ptyalin)), etc.Be suitable for amylase of the present invention include but not limited to animal amylase, bacterial amylase, fungal amylase (for example aspergillosis amylase: for example Amylase EC), vegetable diastase, restructuring amylase (amylase that is for example produced by the host cell that is fit to by recombinant DNA technology, this host cell be selected from following any one: the antibacterial of cultivation, yeast, fungus, plant, insecticide or mammiferous host cell; Or comprise and naturally occurring sequence homology or the restructuring amylase of consistent aminoacid sequence basically; By with the naturally occurring diastatic nucleic acid homology of coding or the amylase of consistent nucleic acid coding basically, etc.), the amylase of chemical modification, and composition thereof.

Protease normally makes the enzyme (protease, peptidase, proteolytic enzyme) of the peptide bond fission between the aminoacid of protein.Be suitable for protease limiting examples of the present invention and comprise serine protease, serine/threonine protein enzyme, cysteine proteinase, aspartic protease (for example plasmodium aspartic protease), metalloproteases and hydroxyproline enzyme.In addition, be suitable for protease of the present invention include but not limited to animal protease, bacterialprotease, fungal proteinase (for example Semialkaline Protease), plant rennet, recombiant protein enzyme (protease that is for example produced by the host cell that is fit to by recombinant DNA technology, this host cell be selected from following any one: the antibacterial of cultivation, yeast, fungus, plant, insecticide or mammiferous host cell; Or comprise and naturally occurring sequence homology or the recombiant protein enzyme of consistent aminoacid sequence basically; By with nucleic acid homology or the protease of consistent nucleic acid coding basically of the naturally occurring protease of coding, etc.), the protease of chemical modification, and composition thereof.

Compositions of the present invention can comprise one or more lipases (that is, a kind of lipase, or two or more lipases), one or more amylase (are a kind of amylase, or two or more amylase), one or more protease (are a kind of protease, or two or more protease), one or more lipases and one or more diastatic mixture, the mixture of one or more lipases and one or more protease, the mixture of one or more amylase and one or more protease, or the mixture of one or more lipases and one or more amylase and one or more protease.

In one embodiment, digestive enzyme is the extract of Pancreas Sus domestica, this extract comprises different lipases (for example, lipase, colipase, phospholipase A2, cholesteryl esterase), protease (for example trypsin, chymase, Carboxypeptidase A and B, elastoser, kininogenase, trypsin inhibitor), amylase and nuclease (ribonuclease, deoxyribonuclease) randomly.In another embodiment, this digestive enzyme is in fact similar to people's pancreatic juice.In another embodiment again, this digestive enzyme is pancreatic lipase USP.

Although the Pancreas Sus domestica enzyme preparation is widely used, containing about 75% the cattle enzyme preparation than the low fat enzymatic activity is a kind of succedaneum for the patient who does not consume the pig product.The microorganism formulation that also has pancreatin (lipase, amylase and protease).Some antibacterial (for example plant seedbed burkholderia) and fungus (for example aspergillus niger, Rhizopus arrhizus) have shown to produce to have substantial lipolysis activity and to the pancreatin of the larger resistance of gastric acid degraded.

Lipase active in these compositionss can be from about 2,500 to about 28, the 000IU(USP method), from about 2,700 to about 3,300IU, from about 4,500 to about 5,500IU, from about 9,000 to about 11,000IU, from about 13,500 to about 16,500IU and from about 18,000 to about 22,000IU, from about 25,000 to about 27,500IU and all scope and subrange therebetween.Amylase activity in these compositionss can be from about 6,000 to about 22,500IU (USP), for example from about 6,400 to about 26,300IU, from about 10,700 to about 43,800IU, from about 21,500 to about 87,500IU, from about 32,100 to about 131,300IU, from about 42,900 to about 175,000IU, from about 53,600 to about 218,700IU and all scope and subrange therebetween.Proteinase activity can be from about 5,000 to about 130 in these compositionss, the 000IU(USP method), for example from about 5,000 to about 15,400IU, from about 8,400 to about 25,700IU, from about 16,800 to about 51,300IU, from about 25,000 to about 77,000IU, from about 33,500 to about 102,800IU, from about 41,800IU is to about 128,300IU and all scope and subrange therebetween.

In one embodiment, the scope of lipase active is from about 2,700 to about 3, the scope of 300IU, amylase activity is from about 6,400 to about 26, and the scope of 300IU and proteinase activity is from about 5,000 to about 15,400IU(USP).In another embodiment, the scope of lipase active is from about 4,500 to about 5, the scope of 500IU, amylase activity is from about 10,700 to about 43, and the scope of 800IU and proteinase activity is from about 8,400 to about 25,700IU(USP).In another embodiment, the scope of lipase active is to be from about 21 from about 9,000 scopes to about 11000IU, amylase activity, 500 to about 87,500IU and proteinase activity scope are to about 51,300IU(USP) from about 16,800.In another embodiment, the scope of lipase active is from about 13,500 to about 16, the scope of 500IU, amylase activity is from about 32,100 to about 131, and the scope of 300IU and proteinase activity is from about 25,000 to about 77,000IU(USP).In another embodiment again, the scope of lipase active is from about 18,000 to about 22, the scope of 000IU, amylase activity is from about 42,900 to about 175, and the scope of 000IU and proteinase activity is from about 33,500 to about 102,800IU(USP).In another embodiment again, the scope of lipase active is from about 25,000 to about 27, the scope of 500IU, amylase activity is from about 53,600 to about 218, and the scope of 700IU and proteinase activity is from about 41,800IU is to about 128,300IU(USP).

In another embodiment again, the scope of lipase active is from about 5,000 European Pharmacopoeia (PhEur) lipase unit is to about 30, in the scope of 000 European Pharmacopoeia lipase unit, can approximately be 5,000 or about 10,000 or about 15,000 or about 20,000 or about 30,000 European Pharmacopoeia lipase unit.

The scope of the ratio of the amylase/lipase in these compositionss can be from about 1 to about 10, and in certain embodiments, the ratio of amylase/lipase can be to carry out enzymatic assays from about 2.38 to about 8.75(according to USP).The scope of the ratio of the protease/lipase in these compositionss of the present invention or peroral dosage form can be from about 1 to about 8, is to carry out enzymatic assays from about 1.86 to about 5.13(according to USP in specific embodiment).

The total amount of the digestive enzyme in compositions of the present invention or peroral dosage form (by weight) can be about 20%-100%, approximately 40%-100%, approximately 40%-90%, approximately 40%-80%, approximately 40%-70%, approximately 40%-60%, approximately 40%-50% and all scope or subrange therebetween, perhaps about 20%, about 30%, about 40%, about 50%, about 60%, about 70%, about 80%, about 90% or about 100%.In one embodiment, the total amount of digestive enzyme is 40%-80%.In another embodiment, the total amount of digestive enzyme (for example pancreatic lipase) is about 55%-65%.

Term " granule " includes but not limited to microgranule (microparticle), microgranule (microgranule), beadlet ball (bead pellet), pellet (granulate), microsphere (microspheres), powder etc., typically have such as the size by the measured following scope of screening: from about 100 μ m to about 800 μ m, comprise from about 200 μ m to about 800 μ m, about 200 μ m are to about 700 μ m, about 200 μ m are to about 600 μ m, about 200 μ m are to about 500 μ m, about 200 μ m are to about 400 μ m, about 250 μ m are to about 800 μ m, about 250 μ m are to about 700 μ m, about 250 μ m are to about 600 μ m, about 250 μ m are to about 500 μ m, about 300 μ m are to about 800 μ m, about 300 μ m are to about 700 μ m, about 300 μ m are to about 600 μ m, about 300 μ m are to about 500 μ m, about 400 μ m are to about 800 μ m, about 400 μ m are to about 700 μ m, about 400 μ m are to about 600 μ m, about 400 μ m are to about 500 μ m, about 700 μ m are to about 800 μ m and all subrange therebetween.

These granules (for example micropill and microgranule) can have one or more coatings; these coatings can be protected these enzymes to avoid the impact of external environment condition (for example avoiding moisture, the protectiveness coating) or can be used as diffusion barrier (sealing coating) or can discharge (functional coatings) by regulating drug.This coated composition comprises: one or more hydrophilic polymers and one or more plasticizers and the pharmaceutically acceptable hydrophobic material of choosing wantonly, and composition thereof.Described hydrophobic material can have anti-adhesive properties, for example Talcum, magnesium stearate, colloidal silica, for example stearate, cetylate or fatty acid ester (for example glyceryl monostearate, Palmic acid tristerin, and composition thereof).According to the source of digestive enzyme mixture and the desired use of compositions, the ratio of hydrophilic polymer and hydrophobic agents by weight can be in the scope from about 10:1 to about 1:10.In another embodiment, the ratio of hydrophilic polymer and hydrophobic agents by weight can be in the scope from about 5:1 to about 1:5.The limiting examples of hydrophilic polymer comprises that for example hydroxypropyl cellulose, hydroxypropyl emthylcellulose, polyvinyl alcohol, ethylene pyrrolidone-vinyl acetate copolymer are (for example from BASF's

VA 64), certain low viscosity ethyl cellulose (for example use Ubbelohde viscometers to measure at 25 ° of C in 80/20 toluene/alcohol, viscosity is the solution of 10cps or lower 5%), and composition thereof.

The limiting examples of the plasticizer that is fit to comprises: glyceryl triacetate, tributyl citrate, triethyl citrate, acetyl tributyl citrate, diethyl phthalate, dibutyl sebacate, Polyethylene Glycol, polypropylene glycol, Oleum Ricini, acetylated monoglyceride and acetylated diglycerides, hexadecanol, and composition thereof.In one embodiment, this plasticizer is a kind of non-phthalic ester plasticizer.

In one embodiment, comprise that the hydrophilic polymer that seals coating is hydroxypropyl cellulose (for example Klucel LF) associating low viscosity ethyl cellulose (for example top grade ethyl cellulose standard substance (Ethylcellulose Standard Premium) 7 or 10), and this plasticizer is triethyl citrate.In another embodiment, this hydrophilic polymer that comprises coating is hydroxypropyl cellulose, and this plasticizer is triethyl citrate, and this antiplastering aid is Talcum.In certain other embodiments, this hydrophilic polymer is the mixture of a kind of hydroxypropyl cellulose and low viscosity ethyl cellulose, and this plasticizer is the tributyl sebacate, and this hydrophobic agents is the Palmic acid tristerin.The sealing coating can consist of the sealant coating that contains medicine core weight from about 1% to about 20%, for example about 1%, about 2%, about 3%, about 4%, about 5%, about 7%, about 10%, about 12%, about 15%, about 17% or about 20%, be included in therebetween all scopes and subrange.

Term " be arranged in ... on (disposed over) ", for example about a kind of coating on a kind of substrate, refer to coating for example for substrate relative position, do not contact but require that this coating is in directly with this substrate.For example, " being arranged in (disposed over) " suprabasil first coating can be directly and substrate contact, or one or more intervention materials or coating can insert between first coating and this substrate.In other words; for example, being arranged in delayed release (DR) on micropill or the microgranule or enteric polymer coatings can refer to a kind ofly directly be arranged in enteric coating on the granule, maybe can refer to a kind of DR coating (this protectiveness coating is arranged on the granule) that is arranged on the protectiveness coating.When the coatings protect medicine was avoided affecting of gastrointestinal tract environment, this coated composition comprised: one or more enteric polymers and one or more plasticizers.Such coating can be arranged on the micropill of coating not or the microgranule or on (for example protectiveness or sealing coating) granule of coating.

A kind of polymer of protecting digestive enzyme to avoid the impact of gastric content of term " enteric polymer " expression; for example in the acid pH level (for example; the pH of stomach) but soluble higher pH level (for example in lower gastrointestinal tract) decompose the polymer of dissolving or have under one's belt enough slow aquation or erosive velocity with assurance gastric content less polymer relative to the contact of digestive enzyme, this is opposite with the gastrointestinal remainder.Term as used herein " the pH sensitivity " refers to show the polymer of the dissolubility that relies on pH.Enteric coating comprises at least a enteric polymer and at least a plasticizer (for example Hydroxypropyl methyl cellulose phtalate, HP-55 and triethyl citrate).In one embodiment, enteric coating and plasticizer ratio ranges by weight is to about 9:1 from about 7:3.In another embodiment, enteric polymer and plasticizer ratio by weight is 9:1, and the scope of enteric coating can from about 10wt.% to about 50wt.(based on the weight of micropill or the microgranule of coating).The scope of enteric coating is by weight about 25% to about 40%, and the coating level can be about 10%, about 25%, about 30%, about 33%, about 35%, about 40%, about 50% by weight.

The example that is suitable for enteric polymer of the present invention includes but not limited to: the EUDRAGIT L100 of cellulose acetate phthalate, hydroxypropylmethyl cellulose phthalate, HPMCAS, Opaseal, cellulose acetate succinate, pH sensitivity (for example Eudragit S 100, EudragitL 100, Eudragit FS, etc.), fatty acid, wax, Lac, and composition thereof.In specific embodiments, these enteric polymers are dissolved in organic solvent.

The limiting examples that is suitable for mixing the plasticizer of enteric coat layer comprises: glyceryl triacetate, tributyl citrate, triethyl citrate, acetyl tributyl citrate, hexadecanol, diethyl phthalate, dibutyl sebacate, Polyethylene Glycol, polypropylene glycol, Oleum Ricini, acetylated monoglyceride and acetylated diglycerides, and composition thereof.In one embodiment, this plasticizer is a kind of non-phthalic ester plasticizer.

This enteric polymer can further comprise at least a inorganic reagent, for example can be the Talcum in the scope from about 10:1 to about 1:60 by weight.In another embodiment, enteric polymer and at least a inorganic material ratio ranges by weight are from about 8:1 to about 1:50.In another embodiment, enteric polymer and at least a inorganic material ratio ranges by weight are from about 6:1 to about 1:40.In another embodiment, enteric polymer and at least a inorganic material ratio ranges by weight are from about 5:1 to about 1:30.In another embodiment, enteric polymer and at least a inorganic material ratio by weight are from about 4:1 to about 1:25.In another embodiment, enteric polymer and at least a inorganic material ratio ranges by weight are from about 4:1 to about 1:9.In another embodiment, enteric polymer and at least a inorganic material ratio ranges by weight are from about 10:4 to about 10:7.

In another embodiment again, this enteric coating may further include at least a antiplastering aid.The limiting examples of the antiplastering aid that is fit to comprise colloidal silica, magnesium stearate, Talcum, glyceryl monostearate, and composition thereof.In one embodiment, this antiplastering aid is Talcum.The desired use that depends on enteric polymer or said composition, this enteric polymer and this antiplastering aid ratio by weight can be in the scopes from about 10:0 to about 6:4.In another embodiment, enteric polymer and antiplastering aid ratio ranges by weight is from about 9:1 to about 7:3.

Unless otherwise specified, the weightening finish percentage ratio (with respect to the granule before the coating or the initial weight of beadlet) of the granule (micropill or microgranule) that is provided by this dry coating is provided the amount (" coat weight ") of various coating described herein or layer.Therefore, 10% coat weight has referred to increase the dry coationg of 10% particle weight.

Compositions of the present invention comprises containing at least aly have approximately or less than the shaping micropill of the digestive enzyme of the median particle of 30 μ m, these micropills are shaped by following: controllably round as a ball or powder layering in the device that the is fit to Granurex GX-35 of Vector company (for example from), according to US 6,569,462 or similarly be disclosed in powder layering in the pan coating machine, randomly with the optional hydrophilic polymer solution that contains hydrophobic antiplastering aid these micropills are carried out coating.Coating and the micropill of coating not, especially those micropills that comprise the digestive enzyme mixture that comes from pig randomly with contain enteric polymer and randomly the resistant to gastric juice coating of plasticizer carry out coating.

Manufacturing (no matter being by in check spheronization or powder layering) with spherula micropill of smooth surface structure need to be used has median diameter less than 30 μ m, preferably less than the digestive enzyme of 20 μ m, to obtain to have for the micropill with the smooth morphology of functional polymer coating.A kind of laser particle size analyzer (for example Malvern Instruments'Mastersizer) typically is used to measure by " stem cell " or " wet cell " method the particle size distribution of fine powder and graininess microgranule.Measure the suspension of powder with little angle laser beam (low angle laser beam), and calculate particle size distribution according to the explanation of user's manual (Malvern Mastersizer elemental user handbook, QS small amount sample dispersal device user's manual).Volume median diameter d (v, 0.5) is defined as wherein 50% distribution to be thereon and 50% to be diameter under it.Volume median diameter d (v, 0.9) be defined as 90% volume distributed median wherein be under this value and 10% be on diameter.It is under this value and 90% be diameter on this value that volume diameter d (v, 0.1) is defined as 10% volume distributed median wherein.In specific embodiments of the present invention, be from about 400 μ m to about 600 μ m for the particle size range of micropill core.And by using a folded sieve to measure the particle size distribution of fine powder and microgranule through the put meter method.

In check round as a ball and powder delaminating process both needs micronized drug particles (for example, what make us wishing most is: d (v, 0.5)＜20 μ m and d (v, 0.9)＜50 μ m).For these fine powders are remained within the product bed, in the course of processing, need to optimize/balance and control air velocity and total air-flow.By active matter being added with powder type rather than by with its dissolving or be suspended in the polymer adhesive and spraying realizes the saving of plenty of time.This process causes having the higher available output of narrow particle size distribution.

In the powder delaminating process, load the rotor plug-in unit of reactor (for example Granurex GX-35) with the inertia core of the sugared ball that for example has desired granularity.With a kind of digestive enzyme, fluidizer such as Cab-O-Sil(colloidal silica of comprising) and randomly the fine powder mixture of polymer adhesive install in the machine and directly be dispersed in inert core in the heart through accurate powder feeder, a kind of polymer binder solution of meanwhile spraying is to be combined in the digestive enzyme powder on the outside of core material.Therefore, this micropill begins successively to form.The balance of powder feed rate and spray velocity is the parameter of the most critical that remains to be reached in the powder delaminating process, with avoid powder cross wet and cohesion or inert core in the heart invalid adhesion and cause low yield.In conjunction with after becoming micropill, stop spraying and dry these micropills at all free powder.Can be for example by only using the slit air or carrying out drying by the air assembly that puts down a kind of Mov-A-Blo of being called.

In in check round as a ball process with comprising digestive enzyme, fluidizer such as Cab-O-Sil(colloidal silica) and the rotor plug-in unit of the equipment (for example Granurex GX-35) that is fit to of the fine powder mixture filling of polymer adhesive randomly.Polymer binder solution is sprayed on the powder bed of fine powder more with the speed of a control, meanwhile by the speed of powder feeder (K-Tron) with a control powder is added in the auto levelizer.The mist of binder solution helps the digestive enzyme mixture of powders is attached on the micropill that successively forms.In addition, technological parameters such as air velocity, air-flow, product temperature, spray velocity is optimised/control, avoid thus continuous powder bed excessively wet/condense or the invalid adhesion on micropill, cause lower output.

For the micropill that contains digestive enzyme coating or the sealing coating, can be coated with a kind of other enteric coating solution through fluidized bed coating or pan coating or through Granurex GX-35 or similar fashion.

Except in check round as a ball and powder layered approach, the small size particle that comprises digestive enzyme can prepare by coacervation process, and this process is from having at about 250 μ m and 500 μ m(as measured by sieve method) between the pancreatin material of granularity.In this process, with these digestive enzyme granules of solution-treated that comprise the insoluble polymer that is dissolved in hydrophobic organic solvent (for example cyclohexane extraction).This insoluble polymer solution further comprises a kind of phase separation agent.This process comprises: in coagulum reactor, the solution of insoluble polymer, hydrophobic organic solvent and phase separation agent and the digestive enzyme granule of suspension are heated until then 80 ° of C are cooled to this mixture about 25 ° of C.This phase separation agent comprises polyethylene butyl rubber, polybutadiene, polyisobutylene, organosilicon polymer and paraffin.This process does not affect the enzyme stability of these enzymes.The digestive enzyme microgranule that obtains has low water content (below 3%) and has granularity less than 800 μ m, comprises from about 200 to about 700 μ m, from about 200 to about 600 μ m, from about 250 to about 500 μ m and all scope and subrange (as measured by screening) therebetween.Described microgranule with cohesion polymer can carry out coating with enteric coating solution further, and this enteric coating solution comprises the enteric polymer that is dissolved in the pharmaceutically acceptable solvent.This enteric coating step comprises by fluidized bed coating or by pan coating carries out coating with enteric coating solution to these microgranules.Preferred enteric polymer dissolves in organic solvent and is hydroxypropylmethyl cellulose phthalate, and preferred solvent is acetone.The enteric coated article agent that obtains have less than about 3%, preferably less than about 2% water content, they can have about 1.2% water content (by the loss on drying in the USP method (LoD) experimental measurement).

The compositions that comprises the low size granule with at least a digestive enzyme of the present invention and peroral dosage form have approximately or less than 4.5%, approximately or less than 3%, approximately or less than 2.5%, approximately or less than 2%, approximately or less than 1.5% water content, all scope and the subrange (for example between about 1.5% and about 4.5%, between about 1.5% and about 1.5%, between about 1.5% and 2.5%) therebetween that is included.Compositions of the present invention or peroral dosage form storage keep afterwards low water content and with routine maintain higher moisture (for example about more than 4% or higher) compositions to compare be in fact more stable.Measure (LoD, USP method) by loss on drying and carry out the moisture determination of dosage form of the present invention and compositions.

The loss of digestive enzyme activity that these compositionss of the present invention and dosage form show after six months Accelerated stability test is: be not more than about 25%, be not more than about 20%, be not more than about 15%, be not more than about 12%, be not more than about 10%, be not more than about 8% or be not more than about 5%; Stability test is included in 40 ° of C in the Nialene bag that under 75% the relative humidity these composition stores is being sealed.

Term " Accelerated stability test " or " storage accelerated test " refer to that these methods can be carried out for simulating the test method of relatively long-term condition of storage on the impact of enzymatic activity within a relatively short time.The Accelerated stability test method is well known in the art, and it is a kind of reliable replacement scheme to the real-time stabilization test, and can predict exactly the shelf-life of biological product." Accelerated stability test " condition like this is well known in the art, and be according to " International Conference on Harmonization of Technical Requirements for Registration of Pharmaceuticals for Human Use: the stability test Ql A of new raw material medicine and preparation " (International Conference for Harmonization ofTechnical Requirements for Registration of Pharmaceuticals for HumanUse:Stability Testing of New Drug Substances and Products Ql A), combination therewith by reference.

The digestive enzyme compositions that these have little pancreatin granules (for example micropill or microgranule) of the present invention can be used for preparing pharmaceutical dosage form (for example capsule, sachet and rapid dispersion sheet), and these pharmaceutical dosage forms are suitable for experiencing pediatric patient, the elderly patients of swallow regular tablets/capsules difficulty and/or the patient with dysphagia.These dosage forms are suitable for oral administration and the enteral administration in patient.For example capsule formulation can follow food to swallow or disperse.

The capsule that stand-by little micropill or microgranule are filled can be hydroxypropyl methylcellulose capsules, and they have by weight about 2% or lower water content, can be with they dryings before with the micropill of a plurality of coatings or microgranule filling.

Compositions of the present invention can also be mixed with sachet (for example sachet of single dose), and wherein compositions of the present invention is divided into the respectively single dose of packing (for example by each dosage is introduced in the sachet).In use, these sachets are assigned in the aqueous medium of water for example, form thus the suspension that gives patient.Alternately, compositions of the present invention can directly be assigned to the mouth from sachet, or can directly be assigned on the food.When direct consumption or when directly being assigned on the food, these single dose sachets are called " dried sachet ".

Therefore the compositions of the present invention that is in different dosage form may further include one or more pharmaceutically acceptable excipient.Term " excipient " comprises other the pharmaceutically acceptable compositions with the granule blend of one or more active components that contain a kind of compositions (for example digestive enzyme), and excipient is in order to improve technique, stability, palatability, etc.The limiting examples of the excipient that is fit to comprise pharmaceutically acceptable binding agent, sweetener, essence, stabilizing agent, disintegrating agent, lubricant, fluidizer, diluent, and composition thereof.Technical staff in the medicine formulation art should be understood that, specific excipient can be carried out several functions in compositions.Therefore, for example, a kind of binding agent can also have the function of filler.

The limiting examples of the lubricant that is fit to comprise calcium stearate, magnesium stearate, sodium stearyl fumarate, stearic acid, zinc stearate, Talcum, wax, glyceryl behenate, hydrogenated vegetable oil,

And composition thereof.The limiting examples of the fluidizer that is fit to comprise colloidal silica, Talcum, and composition thereof.The limiting examples of the stabilizing agent that is fit to comprise trehalose, proline, glucosan, maltose, sucrose, mannitol, polyhydric alcohol, silica gel, aminoguanidine, pyridoxamine, and composition thereof.

The limiting examples of disintegrating agent comprise crospovidone (for example Polyplasdone XL, Polyplasdone XL-10), cross-linking sodium carboxymethyl cellulose (for example Ac-Di-Sol), Explotab (for example Explotab, Explotab CV), and composition thereof (for example microcrystalline Cellulose and Explotab or cross-linking sodium carboxymethyl cellulose and crospovidone).

The amount of disintegrating agent can be in the scope of about any the following: approximately 0.1%-30%, approximately 1%-30%, approximately l%-25%, approximately l%-20%, approximately 1%-15%, approximately 1%-10%, approximately l%-5%, approximately 5%-10%, approximately 5%-15%, approximately 5%-20%, approximately 5%-25% or approximately 5%-30% and therebetween all scopes and subrange.In one embodiment, the amount of this disintegrating agent is about 2%-4% or about 2%-3% or about 2.5%.

The diluent that is fit to and the limiting examples of filler comprise calcium phosphate dibasic anhydrous, calcium phosphate dibasic anhydrous dihydrate, tricalcium phosphate, cellulose, lactose, magnesium carbonate, microcrystalline Cellulose, microcrystalline Cellulose, starch, calcium phosphate, lactose, sucrose, mannitol, sorbitol, and composition thereof.In one embodiment, this diluent is microcrystalline Cellulose (for example Avicel (Avicel)).In another embodiment, this diluent is starch.In another embodiment, this diluent be lactose (for example, Pharmatol).In another embodiment, these compositionss of the present invention can comprise the combination of diluent, and these diluent are microcrystalline Cellulose, starch and lactose for example.

The amount of diluent can be in the scope of about any the following: approximately 0.1%-99%, approximately 1%-30%, approximately l%-25%, approximately l%-20%, approximately 1%-15%, approximately 1%-10%, approximately l%-5%, approximately 5%-10%, approximately 5%-15%, approximately 5%-20%, approximately 5%-25% or approximately 5%-30% and therebetween all scopes and subrange.In one embodiment, the amount of this diluent is about 2%-5%, about 3%-5% or about 4%.

These compositionss of the present invention can be by filling needed amount micropill or the microgranule of not coating be formulated as capsule and/or can be formulated as the granule of resistant to gastric juice polymer coating by using methods known in the art.Alternately, this digestive enzyme compositions can be formulated as the rapid dispersion sheet.Formation can comprise as the step of the peroral dosage form of rapid dispersion sheet (RDT): for example, use a kind of rotary tablet machine that a kind of micropill of described functional polymer coating or blend of microgranule and at least a pharmaceutically acceptable excipient of comprising is compacted into rapid dispersion sheet form, and if necessary suitably a kind of sign of hot pressure and/or mark.These rapid dispersion sheets are adapted among the experimenter or need to be used among the patient of Drug therapy oral administration, be used for by following a kind of administering mode treatment morbid state :-(1) swallowing whole tablets, (2) tablet is broken into for the two halves of swallowing separately, and (3) are distributed to tablet in water, swirl shape food (swirl) and the beverage of about 150mL.Formed rapid dispersion sheet will provide thus: the rapid dispersion during with water or body fluid until from the resistant to gastric juice of discharging and digestive enzyme the small intestinal intestinal fast, basically discharge completely.Before compressing, compacted mixture is lubricated internally with a kind of lubricant (for example magnesium stearate) or can lubricate drift and mould with a kind of external lubrication system (for example Matsui ExLube).

These compositionss of the present invention or dosage form (for example tablet or capsule or sachet) can be stored in the suitable packing.This is packaged in and should makes the dampness intrusion be reduced to bottom line in transportation and/or the storage process, and it is damp-prrof packing and further contains desiccant; This packing comprises sealed container, and the sealing container is made of barrier material; This desiccant (be a kind of absorb water, with the material of water reaction or adsorbed water, can reduce thus the humidity of package interior) and at least a dosage form in the sealing container.This barrier material is selected from lower group, and this group is comprised of the following: the plastics of metal, glass, plastics and metallic cover; And this desiccant is selected from lower group, and this group is comprised of the following: molecular sieve, clay, silica gel, active carbon, and composition thereof.Term " water vapor proof barrier packaging (moisture proof) " refers to have annual packing less than the about every cm3 vessel water of 0.5mg water permeability.

In the patient who suffers the disease relevant with the digestive enzyme shortage or imbalance, these compositionss of the present invention provide the absorption of the fat, protein and the carbohydrate that improve.In one embodiment, compositions of the present invention, pancreatic lipase or pancreatin compositions can be used for treating the exocrine pancreatic function relevant with various disease not complete (EPI) particularly.These diseases include but not limited to cystic fibrosis (CF).In some embodiments, such compositions can substantially be alleviated the malabsorption relevant with EPI (for example fat) among cystic fibrosis patient and other patients (comprising pediatric patient).In some embodiments, such compositions can increase to about at least 85% or more with the CFA among the cystic fibrosis patient (CF-A).Can use (or need not) realize such result with the administering drug combinations of other medicaments or compositions.In one embodiment, can realize such CF-A result without the administering drug combinations of proton pump inhibitor.

For being accredited as the have low GI pH level patient of (for example GI pH level＜about 4), the result that can be improved together with proton pump inhibitor, antacid and other medicines that improves gastrointestinal tract pH by giving these compositionss of the present invention or dosage form.For example, these compositionss of the present invention or dosage form can separate with proton pump inhibitor, antacid or other drug and give (or proton pump inhibitor, antacid, etc. give before, with its simultaneously or after it).Alternately, this proton pump inhibitor, antacid or other drug can be a kind of one-pack type with pancreatin combination of compositions of the present invention.

In another embodiment again, the invention provides a kind for the treatment of or prevention and have the method that lacks the patient of relevant imbalance with digestive enzyme, the method comprises: a kind of compositions of the present invention is given it is had the mammal of needs, said composition comprise the digestive enzyme mixture that contains animal, microorganism, fungus, bacterial origin of coating not granule, comprise with the granule of the digestive enzyme mixture that comes from pig of resistant to gastric juice polymer coating or the mixture of the granule of the granule of coating and enteric coating not.In one embodiment, this mammal is the people.

In another embodiment again, the invention provides a kind for the treatment of or prevention and have the method that lacks the patient of relevant imbalance with digestive enzyme, the method comprises the patient who a kind of compositions of the present invention or dosage form is given it is had needs, wherein compositions of the present invention or dosage form, except at least a digestive enzyme, comprise the medicament of a kind of proton pump inhibitor, antacid or other raisings GI pH.In another embodiment again, the invention provides a kind for the treatment of or prevention has the method that lacks the patient of relevant imbalance with digestive enzyme, the method comprises a kind of compositions of the present invention or dosage form and comprises the dosage combination administration of the medicament of a kind of proton pump inhibitor, antacid or other raisings GI pH.

Can comprise with the imbalance of compositions of the present invention or dosage form treatment patient wherein not or have low-level digestive enzyme or wherein client need augment the disease of digestive enzyme.For example, these diseases can comprise cystic fibrosis, chronic pancreatitis, other pancreatic diseases (hereditary pancreatitis for example, pancreatitis and allograft pancreatitis after the wound, hemochromatosis, Schwachman syndrome, lipomatosis, or hyperparathyroidism), the side effect of cancer or treatment of cancer, operating side effect (for example gastrointestinal bypass operation, Whipple operation, whole pancreatectomys, etc.) or wherein pancreatin can not arrive other diseases of intestinal, bad mixing (Billroth II formula gastrectomy for example, the gastric bypass operation of other types, gastrinoma, etc.), Drug therapy (is for example used metformin, or those autoimmune diseasees that are used for the treatment of the HIV symptom and may damage pancreas Drug therapy of diabetes for example) side effect, (for example pancreas and calculus of bile duct are sick for obstruction, pancreas and Tumors of Duodenum, ductal strictures), the malabsorption relevant with celiac disease, food anaphylaxis and aging.

The amount that compositions of the present invention or dosage form give mammal (for example, people) every day depends on expected result.Skilled doctor can leave according to him the dosage of needs to the diagnosis that disease to be treated is arranged.

For example, according to the suggestion of US FDA, for treatment people's digestive enzyme not enough (for example, relevant with cystic fibrosis), initial dose should be 500 to 1000 lipase unit/kg/ every meal, and accumulated dose is no more than the every meal of 2500 lipase unit/kg/ or 4000 lipase unit/g fat/every meal.Typically, a patient should accept at least 4 dosage form/skies, preferably follows the food administration.

For all purposes, all carry out combination with its full content by reference at these all lists of references of quoting.

Example

Vitro efficacy/the resistant to gastric juice of the micropill of example 1-3/solubility test.

Use is equipped with the potentiometric titrimeter of microburet, calomel-glass electrode system, resistance thermometer by the titration measuring lipase active of checking.USP pancreatin lipase RS or pancreatic lipase working standard.Also determine amylase activity by the titrimetry of checking, and protease is to determine by the UV detection test of checking.Realize identifying by the chromatogram (for example, at the tested enzyme (lipase, amylase and protease) of some relative retention time and the characteristic peak of reference/working standard) that relatively obtains with qualified RP-HPLC method.The peak area of the characteristic peak between test article and the reference/working standard must satisfy this standard.When according to current USP general rule＜711〉chapter by using USP instrument 1(at the basket that turns of 100rpm) during the test dissolubility, the simulated gastric fluid TS(that the digestive enzyme of certain percentage is dissolved in 800mL does not have enzyme, at 37 ± 0.5 ° of C) lasting 60min(resistant to gastric juice) in, and after this be dissolved in the phosphate buffer (by 2g sodium chloride and 9.20g dihydric phosphate are dissolved in the 1000ml water, and regulate pH to 6.0 ± 0.05 and obtain with the 1N sodium hydroxide) of 800mL pH6.0 and continue 30min; And detect 60 and the lipase active of the sample extracted out during 90min by the constant-current titration method of using checking.

Loss on drying detects (LoD) according to current USP＜731〉chapter carries out; Ground sample for 2g detects; Under vacuum, in the baking oven of 60 ° of C, determine loss on drying after dry lasting 4 hours.

Free phthalic acid content: free phthalic acid content be by qualified HPLC method (UV detections) with contrast with reference to phthalic acid measure/quantitative.

Example 1

Example 1.A is by the pancreatic lipase micropill of powder layering

With polyvidone (PVP K-30; 50g) slowly be added to 50/50 isopropyl alcohol/purify waste water (500g), constantly stir to prepare simultaneously the polymer binder solution that a kind of solid content is 10%w/w.Will from the pancreatic lipase (2000g) of science experimental protein chamber (Scientific Protein Laboratories) (LotSl) with colloidal silica (a kind of fluidizer is from the Syloid of WR Grace company) and polyvidone (50g) blend in the V-type blender of 10g.In the product bowl (product bowl) of sugared ball (60-80 order or 170-250 μ m diameter) threading from the Granurex GX-35 of Vector company (Iowa, the U.S.).With this PVP binder solution of 10% with the speed of control be sprayed to rotation material bed in, simultaneously that the digestive enzyme mixture of powders is reinforced with the speed of control via powder feeder.Optimizing Process Parameters-process air temperature in the ball forming process: about 19-20 ° of C; Product temperature: 16 ± 2 ° of C; Spinner velocity: 425RPM; Extraneous air is supplied with: 150L/min; The about 8mL/min of spray velocity: 15RPM(); Pressure drop between slit: 1.3-11mm water column.Optimizing Process Parameters in the ball dry run-plant air volume: 30CFM; Process air temperature: about 60 ° of C; Product temperature: 35 ° of C(stop drying); Spinner velocity: 180RPM; Slit volume of air: 10CFM; Process time: 40min.Therefore the micropill (LotS2) that produces has 4.1% water content (loss on drying), and the typical LoDs of the raw material lot number that imports into is 1.5-2.0%.The composition of micropill: pancreatin: 82.5%; Sugar ball: 14.0%; And polyvidone: 3.5%.As passing through the measured particle size distribution-d (0.1) of Malvern laser particle analyzer: 370 μ m; D (0.5): 520 μ m; D (0.9): 733 μ m.The particle size distribution data that uses put meter to measure is presented in the following table 1.

Table 1: the particle size distribution of pancreatin micropill (LotS2)

Mesh size	Micron	Keep %
			14	1400	0.0
20	850	0.3
			30	600	10.1
40	425	74.1
			50	300	15.4
80	180	0.2
			Dish	?	0

Resistant to gastric juice coating (the LotS3 of example 1.B micropill; Weightening finish: up to 45wt.%)

Hydroxypropyl methyl cellulose phtalate (HP-55,785.16g) slowly is added in 90/10 mixture of acetone and water, constantly stirs simultaneously until dissolving adds diethyl phthalate (DEP afterwards; 196.15g), until this plasticizer dissolving.A kind of Glatt GPCG3, it comprises following equipment: 7 " pillar, distance that bottom spray Wurster 22mm is high be the partition column gap of 15mm with ' D ' bottom air distribution grid that 200 order products keep sieve (10mm hole nozzle) covering; Use the micropill from above example 1.A to load this Glatt GPCG3, and under the spraying flow velocity of the intake velocity of the atomization air pressure of the product temperature of 37 ± 1 ° of C, 1.5 bar, 50-60m/s and 15-40mL/min, carry out coating to reach by weight 45% DR coating level with Hydroxypropyl methyl cellulose phtalate solution (15% solid content).Coating level 25%, 30%, 35% and 40% is extracted sample out.Test is at the resistant to gastric juice of the micropill of the coating level of 35wt.%, 45wt.%.Based on these data, judge that the delayed release coating of 35%w/w is enough to give resistant to gastric juice to micropill.

(the weightening finish: 35wt.%) of the resistant to gastric juice coating of example 1.C micropill

Coating level with 35wt.% prepares a collection of resistant to gastric juice micropill with the HP-55/DEP coating.Process conditions-product temperature: 37 ° of C-42 ° of C; Plant air flow velocity: about 5-60m/s.This batch coated micropill has 2.4% LoD after 105 ° of C dryings.The particle size distribution that delayed release pancreatin micropill has is: d (0.1): 445 μ m; D (0.5): 605 μ m; D (0.9): 827 μ m.

The stability test of example 1.D DR coated micropill (LotS3)

As previously discussed, carry out for the identifying of lipase, amylase and protease (reference standard that comprises them), confirm, effectiveness, resistant to gastric juice and be 6.0 completely release at pH, and the test of the resistant to gastric juice of the coated micropill of digestive enzyme.The initial testing result provides in following table 2.Owing in 30min, discharging more than 95% (detecting), considering that the resistant to gastric juice test is dispensable.The vial that will contain the gas-tight seal of delayed release micropill is placed for stability at 25 ° of C/60%RH and 40 ° of C/75%RH.

Table 2: resistant to gastric juice micropill (LotS4)

(the weightening finish: 28wt.%) of the resistant to gastric juice coating of example 1.E micropill

Use micropill (LotS2) also to prepare a collection of resistant to gastric juice micropill of the solution coating of the HP-55/DEP that is used in 80/20 in 100% acetone (containing the 10g Talcum), its coating level is 28wt.%.Process conditions-product temperature: 31-33.52 ° C; Plant air volume: 65-70CFM; Spray velocity: 15-30g/min.

Example 2

Example 2.A is by the pancreatic lipase micropill of powder layering

With polyvidone (PVP K-30; 50g) slowly be added to isopropyl alcohol (650g), constantly stir to prepare simultaneously the polymer binder solution that a kind of solid content is 7%w/w.Will from the pancreatic lipase (2000g) of science experimental protein chamber (Scientific Protein Laboratories) (LotSl) with colloidal silica (a kind of fluidizer is from the Syloid of WR Grace company) and polyvidone (50g) blend in the V-type blender of 10g.In the product bowl of sugared ball (60-80 order or 170-250 μ m diameter) threading from the Granurex GX-35 of Vector company (Iowa, the U.S.).With this PVP binder solution of 7% with the speed of control be sprayed to rotation material bed in, simultaneously that the digestive enzyme mixture of powders is reinforced with the speed of control via powder feeder.Optimizing Process Parameters-process air temperature in the ball forming process: about 19-20 ° of C; Product temperature: 16 ± 2 ° of C; Spinner velocity: 425RPM; Extraneous air is supplied with: 150L/min; The about 8mL/min of spray velocity: 15RPM(); Pressure drop between slit: 1.3-11mm water column.Optimizing Process Parameters in the dry run of ball-plant air volume: 30CFM; Process air temperature: about 60 ° of C; Product temperature: 35 ° of C(stop drying); Spinner velocity: 180RPM; Slit volume of air: 10CFM; Process time: 40min.

(the weightening finish: 30wt.%) of the resistant to gastric juice coating of example 2.B micropill

In Granurex GX-35, with resistant to gastric juice polymer HP-55/TEC/ Talcum (ratio: 10/1/5) will carry out coating from the micropill of above example 2.A with the coating level (LotS5) of a 30wt.%.Hydroxypropyl methyl cellulose phtalate (HP-55) slowly is added in the acetone in the stainless steel tank, simultaneously continuous stirring and dissolving.Triethyl citrate (TEC) is added in the solution, dissolves, and Talcum (a kind of basifier) is added in the coating solution, thereby obtain uniform dispersion.Process conditions-product temperature: 37-42 ° C; Plant air flow velocity: about 5-60m/s.

Example 3

Example 3.A is by in check round as a ball pancreatic lipase micropill

With polyvidone (PVP K-30; 50g) slowly be added to 90/10 isopropyl alcohol/in purifying waste water, constantly stir to prepare simultaneously the polymer binder solution that a kind of solid content is 7%w/w.Will be from SPL(2000g) the pancreatic lipase powder and colloidal silica (a kind of fluidizer of 10g, Cab-O-Sil M-5P from Cabot company) and polyvidone (90g) blend in the V-type blender, then pack in the product bowl from the Granurex GX-35 of Vector company (Iowa, the U.S.).PVP binder solution with this 7% with the speed of a control be sprayed to rotation material bed in, meanwhile use powder feeder (K-Tron) with the speed of a control powder to be added in the auto levelizer.Optimizing Process Parameters-process air temperature in the ball forming process: about 19-20 ° of C; Product temperature: 16 ± 2 ° of C; Spinner velocity: 180RPM; Slit volume of air: 10CFM; The about 8mL/min of spray velocity: 15RPM(); Pressure drop between slit: 1.3-11mm water column; Process time: 40min.

The moistureproof coating of example 3.B micropill

Klucel LF slowly is added in the dehydrated alcohol in the stainless steel tank, simultaneously continuous stirring and dissolving.Ethyl cellulose (EC-10) slowly is added to Klucel solution, simultaneously continuous stirring and dissolving.Magnesium stearate (Mgst) is added to coating solution, thereby obtains uniform dispersion.A kind of Glatt GPCG 3, it comprises following equipment: 6 " bottom spray Wurster 8 " high pillar, distance be the partition column gap of 15mm with ' D ' bottom air distribution grid that 200 order products keep sieve (1.0mm hole nozzle) covering; Use the micropill (1200g) from above example 3.A to be loaded into this Glatt GPCG 3; and the moistureproof coating solution (ratio is 30/45/25 Klucel/EC-10/Mgst, and solid content is 10wt.%) with protectiveness is increased to 20mL/min gradually with 5mL/min() with coating of pellets.

The resistant to gastric juice coating of example 3.C micropill

In as above disclosed Glatt GPCG 3, use resistant to gastric juice HP-55/TEC(ratio: 90/10) coating will be from the coating of pellets of above example 3.A with the coating level of a 30wt.%.

Example 4

The moistureproof coating of example 4.A micropill

Klucel LF slowly is added to purifies waste water, simultaneously continuous stirring and dissolving.Ethyl cellulose (EC-10) slowly is added to Klucel solution, simultaneously continuous stirring and dissolving.To use moistureproof coating solution (Klucel/EC-10 40/60, solid content the are 10wt.%) coating of protectiveness to obtain 10% weightening finish from the micropill (1200g) of above example 3.A.

The resistant to gastric juice coating of example 4.B micropill

The digestive enzyme capsule of example 4.C modified release

Be filled into the MR capsule that comprises digestive enzyme in the HPMC capsule with generation with the micropill of above moistureproof coating from example 3.B and from the micropill of the resistant to gastric juice coating of example 4.B with the digestive enzyme weight ratio of 1:1.In the vial of gas-tight seal, these vials randomly contain the desiccant of molecular sieve type with these HPMC capsulations.

The rapid dispersion sheet of example 4.D digestive enzyme

At first with the micropill of the resistant to gastric juice coating of above 75-85 part from example 4.B and the spray-dired mannitol of 10-15 part, the microcrystalline Cellulose (Avicel PHI02) of 10-15 part, the low replacement HPC(disintegrating agent of 2-7 part) and FD and erythrosine (C Red) blend in the V-type blender of 0.2-0.5 part continue 20 minutes, and then 0.5 part sodium stearyl fumarate is added in this blender, continues to come in about 10 minutes equably lubricant by mixing.By use rotary tablet machine with consequent compression blend compress be 500 or the RDT(rapid dispersion sheet of 1,000mg).

Example 5

The micronization of example 5.A pancreatic lipase

To spray pharmacy room (JET PHARMA) micronization d (0.95) to form 22.8 μ m under with the nitrogen purging of medium energy level from the pancreatic lipase of the d with 115 μ m (0.95) of Nordmark Arzneimittel GmbH.

Example 5.B is via the layering of gravity feeder powder:

Assemble a ventilation seed-coating machine (Pellegrini GS), be equipped with powder feeder, gas cap spraying system (aircap spraying system) and peristaltic pump.Will be as in the micronized pancreatin disclosed in the above example 5 and lactose and colloidal silica blend.Polymer adhesive and Tween 80 are dissolved in the solvent mixture that is fit in the rustless steel container, constantly stir simultaneously.Will be in the ventilation seed-coating machine of 15RPM rotation at the sugared ball (60-80 order) of 30 ° of C preheatings with discontinuous circulated layered, this circulation is: via the layering of the pancreatin mixture of powders of gravity feeder, binder solution spraying and at inlet temperature setting and the about 250-300m of 40 ° of C ³/ hour the drying that arranges of air-flow.In case medicine carrying is complete, with these micropill dryings to distillate residual solvent, be cooled to room temperature and use suitable sieve sub-sieve to discard oversize (that is,〉700 μ m) and thinner (that is,＜300 μ m) material.

Example 5.C is via the powder layering of static feeder

Assembled a ventilation seed-coating machine (Pellegrini GS), this seed-coating machine has been equipped with powder feeder, gas cap spraying system and the peristaltic pump that is connected with static gun.Will be as in the micronized pancreatin disclosed in the above example 5 and lactose and colloidal silica blend.Polymer adhesive and Tween 80 are dissolved in the solvent mixture that is fit in the rustless steel container, constantly stir simultaneously.By side by side adding pancreatin mixture of powders, spray adhesive solution via the static feeder and at the inlet temperature setting of 45 ° of C and about 250m ³/ hour the drying that arranges of air-flow, will be in the ventilation seed-coating machine of 15RPM rotation in sugared ball (60-80 order) layering of 30 ° of C preheatings.In case medicine carrying is complete, with these micropill dryings to distillate residual solvent, be cooled to room temperature and use suitable sieve sub-sieve to discard oversize (that is,〉700 μ m) and thinner (that is,＜300 μ m) material.

To further use such as front disclosed protection against the tide and/or resistant to gastric juice coating from the micropill of example 5.B or example 5.C and carry out coating to give protection against the tide and/or resistant to gastric juice characteristic.Can with the not coating of desired amount or randomly the micropill of moistureproof coating and/or the microgranule of resistant to gastric juice coating are filled in HPMC or gelatine capsule or the sachet, or with these micropills and pharmaceutically acceptable excipient blend, and be compacted into the rapid dispersion sheet to produce the digestive enzyme of desirable modified release, for the patient's who needs Drug therapy oral administration.

Embodiment 6: the sign of initial pancreatin material

Analyzed the pancreatin original material, i.e. the outward appearance of pancreatin LotNl, enzymatic activity and protease dissolution.Carry out Dissolution Rate Testing at pH 6.0, and select the conduct of protease rather than lipase for assessment of the analogue enztme of the dissolution of microgranule, in 30 minutes long processs of the test, lipase in dissolve medium, degrade (level of lipase drops to and only has 80% after about 5 minutes, and is reduced to 73% after 30 minutes).Protease dissolution and enzymatic activity (use and measure based on the method for " pancreatic lipase: to the mensuration of proteinase activity " in " American Pharmacopeia ") are presented in the following table 3.Particle size distribution is presented in the table 4.

Dissolution and the enzymatic activity of table 3:LotNl

Table 4: the particle size distribution of pancreatin LotN1 (sieve method)

Example 7 thermal cycles are on the impact of the pancreatin in the cyclohexane extraction

Carry out the test for the stability of the heat that produces in the coacervation process process and mechanical stress to pancreatin LotN2 in cyclohexane extraction: the pancreatin with 135g under continuous stirring (290RPM) is placed in the reactor that comprises the 1kg cyclohexane extraction and heating, then cooling (table 5).

Table 5: thermal cycle cohesion

After standing thermal cycle, pancreatin is filtered and dried overnight (roughly 16h) in fume hood.With the powder of gained by 500 μ m sieve sub-sieves and be stored in high density polyethylene (HDPE) (HDPE) container.(Fig. 4 A) and (Fig. 4 B afterwards before the heat treatment in cyclohexane extraction with the pancreatin LotNl of Zeiss Axioscopic microscope photographing; LotN2) microphotograph does not show the evidence of any significant change of granule on outward appearance, shape and size.These analysis results have confirmed microscopic examination (table 6).

Table 6: enzymatic activity value and protease dissolution-in cyclohexane extraction are before the thermal cycle and afterwards

¹Lipase active: test based on the conventional method of " pancreatic lipase: lipase activity determination " in " American Pharmacopeia " by using.

²Residual cyclohexane extraction: measure by gas chromatogram (being equipped with the GC of headspace sampling apparatus and flame ionization detector).

The protease of LotN2 and lipase active are before the thermal cycle that stands in cyclohexane extraction and do not demonstrate afterwards significant change.After drying at room temperature 16 hours, the residual quantity of cyclohexane extraction is negligible in fume hood, and has confirmed that pancreatin tends to absorb moisture.The protease solubility value reaches 100% within 5 minutes, and does not occur reducing in process of the test.

The preparation of example 8 pancreatin microgranules

The cyclohexane extraction of 1000g is poured in the coagulum reactor.Then, under continuous stirring (290RPM), add pancreatin, ethyl cellulose (amount of from 0.4% to 5% scope) and polyethylene (amount of from 0 to 3% scope).According to the thermal cycle heating gained mixture of table 5, then cooling.With gained pancreatin microgranule washing (one or many), filter and in fume hood dried overnight (approximately 16h), then by the screening of 500 μ m hole sizers and be stored in the HDPE container.Process chart below is provided:

¹In the washing step process, remove

²In the drying steps process, remove

Prepare three batches of microgranules by this method of main use.Coat weight (the %w/w of washing times, ethyl cellulose and polyethylene concentration and the ethyl cellulose that in end-product, condenses; Weightening finish with respect to the microgranule of the weight of initial pancreatin microgranule) is summarized in the table 7.

Table7: cohesion polymer weight, ethyl cellulose concentration, polyethylene concentration and washing times

Outward appearance, particle size distribution, residual solvent levels, dissolution and enzymatic activity with these microgranules of technical Analysis described in above-mentioned example.The microscopic evaluation of three batches of microgranules shows suitable polymer deposition (Fig. 5 A-B, Fig. 6 A-B, Fig. 7 A-B) around the pancreatin material.

Measure size and distribution according to following steps by screening.The microgranule of a certain amount of (25-50g) is poured in the HDPE bottle of 100mL; With 0.2%(w/w) the sieve screening of silicon dioxide by 150 μ m, be added in the microgranule and hand mix 2 minutes; The mixture of microgranule and Syloid 244 was set to 7 digital Octagon apparatus screening 10 minutes with amplitude.Table 8 demonstration, the granularity with microgranule (LotN3) of 5% cohesion polymer weight has the granularity of the microgranule (LotN4, LotN5) of 20% cohesion polymer weight less than those; In preparation process, use identical weight, different amount of polyethylene at LotN4 from LotN5() between do not have significant particle size differences.

Table 8: the particle size distribution of microgranule

Dissolution to LotN3 and LotN4 is measured, and 1% docusate sodium solution that this LotN3 and LotN4 are used in the cyclohexane extraction is processed, thereby obtains to be suitable for the granule of analysis of dissolution.This processing is following to be carried out: at room temperature the surfactant dissolves of 6g is prepared in cyclohexane extraction 1% docusate sodium solution in the cyclohexane extraction of 594g; The microgranule of 22g is poured in the beaker that 250mL contains the 100g docusate sodium solution, then used stainless steel propellor (250RPM) to stir 15 minutes.Microgranule filtered and in fume hood dry approximately 6h, by the screening of 500 μ m hole sizers, then be stored in the HDPE container.This method is applied in all subsequent instance.In table 9, provide dissolution and enzyme to tire.

Table 9: dissolution and enzymatic activity

Lipase in the microgranule and the enzymatic activity of protease (as measuring in above-mentioned example) are close to theoretical value, and the increase of the coat weight of the cohesion polymer of coating reduces the dissolution value.The residual cyclohexane extraction level of LotN3 is 31ppm.

Example9 preparations from the microgranule of the pancreatin with the particle size range (250 μ m-500 μ m) through selecting

Pancreatin LotN1 is sieved by 250 μ m rustless steel hole sizers, and remove little granule (" fine powder ").The part (about 40%) that is retained on the sieve is used to prepare two batches of microgranules.As showing in Fig. 8 A-B, the material of selection comprises the irregular particle of about 300 μ m-400 μ m and the very little granule of about 10 μ m-30 μ m.

Use above-described process conditions, the laboratory scale reactor of the cyclohexane extraction that contains 1kg, prepare two batches of pancreatin microgranules (table 10) with the polyethylene of the amount of scope from 0.55% to 1%.

Table10: cohesion polymer weight, ethyl cellulose concentration, polyethylene concentration and washing times

Microgranule filtered and in fume hood dried overnight (roughly 16h), by the screening of 500 μ m hole sizers, and then be stored in the HDPE container.The outward appearance of analytic product, residual solvent levels, dissolution and enzymatic activity.

Microphotograph (Fig. 9 A-B and Figure 10 A-B) shows that LotN6(prepares with the polyethylene of small amount) comprise two different microgranule groups: (a) contain some fine grain little microgranules and the microgranule that (b) contains larger particles (about 300 μ m); The LotN7 microgranule is more uniform and this particle size distribution of two batches (sieve) is similar (table 11).As what expect from microscopic examination, LotN7 has the fine grained of reduction.

Table 11: the particle size distribution of microgranule

The dissolution value of LotN7 (measuring table 11 after with the docusate sodium pretreatment) is lower than the respective sample that obtains from non-selected pancreatin (LotN3).

Table 12: the dissolution of microgranule LotN7 and mensuration.

Example 10 is from the preparation of the microgranule of the pancreatin of the selectable granularity of tool (＜250 μ m)

Pancreatin LotNl is sieved by 250 μ m rustless steel hole sizers, and use the material by sieve to prepare two batches of microgranules.The magnitude range of the pancreatin granules of selecting is from about 20 μ m to about 250 μ m, and these granules are by brokenly molding (Figure 11 A-B).

Use above-described process conditions, the pancreatin material of selecting is incorporated in the poly laboratory scale reactor that contains 1kg cyclohexane extraction and variable concentrations.Analyze microgranule (table 13).

Table 13: cohesion ethyl cellulose weight, ethyl cellulose concentration, polyethylene concentration, washing times

Microgranule filtered and in fume hood dried overnight (roughly 16h), by the screening of 500 μ m hole sizers, and then be stored in the HDPE container.With those methods analyst outward appearances, residual solvent levels, dissolution and proteinase activity in the above-mentioned example and microphotograph (Figure 11 A-B and 12A-B).The microgranule of LotN8 is slightly less than the microgranule of LotN9 (with the polyethylene preparation of high concentration).

This sieve method demonstration, microgranule larger in the microgranule of LotN8 is slightly more than the microgranule (table 14) of LotN9, and is inconsistent with microscopic examination.This shows can impact evaluation to the different measuring standard of microscope and sieve method, and therefore measuring technique always needs to specify.

Table 14: the particle size distribution of microgranule

Dissolution value (the docusate sodium solution preprocess method with 1%) for LotN9 is lower than the value (table 15) for LotN8.

Table 15: dissolution and proteinase activity

The preparation of pancreatin microgranule scope (〉 the 250 μ m of the selectable granularity of example 11 tools)

From having particle size range (〉 the 250 μ m through selecting) pancreatin, the cohesion polymer of 5% weight prepare several pancreatin microgranules, and these several pancreatin microgranules are to produce by ethyl cellulose and the polyethylene of using the same amount of using in the preparation of LotN7.Under vacuum under the room temperature nitrogen current dry pancreatin microgranule, and sieve with 500 μ m sieves.Residual cyclohexane extraction level is defined as 500ppm.Then particle size distribution, dissolution and the enzyme of determining as previously mentioned each batch are tired.

Table 16: the particle size distribution of pancreatin microgranule

Table 17: the dissolution of pancreatin microgranule and mensuration.

¹Proteinase activity: use based on the conventional method of " pancreatic lipase: protein active is measured " in " American Pharmacopeia " and test.

²Lipase active: use and test based on the conventional method of " pancreatic lipase: lipase activity determination " in " American Pharmacopeia ".

³Amylase activity: use based on the conventional method of " pancreatic lipase: amylase activity is measured " in " American Pharmacopeia " and test.

The preparation of example 12 enteric coating pancreatin microgranules

With pancreatin microgranule LotN10 and LotN11(example 11) put into Glatt-GPGG1 fluidized-bed coating machine (be equipped with 4 " Wurster plug-in unit and Munters ML1350 dehumidifier) and with it with (the HP55:TEC: Talcum=10:1:5) spraying of the coating suspension with following composition (%w/w).

Table 18: the composition of fluidized bed coating suspension

Three batches of enteric coated article agent with different coating levels have been prepared, as shown in the table 19.

Table 19: the enteric coating level of pancreatin microgranule

With end-product by 850 μ m the sieve sub-sieve and as at definite enzymatic activity and dissolubility as shown in the table 20-21.

Table 20: the particle size distribution of enteric coated article agent

Table 21: the composition of enteric coated article agent (loss on drying: 1.2%)

?	Mg/g is theoretical to be formed
		Pancreatin	475,00
Lipase	94×0.475=45UI/mg
		Protease	78×0.475=132UI/mg
Amylase	418×0.475=199UI/mg
		Ethyl cellulose	25,00
HP?55	312,50
		TEC	31,25
Talcum	156,25

Table 22: the enzymatic activity of coated particle agent and dissolution

The toleration of coating pancreatin microgranule LotN13 37 ° of C pH5 turn basket (basket) continue 60min be 43% and at the basket that turns of pH5 to continue 30min be 90%; Toleration under pH1.2 after 30 minutes be 100% and the toleration after 60 minutes be 71%.

The stability test of example 13 enteric coating pancreatin microgranules

The stability of assessment LotN14 under stable acceleration environment: microgranule is sealed in the polyethylene sachet, and then these sachets is incorporated in the NAPE bag of heat-sealing.These products stand the stability test at the relative humidity of 40 ° of C and 75%; After storing 1 month, measure enzymatic activity and dissolution (table 23).

Table 23: enzymatic activity and the dissolution of coating pancreatin microgranule

Preparation and the stability of example 14 coating pancreatin microgranules

Initial pancreatic lipase material (LotMl, 100% pancreatin) has the granularity (use is equipped with the Octagon numeral Automatic sieve of suitable sieve (Endecotte type) to finish) of 300-700 μ m, and the geometric mean diameter of calculating is 355 μ m.Figure 14 demonstration is written into the PSD that is used for these micropills of coating in the fluid bed.The coating suspension has following composition: HP-5510%, Talcum 1%, triethyl citrate 1%, ethanol 80%, acetone 8%.Fluidized bed coating configures to carry out with following technological parameter and equipment: the high 2cm of Wurster and long 15cm, the Type B plate, nozzle 0.8mm, spray velocity 3.5g/min, atomizing pressure 1.4bar, 50 ° of C of intake air temperature, intake air flow velocity 2.0 meter per seconds, 50 ° of C of baking temperature, drying time 15min.These granules be uniformly circle and have a light brown.Pancreatic lipase granule with these acquisitions has prepared dosage form, for example sachet and capsule.By the packing of enteric coating granule acquisition in the Nialene sachet of hand-stuff 2gr, then sachet is welded at 130 ° of C.Fill each hard gelatin capsule with the coated granule of 500mg and obtain these capsule formulations, with these capsule storage in the HDPE bottle.The intrinsic stability data report is in table 24-25.

Table 24.The stability of the enteric coating granule (LotM2) in the Nialene sachet

1 lipase measurement is according to European Pharmacopoeia; The U/FIP/mg value that obtains is by using the 1:14 factor to change into U/USP/mg.

Table 24 is packaged in the stability of the enteric coating granule (LotM3) in the gelatine capsule in the HDPE bottle

Stability data shows, when making up a prescription in the Nialene sachet, the enteric coating granule has guaranteed acceptable behavior.Under the relative humidity of 25 ° of C and 60%, after 12 months, these results for two kinds of dosage forms are very gratifying.As if with regard to enzymatic degradation, Nialene sachet packaging material have guaranteed better behavior.After 12 months, the lipase active that is packaged in the coated granule in the Nialene sachet keeps in fact changing under 25 ° of C, and is filled in the gelatine capsule and the identical preparation that is packaged in the HDPE bottle shows that enzymatic activity reduces.When coated granule being filled into the HPMC(water content below 3%) in capsule rather than the gelatine capsule time, the stability that contains the capsule formulation of identical pancreatic enzymes enteric coated coated granule has improved.

All these examples proves: comprise having of high dose enough little but narrow particle size distribution (for example, as the d (0.1) of the 400-800 μ m by laser diffraction measurement-d (0.9) or have as measure by screening from about 400 to the granularity of about 600 μ m or more preferably about 250 μ m to the granularity of about 500 μ m) granule digestive enzyme pharmaceutical composition or dosage form is suitable for oral or the enteral administration, show the characteristic of acceptable resistant to gastric juice and stability, for pediatric patient, elderly patients and other since dysphagia to be difficult to the patient of swallow regular tablet or capsule significant, thus by between digestive enzyme and food particle better synchronously transportation improve the digestion/absorption of nutrient and therefore improve patient dependence.The high dose, the undersized granule that comprise stabilisation digestive enzyme mixture according to these compositionss of the present invention or dosage form.

Claims

1. pharmaceutical composition that comprises a plurality of granules that contain at least a digestive enzyme, wherein these granules have low size.

2. pharmaceutical composition as claimed in claim 1, wherein these granules have the volume diameter d (v, 0.1) that is not less than about 400 μ m and the volume diameter d (v, 0.9) that is not more than 800 μ m.

3. pharmaceutical composition as claimed in claim 1, wherein these granules have the granularity less than about 800 μ m.

4. such as claim 1 or 3 described pharmaceutical compositions, wherein these granules have about 400 μ m to the granularity of about 600 μ m.

5. such as claim 1 or 3 described pharmaceutical compositions, wherein these granules have about 250 μ m to the granularity of about 500 μ m.

6. such as claim 1,2,3,4 or 5 described pharmaceutical compositions, wherein said granule has at least a coating and these granules comprise: approximately the digestive enzyme mixture of 40%-98% percentage by weight, approximately a kind of polymer, the randomly approximately inert core of 0-30% percentage by weight and randomly one or more pharmaceutically acceptable excipient of 2%-20% percentage by weight.

7. pharmaceutical composition as claimed in claim 6, wherein said granule comprises by weight about at least 60% digestive enzyme mixture.

8. pharmaceutical composition as claimed in claim 6, wherein said granule are micropills and have at least a coating and they comprise: approximately the digestive enzyme mixture of 40%-98% percentage by weight, approximately a kind of water-soluble polymer, the randomly approximately inert core of 0-30% percentage by weight and randomly one or more pharmaceutically acceptable excipient of 2%-10% percentage by weight.

9. pharmaceutical composition as claimed in claim 8, wherein this polymer is a kind of polymer adhesive.

10. pharmaceutical composition as claimed in claim 8 or 9, wherein this polymer adhesive is selected from lower group, and this group is comprised of the following: hydroxypropyl cellulose, polyvidone, methylcellulose, hydroxypropyl emthylcellulose, carboxyl alkyl cellulose, poly(ethylene oxide), vinylpyrrolidone-vinyl acetate copolymer, polysaccharide, and composition thereof.

11. pharmaceutical composition as claimed in claim 6, wherein said granule are microgranules and have at least a coating and they comprise: approximately the digestive enzyme mixture of 80%-95% percentage by weight, approximately a kind of insoluble polymer and one or more pharmaceutically acceptable excipient randomly of 5%-20% percentage by weight.

12. pharmaceutical composition as claimed in claim 11, wherein this insoluble polymer is a kind of cohesion polymer.

13. such as claim 11 or 12 described pharmaceutical compositions, wherein this polymer is ethyl cellulose.

14. such as claim 6,7,8,9 or 10 described pharmaceutical compositions, wherein this coating comprises: one or more hydrophilic polymers, one or more plasticizers and a kind of optional pharmaceutically acceptable hydrophobic material.

15. such as claim 6,7,8,9,10,11,12 or 13 described pharmaceutical compositions, wherein this coating comprises: one or more enteric polymers and one or more plasticizers.

16. such as claim 1,2,3,4,5,6,7,8,9,10,11,12,13,14 or 15 described pharmaceutical compositions, wherein this at least a digestive enzyme is selected from lower group, and this group is comprised of the following: pancreatic lipase, lipase, trypsin, chymase, chymase B, the pancreas peptidase, Carboxypeptidase A, protaminase, GEH, phospholipase, phospholipase A2, the sterol ester hydrolytic enzyme, ribonuclease, deoxyribonuclease, α-amylase, papain, chymopapain, bromelain, ficin, beta amylase, cellulase, beta galactosidase, and composition thereof.

17. such as claim 1,2,3,4,5,6,7,8,9,10,11,12,13,14 or 15 described pharmaceutical compositions, wherein this at least a digestive enzyme is a kind of mixture, and this mixture comprises at least a lipase, at least a amylase and at least a protease.

18. such as claim 1,2,3,4,5,6,7,8,9,10,11,12,13,14 or 15 described pharmaceutical compositions, wherein this at least a digestive enzyme is derived from animal, antibacterial, fungus, plant, recombinant sources or chemical modification.

19. pharmaceutical composition as claimed in claim 14, wherein this hydrophilic polymer is selected from lower group, and this group is comprised of the following: polyvinylpyrrolidone, Polyethylene Glycol, hydroxypropyl emthylcellulose, hydroxypropyl cellulose, low viscosity ethyl cellulose, vinylpyrrolidone-vinyl acetate copolymer, polyvinyl alcohol, and composition thereof.

20. pharmaceutical composition as claimed in claim 14, wherein this hydrophobic material is selected from lower group, and this group is comprised of the following: Talcum, colloidal silica and magnesium stearate, calcium stearate, zinc stearate, fatty acid, glyceryl behenate, Palmic acid tristerin, and composition thereof.

21. pharmaceutical composition as claimed in claim 15, wherein this enteric polymer is selected from lower group, and this group is comprised of the following: cellulose acetate phthalate, hydroxypropylmethyl cellulose phthalate, HPMCAS, Opaseal, and composition thereof.

22. pharmaceutical composition as claimed in claim 15; wherein this plasticizer is selected from lower group, and this group is comprised of the following: glyceryl triacetate, tributyl citrate, triethyl citrate, acetyl tributyl citrate, diethyl phthalate, dibutyl sebacate, Polyethylene Glycol, polypropylene glycol, Oleum Ricini, acetylated monoglyceride, acetylated diglycerides, hexadecanol, and composition thereof.

23. compositions as claimed in claim 15, wherein said enteric coating further comprises a kind of inorganic reagent, and the ratio of this enteric polymer and this inorganic reagent is to about 1:25 by weight from about 4:1.

24. such as claim 1,2,3,4,5,6,7,8,9,10,11,12,13,14,15,16,17,18,19,20,21,22 or 23 described pharmaceutical compositions, wherein said composition has about 3% or the lower water content of measuring by loss on drying.

25. such as claim 1,2,3,4,5,6,7,8,9,10,11,12,13,14 or 15,16,17,18,19,20,21,22,23 or 24 described pharmaceutical compositions, wherein this digestive enzyme shows after 6 months at Accelerated stability test and is not more than about 20% digestive enzyme activity loss.

26. pharmaceutical composition as claimed in claim 25, wherein this Accelerated stability test comprises said composition is stored under 40 ° of C, 75% relative humidity in a kind of Nialene bag of sealing and continues 6 months.

27. one kind for the preparation of the method such as claim 1,2,3,4,5,6,7,8,9,10,11,12,13,14 or 15,16,17,18,19,20,21,22 or 23 described pharmaceutical compositions, the method comprises by in check spheronization, powder layering or coacervation and forms granule.

28. method as claimed in claim 27, wherein this in check spheronization is carried out in the following way: with a kind of mixture of powders and randomly a kind of polymer adhesive and a kind of fluidizer direct in the powder bed in the product chambers simultaneously, a kind of polymer binder solution of spraying simultaneously, wherein this mixture of powders comprises at least a digestive enzyme with the volume median diameter d (v, 0.5) that is not more than about 25 μ m.

29. method as claimed in claim 27, wherein this powder layering is carried out in the following way: a kind of mixture of powders and optional a kind of polymer adhesive and a kind of fluidizer are directed on the inert core that is suspended in the product chambers, a kind of polymer binder solution of spraying simultaneously, wherein this mixture of powders comprises at least a digestive enzyme with the volume median diameter d (v, 0.5) that is not more than about 25 μ m.

30. method as claimed in claim 27, wherein this coacervation is to carry out with a kind of insoluble polymer that is dissolved in a kind of hydrophobic organic solvent in the presence of phase separation agent.

31. method as claimed in claim 30, wherein this insoluble polymer is ethyl cellulose, and this hydrophobic organic solvent is that cyclohexane extraction and this phase separation agent are polyethylene.

32. the method for a pharmaceutical compositions, the method comprises:

A) form the granule of at least a digestive enzyme comprise the d (v, 0.1) that has in the scope of about 400-800 μ m-d (v, 0.9) granularity.

B) randomly use a kind of coated preparation that step granule a) is carried out coating, this coated preparation comprises at least a hydrophilic polymer and at least a plasticizer; And

C) be coated on step granule a) a kind of enteric coating that comprises enteric polymer and optional a kind of plasticizer or step b) granule on.

33. the method for a pharmaceutical compositions, the method comprises:

A) form to comprise and have about 250 μ m to the granule of at least a digestive enzyme of the granularity of about 500 μ m;

34. such as claim 29 or 30 described methods, wherein step a) is undertaken by spheronization, powder layering or coacervation.

35. a dosage form, this dosage form comprise such as claim 1,2,3,4,5,6,7,8,9,10,11,12,13,14 or 15,16,17,18,19,20,21,22 or 23 described compositionss.

36. dosage form as claimed in claim 35, this dosage form are a kind of capsule, sachet or tablet.

37. dosage form as claimed in claim 36, wherein this capsule comprises and has about 3% or the hydroxypropyl emthylcellulose of water content still less.

38. a treatment or prevention have the method that lacks the patient of the imbalance be associated with digestive enzyme, the method comprise with give such as claim 1,2,3,4,5,6,7,8,9,10,11,12,13,14 or 15,16,17,18,19,20,21,22 or 23 described pharmaceutical compositions patient be used for the treatment of digestive system imbalance, exocrine pancreatic function not entirely, cystic fibrosis, I type and/or II diabetes.

39. treat or prevent and have the method that lacks the patient of the imbalance that is associated with digestive enzyme for one kind, the method comprises and will give it is had the patient of needs together with a kind of medicament that increases digestive tract pH such as claim 1,2,3,4,5,6,7,8,9,10,11,12,13,14 or 15,16,17,18,19,20,21,22 or 23 described compositionss.