JP2013525488A - Micropellet composition comprising pancreatin containing digestive enzyme mixture - Google Patents

Abstract

The present invention is intended for use in patients in need, including pediatric patients, elderly patients and adult patients, particularly patients with dysphagia or patients who are suitable for enteral administration using such compositions. The present invention relates to a small particle size composition containing pancreatin containing a digestive enzyme. In addition, the present invention is directed to compositions as particles such as micropellets or microgranules having high potency, high effective yield, and at least 10% -90% being 400-800 μm. In addition, the composition optionally has improved enteric coating and improved stability and enzyme activity associated with conventional enteric coated pancreatic enzyme particle preparations.
[Selection] Figure 2C

Description

CROSS REFERENCE TO RELATED APPLICATIONS This application claims priority to US Provisional Patent Application No. 61 / 330,768, filed May 3, 2010, the entire contents of which are incorporated by reference. It is incorporated herein.

  Pancreatic enzyme supplements were available in the United States prior to the passage of the 1938 Food, Drug and Cosmetic Act. Pancreatin enzymes with and without enteric coatings were formulated and sold until recently without regulatory approval.

  Pancreatic exocrine dysfunction (EPI) resulting from various diseases affecting the pancreas such as pancreatitis, pancreatectomy, cystic fibrosis (CF) was a symptom of using pancreatic enzyme supplements. Pancrelipase and other pancreatic enzyme products (PEPs) can be administered to at least partially ameliorate enzyme deficiencies in the production and / or secretion of pancreatic enzymes necessary to digest nutrients in food . Without these supplements, patients become severely malnourished. If this nutritional disorder is left untreated, especially in infants, it can be life threatening.

  Physiologically acceptable pancreatic enzyme mixtures having lipolytic activity, proteolytic activity and amylolytic activity of microbial origin and / or digestive enzyme mixtures of animal origin, in particular, hydrolysis of fat to glycerol and fatty acids, starch dextrin And catalyze hydrolysis to sugars, hydrolysis of proteins to amino acids and derivatives. Pancreatic enzymes are not absorbed by the gastrointestinal (GI) tract in any appreciable amount. The primary effect endpoint for the pancreatic enzyme mixture is the mean difference in fat absorption coefficient (CFA) between pancreatic and placebo treatments. Measuring both fat excretion and fat intake, CFA is determined by 72-hour stool collection during treatment. The CFA of each patient undergoing placebo treatment is used as the untreated CFA value.

  Pancrelipase is a combination of three major enzyme classes: lipase, protease and amylase, including their various cofactors and coenzymes, and is a digestive enzyme used in several essential body processes. Used to make up for loss or low levels. These enzymes are naturally produced in the pancreas and are important in the digestion of fats, proteins and carbohydrates. Pancrelipase is typically prepared from porcine pancreatic glands, but other sources such as US Pat. No. 6,051,220, US Patent Application Publication No. 2004/0057944. Also, those described in the specification of 2001/0046493 and WO260444429 can be used. These enzymes catalyze the hydrolysis of fat to glycerol and fatty acids, hydrolysis of starch to dextrins and sugars, and hydrolysis of proteins to amino acids and derivatives.

  Pancreatin is a digestive enzyme that is also used to compensate for the loss or low levels of digestive enzymes used in some essential body processes. Pancreatin contains pancreatic enzymes, ie lipases, amylases and proteases. Pancreatin differs from pancrelipase with respect to the activity levels of these three major enzymes.

  Digestion and metabolite absorption by pancreatic enzymes can occur throughout the GI passage. However, pancreatic enzymes show optimal activity under neutral to weakly alkaline conditions. Under stomach conditions, ie in the presence of acid and pepsin, most of the enzymes, especially lipases, can be irreversibly inactivated and lose biological activity. Thus, exogenously administered enzymes are generally protected from inactivation by the stomach and remain intact while passing through the stomach to the duodenum. These enzymes are preferential within 5-30 minutes in the duodenum at pH ≧ 5.5 because the activity of pancreatic enzymes is preserved under such conditions and absorption of metabolites occurs mainly in the upper intestine. To be released.

  Protection of pancreatic enzymes is typically achieved by coating with an enteric coating polymer, which protects the enzyme composition from the acidic environment of the stomach and then releases the enzyme in the small intestine. Is done. Lipase is the most susceptible pancreatic enzyme and the single most important enzyme in the treatment of malabsorption. Typically, lipase activity is monitored to determine the stability of the lipase-containing enzyme composition. While such protection is desirable, uncoated preparations also exist commercially.

  Pancreatic enzyme compositions are typically coated using conventional pan coating methods or fluidized bed coating methods, but in these methods, pancreatic enzyme particles (eg, granules, microtablets, minitablets, etc.) ) Is coated with a polymer solution or polymer suspension at a sufficiently high temperature so that the coating solvent evaporates quickly, thereby applying a relatively dry and solidified polymer coating to the enzyme particles. However, it is difficult to apply a uniform polymer coating on pancreatic enzyme particles, such as a coating suitable for infant feeding by sprinkling, using conventional pan coating methods or fluidized bed coating methods. Further, under such coating conditions, pancreatic enzyme particles are exposed to heat, moisture and oxygen that can affect enzyme stability and thus result in loss of enzyme activity. Accordingly, it would be desirable to obtain pancreatic enzyme particles coated under less severe conditions that maintain enzyme activity and stability.

  Conventional pancreatic enzyme compositions are also composed of relatively large pancreatic enzyme particles, such as pediatric patients or nasogastric (NG) tubes, nasal jejunum (NJ) tubes, gastrostomy (PEG) tubes or jejunostomy tubes, etc. Not very suitable for enteral administration. T.A. Sipos, in US Pat. No. 4,079,125 and US Pat. No. 5,302,400, is a preparation of pancreatin micropellet core that is subsequently coated with an enteric polymer, It teaches preparations including granulation, extrusion and spheronization of enzyme mixtures, binders, disintegrants, effervescent couples and bile acids. The particle size of the enteric coated pellets was 1.4-2.0 mm. U.S. Pat. No. 4,280,971 discloses by extruding a mixture of pancreatin and magnesium stearate granulated with isopropanol and spraying alternately with povidone or polyethylene glycol in isopropanol and pancreatin. It teaches the preparation of 1.5-1.7 mm long strands by spheronizing the dried strands. The particle size of the enteric coated pellets was 0.5-4 mm, preferably 1-2.5 mm. M.M. Maio, in U.S. Patent Application Publication No. 2004011562, discloses the preparation of microspheres comprising pancreatin enzyme and hydrophilic low melt polymer by melt granulation without using any solvent. Microspheres with a particle size range of 10-1500 μm are coated with an enteric polymer. Publications of US Patents such as US Pat. No. 5,378,462, US Pat. No. 5,725,880, and US Patent Application Publication No. 20070148152A1, US Patent Application Publication No. 20070148153A1 Teaches the preparation of a pancreatine micropellet core, which is then extruded with a mixture containing pancreatine, polyethylene glycol (PEG 4000) and sufficient lower alcohol to achieve extrudable firmness. Sphericalize this extrudate in the presence of liquid paraffin or isopropanol and coat with gastric resistant polymer, finally resulting in spherical to elliptical pellets with a minimum diameter of 0.7-1.4 mm or more . Difficulties in formulating pancreatin compositions due to instability of pancreatin in water and / or in the presence of moisture contribute to the aforementioned use of friendly solvents or low melt hydrophilic polymers suitable for melt extrusion spheronization It became. However, these melt extrusion methods typically produce pancreatin enzyme particles having a broad particle size distribution. For the above-mentioned problems related to the relatively large pancreatic enzyme particles of conventional pancreatic enzyme compositions and methods for producing them, pancreatic enzyme compositions composed of relatively small enzyme particles having a narrow particle size distribution are desirable. Let's go.

  Alternative pancreatic compositions have been manufactured. KY Weon et al., In WO2007013752, discloses the preparation of a pancreatin enzyme core by spraying a dispersion containing a pancreatin enzyme in an aqueous solution of a polymeric binder. The main drawback of this process is the difficulty of completing the pancreatin stratification process within 60-90 minutes of formulation preparation to avoid significant loss of activity. A. Margolin et al., In US Patent Application Publication No. 20010046493, US Patent Application Publication No. 20030017144, and International Publication No. 200604529, compositions comprising acid stable microbial lipase crystals, microbial amorphous amylase and microbial protease. As well as methods for treating conditions including EPI without the need for a gastroresistant coating. Galle et al., In U.S. Patent Application Publication No. 20040057944, disclose a preparation of a microbial enzyme mixture that has been reported to be suitable for treating EPI associated with CF. This preparation was able to retain biological activity in the pH range of 4-8, but was inactivated to some extent under the in vivo conditions of CF patients with gastric pH of 2.5-4. US Patent Application No. 12 / 034A80 (US Patent Application Publication No. 2008/0299185) describes a stable digestive enzyme composition. Scharpe, in US Pat. No. 6,051,220, has maltase, amylase and dextrinization activity for use in EPI therapy and up to 75% acid in combination with proteolytic and lipolytic enzymes Disclosed is a composition comprising an acid-stable enzyme or complex of microbial origin containing a stable lipase. US Patent Application Publication No. 20080279839 (US Patent Application No. 12 / 092,255) is a preparation of a digestive enzyme composition that has been shown to be effective in treating EPI associated with CF. At least one microbial lipase, at least one microbial amylase and preferably at least one protease from plants, all of which are preparations that are resistant to inactivation in the pH range 2-8. Teaching. US Pat. No. 6,051,220, US Patent Application Publication No. 20010046493, US Patent Application Publication No. 2003017144, US Patent Application Publication No. 20040057944, International Patent Publication No. 200604529, and Japanese Patent No. 20080279839 also describes pancreatic enzyme preparations. US Pat. No. 7,658,918 describes Zenpep®, a therapeutically effective dose of enzyme mixture in the form of HPMC capsules. Each capsule for oral administration contains enteric coated beads (1.8-1.9 mm for lipase 5,000 USP units, 10,000, 15,000 and 20,000 USP units for lipase). Is 2.2 to 2.5 mm).

  Enzyme dosing starts at 500 lipase units / kg body weight per meal for people older than 4 years and up to 2,500 lipase units / kg body weight per meal (or 10 per day) Or less than 4,000 lipase units / kg body weight), or 4,000 lipase units / g per day. A 500 milligram tablet of pancreatin usually contains about 12,500 USP units of trypsin, 12,500 USP units of amylase, and 1,000 USP units of lipase. Thus, patients are required to swallow several capsules at meals or snacks, thereby complying with dosing regimens and / or administering currently available pancreatin preparations where 90% of the particles are greater than 900 μm. It has become difficult.

  In addition, because there is a significant difference in particle size distribution between pancreatin and food preparations, the synchronized movement of these two preparations through the gastrointestinal tract is more dependent on fat and nutrient sources. Despite being important in terms of good absorption, it is often difficult to achieve and has become a major problem, especially in infants and babies. Choe et al. Have shown that gastric emptying depends only on the particle size and not the chemical composition of the pellet (Choe et al. In Euro J. Pharma Sci. 2001; 14, 347-353). There, 0.7 mm pellets containing APAP or caffeine and gunmachigraphy were used. In addition, they co-administer 0.7 mm and 3.6 mm pellets (APAP), and small particle size 0.7 mm pellets (caffeine) expel significantly faster than large particle size 3.6 mm pellets (APAP). And was absorbed using both a small liquid diet (by 35 minutes) and a standard diet (by 33 minutes) (P <0.05). The difference in gastric emptying time for these pellets was not significant in the fasted state. JH Meyer et al. Show that 1 mm spheres are expelled more consistently and faster than 2.4 or 3.2 mm spheres when taken with a 420 g or 100 g meal (<< 0.01, corresponding t test) (JH Meyer et al. Gastroenterology 1988; 94: 1315-1325). Treatment (eg, encapsulated enteric coated didanosine beads (1 × 200 mg; enteric beads about 2 mm in diameter) and enteric coated didanosine mini tablets (4 × 50 mg; enteric coated about 5 mm in diameter) Based on an open-label, randomized, single-dose, three-phase crossover study of 18 healthy male volunteers aged 18-50 with a drug withdrawal period of at least 1 week between B. Damle et al. Found that the initial gastric emptying time, defined as the time at which 95% or less of the radioactivity of didanosine dosage form for enteric beads is observed in the stomach, is obtained for enteric tablets. It was concluded that the time at which the first quantifiable concentration of didanosine, compared to the enteric beads, was observed in plasma was longer than that given. Therefore, the delay time, defined as the time between gastric emptying and onset of didanosine absorption, for enteric beads was significantly shorter than that for enteric tablets (B. Damle et al. In Br). J. Clin. Pharmacol. 2002; 54 (3): 255-261).

  Accordingly, a pharmaceutically acceptable oral delayed release composition of a pancreatin-containing digestive enzyme mixture (eg, typically protease, lipase and amylase), comprising 90% of enteric coated microparticles There is an unmet need for compositions for use in pediatric, elderly and adult patients with a particle size of ≦ 800 μm. Furthermore, such preparations may be easier to administer, especially in infants and young children.

  Narrow / small particle size distribution, high effective yield, and pharmaceutically acceptable comprising a digestive enzyme mixture of pancreatin-containing micropellets in which the diameter of at least 10% to 90% of the micropellets or microgranules is 400-800 μm A composition was found here. These can be used, for example, to produce stable digestive enzyme compositions and dosage forms suitable for use in pediatric, elderly and adult patients to at least partially ameliorate enzyme deficiencies, for example, Gastro-resistant coating comprising a plasticizer including an adhesive polymer and optionally a hydrophobic anti-tacking agent (such as talc, magnesium stearate, colloidal silicon dioxide and combinations thereof; and optionally low viscosity ethyl cellulose) Or optionally coated with a moisture resistant coating.

FIG. 1 shows a photograph of a Granurex GX-35-GXR processed insert with VEC-Lab3 fitted with a conical rotating plate and a GXR-35 insert. FIG. 2A shows a photograph of a pancreatin-containing digestive enzyme (Lot Sl) from Scientific Protein Laboratories. FIG. 2B shows a photograph of a micropellet (lot S2) prepared by powder stratification in Granurex GX-35. FIG. 2C shows a photograph of an enteric coated micropellet (Lot S3) of digestive enzyme. FIG. 2D shows a photograph of an enteric coated micropellet (Lot S4) of digestive enzyme. FIG. 3A shows a photograph of a pancreatin-containing digestive enzyme from Nordmark. FIG. 3B shows a photograph of microparticulated pancreatin-containing digestive enzyme. FIG. 4A shows a photograph of pancreatin particles (Lot Nl) before heat treatment in cyclohexane. FIG. 4B shows a photograph of pancreatin particles (Lot N2) after heat treatment in cyclohexane. FIG. 5A shows a photomicrograph of pancreatin microgranules (Lot N3, 5% coacervated polymer). FIG. 5B shows a micrograph of pancreatin microgranules (Lot N3, 5% coacervated polymer). FIG. 6A shows a photomicrograph of pancreatin microgranules (Lot N4, 20% coacervated polymer). FIG. 6B shows a photomicrograph of pancreatin microgranules (Lot N4, 20% coacervated polymer). FIG. 7A shows a photomicrograph of pancreatin microgranules (Lot N5, 20% coacervated polymer). FIG. 7B shows a photomicrograph of pancreatin microgranules (Lot N5, 20% coacervated polymer). FIG. 8A shows a photomicrograph of selected pancreatin lot Nl (> 250 μm). FIG. 8B shows a photomicrograph of selected pancreatin lot Nl (> 250 μm). FIG. 9A shows a photomicrograph of pancreatin microgranules (Lot N6, 5% coacervated polymer). FIG. 9A shows a photomicrograph of pancreatin microgranules (Lot N6, 5% coacervated polymer). FIG. 10A shows a photomicrograph of pancreatin microgranules (Lot N7, 5% coacervated polymer). FIG. 10B shows a photomicrograph of pancreatin microgranules (Lot N7, 5% coacervated polymer). FIG. 11A shows a photomicrograph of selected pancreatin lot Nl (<250 μm). FIG. 11B shows a photomicrograph of selected pancreatin lot Nl (<250 μm). FIG. 12A shows a micrograph of pancreatin microgranules (Lot N8, 20% coacervated polymer). FIG. 12B shows a photomicrograph of pancreatin microgranules (Lot N8, 20% coacervated polymer). FIG. 13A shows a photomicrograph of pancreatin microgranules (Lot N9, 20% coacervated polymer). FIG. 13A shows a photomicrograph of pancreatin microgranules (Lot N9, 20% coacervated polymer).

  In various embodiments, the present invention is a small particle size composition comprising pancreatin containing digestive enzymes, wherein pediatric, elderly and adult patients, especially dysphagic or such compositions The present invention relates to a composition for use in patients in need thereof, including patients who are suitable for enteral administration. In additional embodiments, the present invention is directed to compositions in particulate form, such as micropellets or microgranules, with high potency, high effective yield, and at least 10% to 90% are 400-800 μm particles. In addition, the composition optionally has improved enteric coating and improved stability and enzyme activity associated with conventional enteric coated pancreatic enzyme particle preparations.

  The present invention provides a pharmaceutical composition comprising, consisting essentially of, or consisting of a plurality of particles comprising at least one digestive enzyme, wherein the particles have a low particle size dimension. set to target. Specifically, the particles have a volume diameter d (v, 0.1) of 400 μm or more and a volume diameter d (v, 0.9) of 800 μm or less, as measured by laser diffraction, or the particles Has a particle size of less than about 800 μm as measured by sieving. In certain embodiments, the particles, when screened and measured, range from about 200 μm to about 700 μm, from about 200 μm to about 600 μm, from about 400 μm to about 600 μm, or from about 250 μm to about 500 μm, and all ranges in between and It has a partial range of particle sizes.

  The particles comprise 40-98% by weight digestive enzyme mixture, 2-20% by weight polymer, optionally 0-30% by weight inert core, and optionally one or more pharmaceutically acceptable. Excipients comprising, consisting essentially of, or consisting of. The particles can comprise at least 60% by weight of the digestive enzyme mixture. The particles can have one or more coating layers.

  The particles can be micropellets, which are 40-98 wt% digestive enzyme mixture, 2-10 wt% water-soluble polymer, optionally 0-30 wt% inert core, And optionally comprises, consists essentially of or consists of one or more pharmaceutically acceptable excipients. The micropellets can have one or more coating layers. The polymer that is a component of the micropellet is a pharmaceutically acceptable water-soluble polymer, hydroxypropylcellulose, povidone, methylcellulose, hydroxypropylmethylcellulose, carboxyalkylcellulose, polyethylene oxide, vinylpyrrolidone-vinylacetate copolymer, polysaccharide and It can be selected from the group consisting of mixtures thereof. The micropellets can optionally be selected from the group consisting of low viscosity ethyl cellulose, cellulose acetate, cellulose acetate butyrate, polyvinyl acetate, neutral methacrylate copolymer, ammonio-methacrylate copolymer and mixtures thereof. Water-insoluble polymers can be included.

  The particles can further be microgranules, the microgranules comprising 80-95 wt% digestive enzyme mixture, 5-20 wt% water insoluble polymer, and optionally one or more pharmaceutically. Contains, consists essentially of, or consists of acceptable excipients. The water-insoluble polymer of the microgranules is a coacervated polymer deposited on the microgranules. In particular embodiments of the present invention, the water-insoluble polymer is selected from ethyl cellulose, cellulose acetate, cellulose acetate butyrate, polyvinyl acetate, neutral methacrylate copolymer, ammonio-methacrylate copolymer and mixtures thereof.

  The term “digestive enzyme” refers to an enzyme in the digestive tract that breaks down food components so that an organism can absorb it. The term “stabilized digestive enzyme” means a digestive enzyme that maintains substantial enzyme activity after long-term storage. The terms “pancrelipase” or “pancreatin” are also used herein, both terms referring to a mixture of several enzymes including amylase, lipase and protease enzymes.

  Non-limiting classes of digestive enzymes suitable for use in the present invention include lipases, amylases and proteases. Non-limiting examples of digestive enzymes include pancrelipase, lipase, trypsin, chymotrypsin, chymotrypsin B, pancreatopeptidase, carboxypeptidase A, carboxypeptidase B, glycerol ester hydrolase, phospholipase, phospholipase A2, sterol ester hydrolase, Examples include ribonuclease, deoxyribonuclease, α-amylase, papain, chymopapain, bromelain, ficin, β-amylase, cellulase, β-galactosidase and mixtures thereof. These enzymes can be obtained by extraction from the pancreas, artificially produced, or obtained from sources other than the pancreas, such as microbial forms, plants or other animal tissues.

  Lipases are enzymes that catalyze the hydrolysis of lipids to glycerol and simple fatty acids. Examples of lipases suitable for the present invention include, but are not limited to, animal lipases (eg, porcine lipase), bacterial lipases (eg, Pseudomonas lipase and / or Burkholderia lipase), fungal lipases, Plant lipase, recombinant lipase (eg, produced by recombinant DNA technology by culturing a suitable host cell selected from any one of bacterial, yeast, fungus, plant, insect or mammalian host cells Ie, a recombinant lipase comprising an amino acid sequence that is homologous or substantially identical to a naturally occurring sequence, encoded by a nucleic acid that is homologous or substantially identical to a naturally occurring lipase-encoding nucleic acid Lipase), synthetic lipase, chemical repair Lipases and mixtures thereof.

  Amylase is a glycoside hydrolase enzyme that degrades starch, such as α-amylase, β-amylase, acid α-glucosidase, salivary amylase (such as puchialin) and the like. Amylases suitable for use in the present invention include, but are not limited to, animal amylases, bacterial amylases, fungal amylases (eg, Aspergillus amylase such as Aspergillus oryzae amylase), plant amylases, combinations Recombinant amylases (eg, those produced by recombinant DNA technology, ie naturally occurring, by culturing a suitable host cell selected from any one of bacterial, yeast, fungi, plant, insect or mammalian host cells. A recombinant amylase comprising an amino acid sequence that is homologous or substantially identical to an existing sequence, an amylase encoded by a nucleic acid that is homologous or substantially identical to a naturally occurring amylase-encoding nucleic acid, etc. ), Chemical modification Amylase and mixtures thereof.

  Proteases are generally enzymes (proteinases, peptidases, proteolytic enzymes) that cleave peptide bonds between amino acids of proteins. Non-limiting examples of proteases suitable for use in the present invention include serine proteases, threonine proteases, cysteine proteases, aspartic proteases (eg, plasmepsin) metalloproteases and glutamate proteases. In addition, examples of proteases suitable for use in the present invention include, but are not limited to, animal proteases, bacterial proteases, fungal proteases (eg, Aspergillus melleus protease), plant proteases, recombinant Proteases (eg naturally occurring by culturing appropriate host cells selected from any one of bacteria, yeast, fungi, plants, insects or mammalian host cells, ie, naturally occurring A recombinant protease comprising an amino acid sequence that is homologous or substantially identical to the sequence to be encoded, a protease encoded by a nucleic acid that is homologous to or substantially identical to a naturally occurring protease-encoding nucleic acid, etc.) Chemically modified proteases and Mixtures thereof.

  The composition of the present invention comprises one or more lipases (ie, one lipase, or two or more lipases), one or more amylases (ie, one amylase, or two or more amylases). One or more proteases (ie, one or more proteases), a mixture of one or more lipases and one or more amylases, one or more lipases and one or more Including a mixture of a plurality of proteases, a mixture of one or more amylases and one or more proteases, or a mixture of one or more lipases and one or more amylases and one or more proteases be able to.

  In one embodiment, the digestive enzyme comprises a variety of lipases (eg, lipase, colipase, phospholipase A2, cholesterol esterase), proteases (eg, trypsin, chymotrypsin, carboxypeptidase A and B, elastase, kininogenase, trypsin inhibitor), amylase, And optionally a porcine pancreas extract containing nucleases (ribonucleases, deoxyribonucleases). In another embodiment, the digestive enzyme is substantially similar to human pancreatic juice. In yet another embodiment, the digestive enzyme is pancrelipase USP.

  While porcine pancreatic enzyme preparations are widely used, bovine enzyme preparations containing about 75% less lipase activity are an alternative for patients who do not take porcine products. There are also microbial preparations of pancreatic enzymes (lipases, amylases and proteases). Certain bacteria (eg, Burkholderia plantarii) and fungi (eg, Aspergillus niger, Rhizopus arrizus) have substantial lipolytic activity and gastric acid degradation activity. It has been shown to produce pancreatin enzymes with greater resistance.

  The lipase activity of the composition is about 2,500 to about 28,000 IU (USP method), about 2,700 to about 3,300 IU, about 4,500 to about 5,500 IU, about 9,000 to about 11,000 IU. , About 13,500 to about 16,500 IU, and about 18,000 to about 22,000 IU, about 25,000 to about 27,500 IU, and all ranges and subranges therebetween. The composition has an amylase activity of about 6,000 to about 22,500 IU (USP), such as about 6,400 to about 26,300 IU, about 10,700 to about 43,800 IU, about 21,500 to about 87, It can be 500 IU, about 32,100 to about 131,300 IU, about 42,900 to about 175,000 IU, about 53,600 to about 218,700 IU, and all ranges and subranges therebetween. The protease activity of the composition is from about 5,000 to about 130,000 IU (USP), such as from about 5,000 to about 15,400 IU, from about 8,400 to about 25,700 IU, from about 16,800 to about 51, It can be 300 IU, about 25,000 to about 77,000 IU, about 33,500 to about 102,800 IU, about 41,800 IU to about 128,300 IU, and all ranges and subranges therebetween.

  In one embodiment, the lipase activity ranges from about 2,700 to about 3,300 IU, the amylase activity ranges from about 6,400 to about 26,300 IU, and the protease activity ranges from about 5,000 to The range is about 15,400 IU (USP). In another embodiment, the lipase activity ranges from about 4,500 to about 5,500 IU, the amylase activity ranges from about 10,700 to about 43,800 IU, and the protease activity ranges from about 8,400 to It is in the range of about 25,700 IU (USP). In another embodiment, the lipase activity ranges from about 9,000 to about 11,000 IU, the amylase activity ranges from about 21,500 to about 87,500 IU, and the protease activity ranges from about 16,800. It is in the range of about 51,300 IU (USP). In another embodiment, the lipase activity ranges from about 13,500 to about 16,500 IU, the amylase activity ranges from about 32,100 to about 131,300 IU, and the protease activity ranges from about 25,000. To about 77,000 IU (USP). In yet another embodiment, the lipase activity ranges from about 18,000 to about 22,000 IU, the amylase activity ranges from about 42,900 to about 175,000 IU, and the protease activity ranges from about 33,000. The range is from 500 to about 102,800 IU (USP). In yet another embodiment, the lipase activity ranges from about 25,000 to about 27,500 IU, the amylase activity ranges from about 53,600 to about 218,700 IU, and the protease activity ranges from about 41, The range is from 800 IU to about 128,300 IU (USP).

  In yet another embodiment, the lipase activity ranges from about 5,000 PhEur lipase units to about 30,000 PhEur lipase units, and the activity is about 5,000 or about 10,000 or about 15,000 or 20,000. 000 or about 30,000 PhEur lipase units.

  The ratio of amylase / lipase in the composition can range from about 1 to about 10, and in certain embodiments, the ratio of amylase / lipase is from about 2.38 to about 8.75 (the enzyme assay is Implemented in accordance with USP). The protease / lipase ratio in the compositions or oral dosage forms of the present invention can range from about 1 to about 8, and in certain embodiments from about 1.86 to about 5.13 (enzyme assay). Is implemented in accordance with USP).

  The total amount (by weight) of the digestive enzyme in the composition or dosage form of the present invention is about 20-100%, about 40-100%, about 40-90%, about 40-80%, about 40-70%. About 40-60%, about 40-50%, and all or subranges therebetween, or about 20%, about 30%, about 40%, about 50%, about 60%, about 70%, It can be 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 (eg, pancrelipase) is about 55-65%.

  The term “particle” includes, but is not limited to, about 200 μm to about 800 μm, about 200 μm to about 700 μm, about 200 μm to about 600 μm, about 200 μm to about 500 μm, about 200 μm to about 400 μm, about 250 μm, as measured by sieving. To about 800 μm, about 250 μm to about 700 μm, about 250 μm to about 600 μm, about 250 μm to about 500 μm, about 300 μm to about 800 μm, about 300 μm to about 700 μm, about 300 μm to about 600 μm, about 300 μm to about 500 μm, about 400 μm to about Particle sizes typically in the range of about 100 μm to about 800 μm, including 800 μm, about 400 μm to about 700 μm, about 400 μm to about 600 μm, about 400 μm to about 500 μm, about 700 μm to about 800 μm and all subranges therebetween Having microparticles, microgranules, bee Pellets, granulates, microspheres, powders and the like.

  Particles (such as micropellets and microgranules) can protect the enzyme from the external environment (such as from moisture, a protective coating), or can function as a separation membrane (sealing coating), or regulate drug release (Functional coating) can have one or more coatings. The coating composition comprises one or more hydrophilic polymers, and one or more plasticizers, and optionally pharmaceutically acceptable hydrophobic materials, and mixtures thereof. The hydrophobic material may have anti-tacking properties (eg, talc, magnesium stearate, colloidal silicon dioxide such as stearic acid, palmitic acid, or fatty acid esters such as glyceryl monostearate, glyceryl palmitostearate) , And mixtures thereof). Depending on the source of the digestive enzyme mixture and the intended use of the composition, the ratio of hydrophilic polymer to hydrophobic agent can range from about 10: 1 to about 1:10 by weight. In another embodiment, the ratio of hydrophilic polymer to hydrophobic agent can range from about 5: 1 to about 1: 5 by weight. Non-limiting examples of hydrophilic polymers include hydroxypropyl cellulose, hydroxypropyl-methyl cellulose, polyvinyl alcohol, vinyl pyrrolidone-vinyl acetate copolymer (eg, Kollidon® VA64 from BASF), low viscosity ethyl cellulose ( For example, when measured using a Ubbelohde viscometer, a 5% solution in 80/20 toluene / alcohol has a viscosity at 25 ° C. of 10 cps or less) and mixtures thereof.

  Non-limiting examples of suitable plasticizers include triacetin, tributyl citrate, triethyl citrate, tri-n-butyl acetyl citrate, diethyl phthalate, dibutyl sebacate, polyethylene glycol, polypropylene glycol, castor oil, acetylated Monoglycerides, acetylated diglycerides, cetyl alcohol and mixtures thereof. In one embodiment, the plasticizer is a non-phthalate plasticizer.

  In one embodiment, the hydrophilic polymer comprising the sealing coating is hydroxypropyl cellulose (eg, Klucel LF) in combination with low viscosity ethyl cellulose (eg, Ethylcellulose Standard Premium 7 or 10), and the plasticizer is triethyl citrate. In another embodiment, the hydrophilic polymer comprising the coating is hydroxypropyl cellulose, the plasticizer is triethyl citrate, and the anti-tacking agent is talc. In certain other embodiments, the hydrophilic polymer is a mixture of hydroxypropyl cellulose and low viscosity ethyl cellulose, the plasticizer is tributyl sebacate, and the hydrophobic agent is glyceryl palmitate-stearate. The sealant coating is about 1% to about 20% by weight of the core coated with the drug-containing sealant, such as about 1%, about 2%, about 3%, about 4%, about 5%, about 7%, About 10%, about 12%, about 15%, about 17%, or about 20% (including all ranges and subranges therebetween) can be configured.

  For example, with respect to coating on a substrate, the term “arranged on” refers to, for example, the relative position of the coating with respect to the substrate and does not require the coating to be in direct contact with the substrate. For example, a first coating “placed on” a substrate may be in direct contact with the substrate, or one or more intervening materials or coatings may be between the first coating and the substrate. Sometimes inserted. In other words, for example, a delayed release (DR) or enteric polymer coating disposed on a micropellet or microgranules refers to an enteric coating deposited directly on the particle, or on the particle. It may also refer to the DR coating deposited on the deposited protective coating. Where the coating protects the drug from the gastrointestinal environment, the coating composition includes one or more enteric polymers and one or more plasticizers. This type of coating can be placed on uncoated micropellets or microgranules, or on coated (eg, protectively coated or hermetically coated) particles.

  The term “enteric polymer” refers to a polymer that protects digestive enzymes from gastric contents, eg, insoluble at acidic pH levels (eg, in the stomach) but higher pH levels (eg, in the lower gastrointestinal tract). A sufficiently slow hydration or erosion rate that ensures that the degradation or dissolution of the polymer, or gastric contents and digestive enzymes, is relatively low in the stomach, as opposed to the rest of the gastrointestinal tract Means a polymer having The term “pH sensitive” as used herein refers to a polymer that exhibits pH-dependent solubility. The enteric coating includes at least one enteric polymer and at least one plasticizer (eg, hypromellose phthalate, HP-55, and triethyl citrate). In one embodiment, the ratio of enteric polymer to plasticizer ranges from about 7: 3 to about 9: 1 by weight. In another embodiment, the ratio of enteric polymer to plasticizer is 9: 1 by weight and the enteric coating is about 10 wt% to about 10 wt% based on the weight of the coated micropellets or microgranules. It can be in the range of about 50% by weight. Enteric coatings range from about 25% to about 40% by weight, and coating levels are about 10%, about 25%, about 30%, about 33%, about 35%, about 40%, about 40% by weight. It can be 50%.

  Examples of enteric polymers suitable for the present invention include, but are not limited to, cellulose acetate phthalate and hydroxypropyl methylcellulose fullerate, hydroxypropyl methylcellulose acetate succinate, polyvinyl acetate phthalate, cellulose acetate succinate, pH sensitive methacrylic acid. Acid-methyl methacrylate copolymers (eg, Eudragit S 100, Eudragit L 100, Eudragit FS, etc.), fatty acids, waxes, shellac and mixtures thereof. In certain embodiments, the enteric polymer is soluble in an organic solvent.

  Non-limiting examples of plasticizers suitable for incorporation into the enteric coating layer include triacetin, tributyl citrate, triethyl citrate, tri-n-butyl acetyl citrate, cetyl alcohol, diethyl phthalate, dibutyl sebacate, Examples include polyethylene glycol, polypropylene glycol, castor oil, acetylated monoglyceride, acetylated diglyceride and mixtures thereof. In one embodiment, the plasticizer is a non-phthalate plasticizer.

  The enteric polymer can further comprise at least one inorganic agent such as talc, which can range from about 10: 1 to about 1:60 by weight. In another embodiment, the ratio of enteric polymer to at least one inorganic material ranges from about 8: 1 to about 1:50 by weight. In another embodiment, the ratio of enteric polymer to at least one inorganic material ranges from about 6: 1 to about 1:40 by weight. In another embodiment, the ratio of enteric polymer to at least one inorganic material ranges from about 5: 1 to about 1:30 by weight. In another embodiment, the ratio of enteric polymer to at least one inorganic material ranges from about 4: 1 to about 1:25 by weight. In another embodiment, the ratio of enteric polymer to at least one inorganic material ranges from about 4: 1 to about 1: 9 by weight. In another embodiment, the ratio of enteric polymer to at least one inorganic material ranges from about 10: 4 to about 10: 7 by weight.

  In yet another embodiment, the enteric coating can further comprise at least one anti-tacking agent. Non-limiting examples of suitable anti-tacking agents include colloidal silicon dioxide, magnesium stearate, talc, glyceryl monostearate and mixtures thereof. In one embodiment, the anti-tacking agent is talc. Depending on the intended use of the enteric polymer or composition, the ratio of enteric polymer to anti-tacking agent can range from about 10: 0 to about 6: 4 by weight. In another embodiment, the ratio of enteric polymer to anti-tacking agent ranges from about 9: 1 to about 7: 3 by weight.

  Unless otherwise indicated, the amounts of various coatings or layers described herein (“coating weight”) are applied to particles (micrometers) added by dry coating relative to the initial weight of the particles or beads before coating. Expressed as percent weight increase of the pellets or microgranules). Thus, 10% coating weight refers to a dry coating that increases particle weight by 10%.

  The composition of the present invention is a controlled spheronization or powder layering with suitable device (such as Granurex GX-35 from Vector Corporation), pan coating based on the disclosure of US Pat. No. 6,569,462 At least one having a median particle size of about 30 μm or less, optionally by coating the micropellets with a hydrophilic polymer solution optionally containing a hydrophobic anti-tacking agent, such as in-machine powder layering Forming a micropellet containing seed digestive enzymes. Both coated and uncoated micropellets are optional, especially in the case of micropellets containing porcine-derived digestive enzyme mixtures, with gastroresistant coatings containing enteric polymers and optionally plasticizers. Coated.

  For the production of small spherical micropellets with smooth surface texture, either by controlled spheronization or powder layering, to achieve micropellets with smooth morphology for coating with functional polymers In addition, it is necessary to use digestive enzymes having a median diameter of less than 30 μm, preferably less than 20 μm. Laser particle size analyzers such as the Mastersizer from Malvern Instruments are typically used to measure the particle size distribution of fine powders and granular microparticles by the “dry cell” or “wet cell” method. The powder suspension is measured using a low-angle laser beam and the particle size distribution is calculated as indicated in the user manual (The Small Volume Master Sample manual Dispersion Unit Dispersion Manual). The volume median diameter d (v, 0.5) was defined as the diameter over 50% and under 50% of the distribution. The volume diameter d (v, 0.9) was defined as the diameter where 90% of the volume distribution was below this value and greater than 10%. The volume diameter d (v, 0.1) was defined as the diameter where 10% of the volume distribution was below this value and 90% was above this value. In certain embodiments of the invention, the particle size range of the micropellet core is from about 400 μm to about 600 μm. The particle size distribution of the fine powders and microparticles is also measured by the sonic shifter method using a series of sieves.

  Both controlled spheronization and powder stratification steps require micronized drug particles (eg most desirably: d (v, 0.5) <20 μm and d (v, 0.9) <50 μm). In order to retain such fine powder inside the product layer, both air velocity and total air flow need to be optimized / balanced and controlled during the process. Significant time savings are achieved by adding the active in powder form rather than by dissolution or suspension in a polymer binder solution and spraying. This process provides a high effective yield with a narrow particle size distribution.

  During powder layering, the rotor insert of a reactor (such as Granurex GX-35) is loaded with an inert core such as sugar spheres of the desired particle size. A fine powder mixture containing digestive enzymes, a flow-aid such as Cab-O-Sil (colloidal silicon dioxide) and optionally a polymer binder are fed to the machine by a high precision powder feeder, The polymer binder solution for binding the digestive enzyme powder to the outside of the core material is simultaneously sprayed and dispersed directly on the inert core. Therefore, the micropellets begin to grow while layering. Balancing the powder feed rate and spray rate during powder layering to avoid either overwetting and agglomeration or inefficient sticking of the powder to the inert core leading to low yields It is the most important parameter to achieve. After all the free powder has been combined as micropellets, spraying is stopped and the micropellets are dried. Drying can be performed, for example, by using only slit air or by weakening an air device called Mov-A-Blo.

  During controlled spheronization, the rotor insert of suitable equipment (such as Granurex GX-35), digestive enzymes, flow aids such as Cab-O-Sil (colloidal silicon dioxide) and optionally polymer binders With a fine powder mixture. As the powder is added into the unit by a powder feeder (K-Tron) at a controlled rate, the polymer binder solution is simultaneously sprayed onto the fine powder layer at a controlled rate. The fine mist of the binder solution facilitates the binding of the digestive enzyme powder mixture onto the micropellets that grow while layering. In addition, process parameters such as air velocity, air flow rate, product temperature, spraying rate are optimized / controlled, thereby resulting in inefficiency of continuous powder layer on wet / agglomerate or micropellets causing low yield Avoid general sticking.

  Enteric coating solution can be further applied to micropellets containing uncoated or seal-coated digestive enzymes via fluid bed coating or pan coating, or via Granurex GX-35, etc. .

  In addition to controlled spheronization and powder stratification methods, small particle size particles containing digestive enzymes start with a pancreatin raw material having a particle size (as measured by sieving methods) between about 250 μm and 500 μm. Can be prepared by a coacervation step. In this step, digestive enzyme particles are treated with a solution containing a water-insoluble polymer dissolved in a hydrophobic organic solvent such as cyclohexane. The water-insoluble polymer solution further contains a phase separation agent. This step heats the solution of insoluble polymer, hydrophobic organic solvent and phase separator and suspended digestive enzyme particles to 80 ° C. in a coacervation reactor and then cools the mixture to about 25 ° C. Including that. Phase separation agents include polyethylene butyl rubber, polybutadiene, polyisobutylene, organosilicon polymers and paraffin. This process does not affect the enzymatic stability of the enzyme. The resulting digestive enzyme microgranules have a low moisture content (less than 3%) and are about 200 to about 700 microns, about 200 to about 600 microns, about 250 to about 500 microns, and all ranges in between And having a particle size (when measured by sieving) of less than about 800 microns, including subranges. The microgranules having a coacervated polymer can be further coated with an enteric coating solution comprising an enteric polymer dissolved in a pharmaceutically acceptable solvent. The enteric coating step includes coating the microgranules with a fluidized bed coating means or pan coating means using an enteric coating solution. A preferred enteric polymer is one that is soluble in an organic solvent and is hydroxypropylmethylcellulose phthalate. A preferred solvent is acetone. The resulting enteric-coated microgranules have a water content of less than about 3%, preferably less than about 2%, and may be about 1.2% (according to loss on drying (LoD) test (USP method)). When measuring).

  The water content of the compositions and oral dosage forms of the present invention comprising particles of low particle size dimension containing at least one digestive enzyme is about 4,5% or less, about 3% or less, about 2.5% or less About 2% or less, about 1.5% or less, and all ranges and subranges between them (eg, between about 1.5% to about 4.5%, about 1.5% to about 1 0.5%, between about 1.5% and about 2.5%). The compositions or oral dosage forms of the present invention maintain a low moisture content upon storage and are substantially more stable as compared to conventional compositions that are maintained at a high moisture content, eg, 4% or higher. The water content of the dosage form and composition of the present invention is measured by the loss on drying measurement method (LoD, USP method).

  The loss of digestive enzyme activity exhibited by the compositions and dosage forms of the present invention is about 25% or less, about 20% or less, about 15% or less, about 12% or less, about 10% after 6 months of accelerated stability testing. Hereinafter, it is about 8% or less or about 5% or less. This stability test involves storing the composition in a sealed Nialene bag at 40 ° C. and 75% relative humidity.

  The term “accelerated stability test” or “accelerated storage test” refers to a test method used to simulate the effect of relatively long storage conditions on enzyme activity, which is performed in a relatively short time. can do. Accelerated stability testing is known in the art to be a reliable alternative to real-time stability testing and can accurately predict the lifetime of a biological product. The conditions of such “accelerated stability tests” are known in the art and are incorporated herein by reference, International Conference for Harmonization of Technical Requirements for Registration of Pharmaceuticals for Pharmaceuticals. Conforms to Substances and Products QlA.

  The digestive enzyme composition containing fine pancreatin particles (such as micropellets or microgranules) of the present invention is a pediatric patient, elderly patient and / or patient with dysphagia who feels difficulty swallowing conventional tablets / capsules Can be used to prepare pharmaceutical dosage forms (eg, capsules, sachets and rapidly dispersing tablets) suitable for These dosage forms are suitable for oral and enteral administration to patients. Dosage forms such as capsules can be swallowed or dispersed with food.

  The capsules filled with fine micropellets or microgranules can be hydropropyl-methylcellulose capsules, whose water content is not more than about 2% by weight and before filling with multiple coated micropellets or microgranules. Can be dried.

  The compositions of the invention can also be formulated into sachets, such as single dose sachets, in which the compositions of the invention are packaged separately, for example by placing each dose in a sachet. Divide into single doses. In use, these sachets are formulated in an aqueous medium such as water, thereby forming a suspension for administration to the patient. Alternatively, the compositions of the invention can be administered directly to the mouth from a sachet or formulated directly into food. Such single dose sachets are referred to as “dry sachets” when taken directly or formulated directly into food.

  Accordingly, the compositions of the present invention in various dosage forms can further comprise one or more pharmaceutically acceptable excipients. The term “excipient” refers to other pharmaceutically acceptable ingredients blended with particles containing the active ingredients (eg, digestive enzymes) of the composition to improve processability, stability, palatability, etc. including. Non-limiting examples of suitable excipients include pharmaceutically acceptable binders, sweeteners, flavorings, stabilizers, disintegrants, lubricants, glidants, diluents and mixtures thereof. Can be mentioned. One skilled in the art of pharmaceutical formulation will recognize that certain excipients may serve multiple functions in the composition. Thus, for example, the binder can also function as a bulking agent.

  Non-limiting examples of suitable lubricants include calcium stearate, magnesium stearate, sodium stearyl fumarate, stearic acid, zinc stearate, talc, wax, glyceryl behenate, Sterotex®, Stearowet® Trademark) and mixtures thereof. Non-limiting examples of suitable glidants include colloidal silicon dioxide, talc and mixtures thereof. Non-limiting examples of suitable stabilizers include trehalose, proline, dextran, maltose, sucrose, mannitol, polyol, silica gel, aminoguanidine, pyridoxamine and mixtures thereof.

  Non-limiting examples of disintegrants include crospovidone (eg, Polyplastdone XL, Polyplastdone XL-10), croscarmellose sodium (eg, Ac-Di-Sol), sodium starch glycolate (eg, Explotab, Explotab CV ) And mixtures thereof, microcrystalline cellulose, sodium starch glycolate or croscarmellose sodium and crospovidone.

  The amount of disintegrant is about 0.1-30%, about 1% -30%, about 1% -25%, about 1% -20%, about 1% -15%, about 1% -10%, about 1% to 5%, about 5% to 10%, about 5% to 15%, about 5% to 20%, about 5% to 25%, or about 5% to 30%, and all ranges in between and Any range of a partial range may be sufficient. In one embodiment, the amount of disintegrant is about 2% to 4% or about 2% to 3% or about 2.5%.

  Non-limiting examples of suitable diluents and bulking agents include anhydrous calcium hydrogen phosphate, anhydrous calcium hydrogen phosphate dihydrate, tricalcium phosphate, cellulose, lactose, magnesium carbonate, microcrystalline cellulose, microcrystalline cellulose , Starch, calcium phosphate, lactose, sucrose, mannitol, sorbitol and mixtures thereof. In one embodiment, the diluent is microcrystalline cellulose (eg, Avicel). In another embodiment, the diluent is starch. In another embodiment, the diluent is lactose (eg, Pharmatrol). In another embodiment, the composition of the present invention may comprise a combination of diluents such as microcrystalline cellulose, starch and lactose.

  The amount of diluent is about 0.1 to 99%, about 1% to 30%, about 1% to 25%, about 1% to 20%, about 1% to 15%, about 1% to 10%, about 1% to 5%, about 5% to 10%, about 5% to 15%, about 5% to 20%, about 5% to 25%, or about 5% to 30%, and all ranges in between and Any range of a partial range may be sufficient. In one embodiment, the amount of diluent is about 2% to 5%, about 3% to 5%, or about 4%.

  The composition of the present invention is formulated as a capsule by filling the required amount of uncoated micropellets or microgranules and / or particles coated with gastroresistant polymer using methods known in the art. Can be Alternatively, the digestive enzyme composition can be formulated as a rapidly dispersing tablet. The step of forming an oral dosage form as a rapidly dispersible tablet (RDT) comprises, for example, micropellets or microgranules coated with said functional polymer and at least one pharmaceutically acceptable excipient. The blend can include compression into a rapidly dispersible tablet form using a rotary tablet press and suitable tooling with a logo and / or score if desired. Rapidly dispersible tablets include (1) a mode of swallowing the entire tablet, (2) a mode of swallowing the tablet in half, and (3) about 150 mL of water, swirl and beverage. Suitable for oral administration to a subject or patient in need of an agent for treating a disease state by one of the dispersed modes of administration. The rapidly dispersible tablets thus formed disperse rapidly upon contact with water or bodily fluids, are gastroresistant until excreted from the stomach, and rapidly and substantially digestive enzymes in the small intestine. It will release completely. The compressed mixture can be smoothed from the inside using a lubricant such as magnesium stearate, or an external lubrication device (such as Matsui ExLube) can be used to smooth the punch and die prior to compression.

The compositions or dosage forms of the invention (eg, tablets or capsules or sachets) can be stored in a suitable package. The package should minimize moisture ingress during shipping and / or storage, is moisture-proof and contains a desiccant. The package includes a sealed container composed of a moisture resistant material. A desiccant (ie, a substance that absorbs water, reacts with water, or absorbs water, thereby reducing humidity inside the package) and at least one dosage form; Located inside a closed container. The moisture resistant material is selected from the group consisting of metal, glass, plastic and metal-coated plastic, and the desiccant is selected from the group consisting of molecular sieve, clay, silica gel, activated carbon and mixtures thereof. The term “moisture-proof” refers to a package that has a water permeability of less than about 0.5 mg / cm ³ of container per year.

  The compositions of the present invention improve fat, protein and carbohydrate absorption in patients suffering from symptoms or diseases associated with digestive enzyme deficiency. In one embodiment, the compositions of the invention, specifically pancrelipase compositions or pancreatin compositions, can be used to treat exocrine pancreatic dysfunction (EPI) associated with various diseases. Such diseases include, but are not limited to, cystic fibrosis (CF). In some embodiments, such compositions can substantially alleviate EPI-related malabsorption (eg, fat) in other patients, including cystic fibrosis patients and pediatric patients. . In some embodiments, such compositions can increase fat absorption coefficient (CF-A) to at least about 85% or more in cystic fibrosis patients. Such a result can be achieved with or without co-administration with other agents or compositions. In one embodiment, such CF-A results are achieved without co-administration of proton pump inhibitors.

  For patients with confirmed GI pH levels (eg, GI pH levels <about 4), the compositions or administrations of the invention together with proton pump inhibitors, antacids and other drugs that raise the pH of the GI tract Improved results can be obtained by administering the dosage form. For example, the composition or dosage form of the present invention is administered separately from the proton pump inhibitor, antacid, or other drug (before, simultaneously with, or after administration of the proton pump inhibitor, antacid, etc.) can do. Alternatively, proton pump inhibitors, antacids or other drugs can be used in combination with the pancreatin composition of the present invention as a single dosage form.

  In yet another embodiment, the present invention is a method of treating or preventing a patient with a disease associated with digestive enzyme deficiency, comprising a mixture of digestive enzymes originating from animals, microorganisms, fungi, bacteria, and not coated Needed is a composition of the invention comprising particles, particles comprising a porcine-derived digestive enzyme mixture coated with a gastroresistant polymer, or a mixture of both uncoated and enteric coated particles A method comprising administering to said mammal. In one embodiment, the mammal is a human.

  In yet another embodiment, the invention is a method of treating or preventing a patient with a disease associated with digestive enzyme deficiency, wherein the composition or dosage form of the invention is administered to a patient in need thereof. Wherein the composition or dosage form of the present invention comprises a proton pump inhibitor, an antacid, or other agent that increases GI pH in addition to at least one digestive enzyme. In yet another embodiment, the present invention is a method of treating a patient associated with digestive enzyme deficiency or preventing a disease associated with digestive enzyme deficiency comprising increasing a proton pump inhibitor, antacid or GIpH There is provided a method comprising administering a composition or dosage form of the invention in combination with a dosage form comprising other agents to be administered.

  Diseases that can be treated using the compositions or dosage forms of the present invention include conditions in which the patient has no or low levels of digestive enzymes, or conditions in which the patient requires supplementation of digestive enzymes. For example, such symptoms include cystic fibrosis, chronic pancreatitis, other pancreatic diseases (eg, hereditary, post-traumatic and allograft pancreatitis, hemochromatosis, Schwabman syndrome, lipomatosis, or accessory Hyperthyroidism), side effects of cancer or cancer treatment, side effects of surgery (eg gastrointestinal bypass surgery, whipple, total pancreatectomy, etc.) or other symptoms where pancreatic enzymes cannot reach the intestines, insufficient mixing ( Used to treat symptoms of autoimmune diseases such as HIV and diabetes, where the pancreas may be compromised) (eg Billroth II gastrectomy, other types of gastric bypass surgery, gastrinoma, etc.) Side effects of drug treatment, such as treatment with metformin or such drugs, obstruction (eg pancreatic and bile duct stones, pancreatic and duodenal neoplasms, ducts窄症), celiac disease, malabsorption include associated with food allergy and age.

  The amount of the composition or dosage form of the invention administered daily to a mammal (eg, a human) will depend on the intended result. The skilled physician can prescribe the required dose based on the diagnosis of the condition to be treated.

  For example, for the treatment of human digestive enzyme deficiency (eg, associated with cystic fibrosis), the starting dose is 500-1000 lipase units / kg / meal according to US FDA recommendations and the total dose is 2500 lipase Should not exceed unit / kg / meal or 4000 lipase units / g fat / meal. Typically, a patient should receive at least 4 dosage forms administered daily, preferably with food.

  All references cited herein are incorporated by reference in their entirety for all purposes.

In vitro efficacy / gastric resistance / dissolution test of the micropellets of Examples 1-3.
Lipase activity is measured by a certified titration method using a potentiometric titrator equipped with a microburette, calomel glass electrode system, resistance thermometer. USP pancreatin lipase RS or pancrelipase standard. Amylase activity is also measured by a certified titration method, while protease activity is measured by a certified UV detection test method. Identification is done by comparison of chromatographic patterns (eg, test enzyme and reference / standard peaks at specific relative retention times characteristic of lipases, amylases and proteases) obtained using the appropriate RP-HPLC method. . The peak area of the characteristic peak between the test substance and the reference / standard substance must satisfy the current specification. USP Apparatus 1 (basket method, 100 rpm), according to current USP General Chapter <711>, in artificial gastric juice TS800 mL, without enzyme at 37 ± 0.5 ° C. for 60 minutes (gastric resistance) Thereafter, pH 6.0 phosphate buffer solution (2 g of sodium chloride and 9.20 g of dihydrogen phosphate are dissolved in 1000 ml of water, and the pH is adjusted to 6.0 ± 0.05 using 1N sodium hydroxide. Percent of digestive enzyme dissolved when the dissolution test was performed in 800 mL for 30 minutes (to meet dissolution standards). Samples removed at 60 and 90 minutes are tested for lipase activity using a certified potentiometric titration method.

  The loss on drying test (LoD) is performed in accordance with the current USP Chapter <731>. This test is carried out on 2 g of the basic sample, and after drying in an oven at 60 ° C. for 4 hours under vacuum, the loss on drying is measured.

  Free phthalic acid content: The free phthalic acid content is detected / quantified by the appropriate HPLC method (UV detection) compared to the reference phthalic acid content.

Example 1
Example 1. A Pancrelipase micropellet by powder layering Povidone (PVP K-30; 50 g) is gradually added to 50/50 isopropanol / purified water (500 g) with constant stirring and a 10% w / w solid polymer A binder solution is prepared. Pancrelipase (Lot S1) from Scientific Protein Laboratories (2000 g) is blended with 10 g of colloidal silica (flow aid, Syloid from WR Grace Co.) and povidone (50 g) in a V-blender. Sugar spheres (60-80 mesh or 170-250 μm in diameter) are loaded into a Granurex GX-35 production bowl from Vector Corporation (Iowa, USA). The 10% PVP binder solution is sprayed at a controlled rate into the rotating material layer while the digestive enzyme powder mixture is fed at a controlled rate by the powder feeder. Optimization process parameters during pellet formation are: process air temperature: about 19-20 ° C., product temperature: 16 ± 2 ° C., rotor speed: 425 RPM, external air supply: 150 L / min, spray rate: 15 RPM (about 8 mL / Min), pressure drop through slit: 1.3-11 mm with water. Optimization process parameters during pellet drying are: processing air volume: 30 CFM, processing air temperature: about 60 ° C., product temperature: 35 ° C. (until drying stopped), rotor speed: 180 RPM, slit air volume: 10 CFM, processing time : 40 minutes. The typical LoD of the incoming raw material lot is 1.5-2.0%, but the water content (loss on drying) of the micropellet produced in this way (lot S2) was 4.1%. The composition of the micropellets is pancreatin: 82.5%, sugar spheres: 14.0%, and povidone: 3.5% as measured by a Malvern laser particle sizer. The particle size distributions are d (0.1): 370 μm, d (0.5): 520 μm, d (0.9): 733 μm. The particle size distribution data measured using a sonic shifter is shown in Table 1 below.

Example 1. B Gastric resistant coating of micropellets (Lot S3, weight increase: up to 45% by weight)
Hypromellose phthalate (HP-55, 785.16 g) was gradually added and dissolved in a 90/10 mixture of acetone and water with constant stirring, then diethyl phthalate (DEP, 196.15 g) was added, This plasticizer is dissolved. A Glatt GPCG 3 equipped with a 7-inch bottom spray Wurster height 22 mm column, a “D” bottom air distribution plate covered with a 200 mesh product retention screen with a 15 mm distribution column gap (1.0 mm port nozzle). Example 1. A micropellet from A and loaded with hypromellose phthalate solution (15% solids) for a DR coating level of 45 wt%, product temperature 37 ± 1 ° C., spray air pressure 1.5 bar, Coating is performed at an inlet air velocity of 50 to 60 m / sec and an atomization flow rate of 15 to 40 mL / min. Samples are removed at coating levels of 25%, 30%, 35% and 40%. Micropellets with coating levels of 35% and 45% by weight are tested for gastric resistance. Based on this data, it is determined that a 35% w / w delayed release coating is sufficient to impart gastric resistance properties on the micropellets.

Example 1. C Gastric resistant coating of micropellets (weight increase: 35% by weight)
A batch of gastroresistant coated micropellets is prepared using HP-55 / DEP to a coating level of 35 wt% (Lot S4). The processing conditions are a product temperature of 37 to 42 ° C. and a processing air speed of about 5 to 60 m / sec. The LoD of the coated batch was 2.4% when dried at 105 ° C. The particle size distribution of the delayed release pancreatin micropellets was d (0.1): 445 μm, d (0.5): 605 μm, d (0.9): 827 μm).

Example 1. DDR coated micropellet (lot S3) stability test digestion for identification, confirmation, efficacy, gastric resistance, and complete release at pH 6.0 of lipase, amylase, and protease enzymes, including standard samples Enzyme gastroresistant coated micropellets are tested as described above. The initial test results are shown in Table 2 below. Since more than 95% is released (detected) in 30 minutes, a gastric resistance test is not considered necessary. Sealed glass bottles containing delayed release micropellets are placed at 25 ° C./60% RH and 40 ° C./75% RH for stability.

Example 1. E Gastric resistant coating of micropellets (weight increase: 28% by weight)
Using a micropellet (Lot S2), gastric resistant coating using HP-55 / DEP (80/20) solution in 100% acetone containing 10 g of talc for a coating level of 28% by weight. A further batch of micropellets is prepared. The treatment conditions are a product temperature of 31 to 35.52 ° C., a treatment air amount of 65 to 70 CFM, and a spray rate of 15 to 30 g / min.

Example 2
Example 2 A Pancrelipase micropellet by powder layering Povidone (PVP K-30; 50 g) is gradually added to isopropanol (650 g) with constant stirring to prepare a 7% w / w solid polymer binder solution. Pancrelipase (Lot S1) from Scientific Protein Laboratories (2000 g) is blended in a V-blender with 10 g colloidal silica (flow aid, Syloid from WR Grace Co.) and povidone (50 g). Sugar spheres (60-80 mesh or 170-250 μm in diameter) are loaded into a Granurex GX-35 production bowl from Vector Corporation (Iowa, USA). The 7% PVP binder solution is sprayed at a controlled rate into the rotating material layer while the digestive enzyme powder mixture is fed at a controlled rate by the powder feeder. Optimization process parameters during pellet formation are: process air temperature: about 19-20 ° C., product temperature: 16 ± 2 ° C., rotor speed: 425 RPM, external air supply: 150 L / min, spray rate: 15 RPM (about 8 mL / Min), pressure drop through slit: 1.3-11 mm with water. Optimization process parameters during pellet drying are: processing air volume: 30 CFM, processing air temperature: about 60 ° C., product temperature: 35 ° C. (until drying stopped), rotor speed: 180 RPM, slit air volume: 10 CFM, processing time : 40 minutes.

Example 2 B Gastric resistant coating of micropellets (weight increase: 30% by weight)
Example 2 above. The micropellets from A are coated with a gastric resistant polymer HP-55 / TEC / talc (ratio: 10/1/5) at a coating level of 30% by weight in Granurex GX-35 (Lot S5) . Hypromellose phthalate (HP-55) is gradually added and dissolved in acetone in a stainless steel tank with constant stirring. Triethyl citrate (TEC) is added and dissolved in this solution, and talc (alkalizing agent) is added to the coating solution to obtain a uniform dispersion. The processing conditions are a product temperature of 37 to 42 ° C. and a processing air speed of about 5 to 60 m / sec.

Example 3
Example 3 A Pancrelipase micropellet with controlled spheronization Povidone (PVP K-30; 50 g) is slowly added to 90/10 isopropanol / purified water with constant stirring to achieve 7% w / w solids polymer binding An agent solution is prepared. Pancrelipase powder from SPL (2000 g) was blended with 10 g colloidal silica (flow aid, Cab-O-Sil M-5P from Cabot Corporation) and povidone (90 g) in a V blender, and Vector Corporation ( Load the production bowl of Granurex GX-35 from Iowa, USA). While adding powder at a controlled rate into the unit by a powder feeder (K-Tron), simultaneously spray 7% PVP polymer binder into the rotating material layer at a controlled rate. Optimization process parameters during pellet formation are: process air temperature: about 19-20 ° C., product temperature: 16 ± 2 ° C., rotor speed: 180 RPM, slit air volume: 10 CFM, spray rate: 15 RPM (about 8 mL / min) ), Pressure drop through slit: 1.3 to 11 mm with water, treatment time: 40 minutes.

Example 3 B Moisture resistant coating of micropellets Klucel LF is slowly added and dissolved in absolute ethanol in a stainless steel tank with constant stirring. Ethylcellulose (EC-10) is gradually added and dissolved in the Klucel solution with constant stirring. Magnesium stearate (Mgst) is added to the coating solution to obtain a uniform dispersion. 6 inch bottom spray Wurster 8 inch high column, “D” bottom air distribution plate covered with 200 mesh product holding screen to Glatt GPCG 3 equipped with 15 mm distribution column gap (1.0 mm port nozzle) Example 3 above. A micropellet from A (1200 g) was loaded and using a protective moisture resistant coating solution (10% by weight solids Klucel / EC-10 / Mgst (30/45/25 ratio)) from 5 mL / min to about 20 mL / min. Coat while increasing to minutes.

Example 3 C. Gastric resistant coating of micropellets Example 3 above. The micropellets from A are coated with a gastric resistant coating of HP-55 / TEC (ratio: 90/10) to a coating level of 30% by weight in Glatt GPCG 3 as disclosed above.

Example 4
Example 4 A Moisture-resistant coating of micropellets Klucel LF is gradually added and dissolved in purified water with constant stirring. Ethylcellulose (EC-10) is gradually added and dissolved in the Klucel solution with constant stirring. Example 3 above. Micropellets (1200 g) from A are coated with this protective moisture-resistant coating solution (10% solids Klucel / EC-10 (40/60)) to a 10% weight gain.

Example 4 B. Gastric resistant coating of micropellets Example 3 above. The micropellets from A are coated with a gastric resistant coating of HP-55 / TEC (ratio: 90/10) to a coating level of 30% by weight in Glatt GPCG 3 as disclosed above.

Example 4 C Modified Release Digestive Enzyme Capsules Example 3 above. 3. Moisture resistant coated micropellets from B and Example 4. Gastric resistant coated micropellets from B are filled into HPMC capsules at a digestive enzyme weight ratio of 1: 1 to produce MR capsules containing digestive enzymes. HPMC capsules are packed into sealed glass bottles optionally containing a molecular sieve type desiccant.

Example 4 D Rapidly dispersible digestive enzyme tablets Example 4 above. 75-85 parts of gastroresistant coated micropellets from B are blended with 10-15 parts spray dried mannitol, 10-15 parts microcrystalline cellulose (Avicel PHI02), 2-7 parts low substituted HPC (disintegrant). FD & C Red 0.2-0.5 parts is first blended in a V blender for 20 minutes, then 0.5 parts of sodium stearyl fumarate is added to the blender and blended for about 10 minutes. Is uniformly dispersed. The compression blend thus produced is compressed into 500 or 1,000 mg RDT (rapidly dispersed tablets) using a rotary tablet press.

Example 5
Example 5 FIG. A Pancrelipase micronization Pancrelipase from Nordmark Arzneimtel GmbH with d (0.95) of 115 μm is micronized at an intermediate energy level of JET PHARMA under a nitrogen purge to yield d (0.95) of 22 To 8 μm.

Example 5 FIG. B. Powder stratification with gravity feeder:
Set up a ventilated coating drum (Pellegrini GS) equipped with powder feeder, air cap spray system and peristal type pump. Example 5 above. Blend the micronized pancreatin disclosed in A with lactose and colloidal silicon dioxide. The polymer binder and Tween 80 are dissolved in a suitable mixed solvent in a stainless steel container with constant stirring. Sugar spheres (60-80 mesh) preheated to 30 ° C. in a ventilated coating drum rotating at 15 RPM are fed into a gravity feed device, a binder solution spray, and an inlet temperature setting of 40 ° C. and an air flow setting of about 250- Through drying at 300 m ³ / hour, layering is performed with discontinuous cycle layering of the pancreatin powder mixture. Once the drug loading is complete, the micropellets are dried to remove residual solvent, cooled to room temperature, screened using a suitable sieve, and excess material (ie> 700 μm) and fine material (ie , <300 μm).

Example 5 FIG. C. Powder stratification with electrostatic feeder Set up a ventilated coating drum (Pellegrini GS) equipped with a powder feeder combined with an electrostatic gun, an air cap spray system and a peristal type pump. Example 5 above. Blend the micronized pancreatin disclosed in A with lactose and colloidal silicon dioxide. The polymer binder and Tween 80 are dissolved in a suitable mixed solvent in a stainless steel container with constant stirring. Sugar spheres (60-80 mesh) preheated to 30 ° C. in a ventilated coating drum rotating at 15 RPM are fed into an electrostatic feeder, a binder solution spray, and an inlet temperature setting of 45 ° C. and an air flow setting of about 250 m. Layer formation by simultaneously feeding pancreatine powder mixture through drying at ³ / hr. Once the drug loading is complete, the micropellets are dried to remove residual solvent, cooled to room temperature, screened using a suitable sieve, and excess material (ie> 700 μm) and fine material (ie , <300 μm).

  Embodiment 5 FIG. B or Example 5 The micropellets from C are further coated with a moisture and / or gastric resistant coating as previously disclosed to impart moisture and / or gastric resistance properties. Fill the HPMC or gelatin capsule or sachet with the required amount of uncoated or optionally moisture-resistant and / or gastroresistant coated micropellets or pharmaceutically It can be blended with acceptable excipients and compressed into rapidly dispersing tablets to produce the desired releasable modified digestive enzyme for oral administration to patients in need of drug treatment.

Example 6: Characterization of Pancreatin Starting Material Pancrelipase starting material-Pancreatin lot Nl appearance, enzyme activity and protease elution rate are analyzed. The dissolution rate test was performed at pH 6.0, and as a model enzyme for microgranule dissolution rate evaluation, a lipase that degrades in the dissolution medium during the 30 minute test procedure (after about 5 minutes the lipase level is only 80% Instead of reducing to 73% after 30 minutes). Table 3 shows protease elution rate and enzyme activity (measured by a method based on United States Pharmacopeia, Pancrelipase: Protease activity assay (United States Pharmacopoeia, Pancrelipase: Assay for Protease activity)). The particle size distribution is shown in Table 4.

Example 7 Effect of Thermal Cycle on Pancreatin in Cyclohexane The stability of pancreatin lot N2 against the heat and mechanical stress generated during the coacervation process performed in cyclohexane is tested as follows. 135 g of pancreatin is placed in a reactor containing 1 kg of cyclohexane and heated and cooled with constant stirring (290 RPM) (Table 5).

After being subjected to a thermal cycle, the pancreatin is filtered and dried overnight (about 16 hours) in a fume hood. The resulting powder is sieved through a 500 μm sieve and stored in a high density polyethylene (HDPE) container. Micrographs of pancreatin lot Nl are taken using a Zeiss Axioscopic microscope before (FIG. 4A) and after (FIG. 4B; lot N2) heat treatment in cyclohexane. These photographs have no evidence of significant changes in the appearance, shape and dimensions of the particles. Microscopic observation is confirmed from the analysis result (Table 6).

  The activity of protease and lipase in lot N2 shows no significant change before and after being subjected to thermal cycling in cyclohexane. The residual amount of cyclohexane after drying at room temperature for 16 hours in a fume hood is negligible, confirming that pancreatin tends to absorb water. Protease elution values reach 100% within 5 minutes and do not appear to decrease during the test.

Example 8 Preparation of pancreatin microgranules 1000 g of cyclohexane is injected into a coacervation reactor. Then, with constant stirring (290 RPM), pancreatin, ethylcellulose (amount in the range of 0.4% to 5%) and polyethylene (amount in the range of 0% to 3%) are added. The resulting mixture is heated and cooled according to the thermal cycle in Table 5. The resulting pancreatin microgranules are washed (one or more times), filtered, dried overnight (about 16 hours) in a fume hood, then sieved through a 500 μm open sieve and stored in HDPE containers . The process flow sheet is shown below.

This procedure is basically used to prepare three batches of microgranules. Table 7 summarizes the number of washes, the concentrations of ethylcellulose and polyethylene, and the coating weight of the coacervated ethylcellulose in the final product (% w / w; weight increase of the microgranules relative to the starting weight of the pancreatin microgranules).

  The appearance, particle size distribution, residual solvent content, dissolution rate and enzyme activity of the microgranules are analyzed using the techniques described in the previous examples. Three lots of microscopic evaluation show that the polymer is properly deposited around the pancreatin material (FIGS. 5A-B, 6A-B and 7A-B).

  The particle size dimension and distribution are measured by sieving according to the following procedure. An amount of microgranules (25-50 g) is placed in a 100 mL HDPE bottle. Sieve 0.2% (w / w) silicon dioxide through a 150 μm screen, add to microgranules and blend manually for 2 minutes. The mixture of microgranules and Syloid 244 is sieved using a digital Octagon device for 10 minutes with an amplitude setting of 7.

From Table 8, the microgranules (lot N3) with a coacervated polymer weight of 5% have a smaller particle size than the microgranules (lot N4, lot N5) with a coacervated polymer weight of 20%. It can be seen that no significant particle size difference is observed between N5 (same weight, different amounts of polyethylene used in the preparation process).

The elution rate is measured for lot N3 and lot N4 treated with a 1% solution of sodium doxate in cyclohexane to obtain particles suitable for elution rate analysis. The processing is performed as follows. A 1% solution of sodium doxate in cyclohexane is prepared by dissolving 6 g of surfactant in 594 g of cyclohexane at room temperature. 22 g of microgranules are placed in a 250 mL beaker containing 100 g of sodium doxate solution and then stirred for 15 minutes using a stainless steel propeller (250 RPM). The microgranules are filtered and dried for about 6 hours in a fume hood, sieved through a 500 μm open sieve and stored in HDPE containers. This method applies to all subsequent examples. The elution rate and enzyme titer are shown in Table 9.

  The enzymatic activity of lipase and protease in the microgranules (measured as in the previous examples) was close to the theoretical value, and as the amount of coacervated polymer applied was increased, the dissolution rate value decreased. Lot N3 has a residual cyclohexane level of 31 ppm.

Example 9 Preparation of Microgranules from Pancreatin of Selected Particle Size Range (250 μm to 500 μm) Pancreatin lot Nl is sieved through a stainless steel sieve with an opening of 250 μm to remove fine particles (“fine powder”). Two fractions of microgranules are prepared using the fraction remaining on the sieve (approximately 40%). As shown in FIGS. 8A-B, the selected material is composed of irregular particles of about 300 μm to 400 μm and very fine particles of about 10 μm to 30 μm (Table 10).

Two batches of pancreatin microgranules are prepared in a laboratory scale reactor containing 1 kg of cyclohexane using the process conditions described above with an amount of polyethylene ranging from 0.55 to 1%.

  The microgranules are filtered and dried overnight (about 16 hours) in a fume hood, sieved through a 500 μm open sieve and then stored in HDPE containers. Analyze product appearance, residual solvent content, dissolution rate and enzyme activity.

From the micrographs (FIGS. 9A-B and FIGS. 10A-B), lot N6 (prepared with less polyethylene) shows two different populations of microgranules: (a) some fine particles. It can be seen that it contains small microgranules containing and (b) microgranules containing larger particles (about 300 μm). Lot N7 microgranules are more uniform and the particle size distribution (sieving) of the two batches is similar (Table 11). As predicted from microscopic observation, the amount of fine particles in lot N7 is decreasing.

The elution rate value for lot N7 (measured after pretreatment with sodium doxate, Table 11) is lower than the corresponding sample obtained from unselected pancreatin (lot N3).

Example 10 Preparation of microgranules from pancreatin of selected particle size (<250 μm) Pancreatin lot Nl is sieved through a 250 μm aperture stainless steel sieve and two batches of microgranules are prepared using the material passed through the sieve. . The selected pancreatin particles have an irregular shape with a particle size ranging from about 20 μm to about 250 μm (FIGS. 11A-B).

The selected pancreatin material is introduced into a laboratory scale reactor containing 1 kg of cyclohexane using the process conditions described above and different concentrations of polyethylene. Microgranules are analyzed (Table 13).

  The microgranules are filtered and dried overnight (about 16 hours) in a fume hood, sieved through a 500 μm open sieve and then stored in HDPE containers. Appearance, residual solvent content, dissolution rate and protease activity and micrographs (FIGS. 11A-B and 12A-B) are analyzed using the method of the previous example. The microgranules of lot N8 are slightly smaller than the microgranules of lot N9 (prepared with higher polyethylene concentration).

Sieving shows that lot N8 microgranules have slightly larger microgranules compared to lot N9 microgranules (Table 14), which is inconsistent with microscopic observations. This shows that different metrics for microscopy and sieving methods can affect the evaluation. Therefore, it is necessary to always specify the measurement method.

The elution rate value of lot N9 (method of pretreatment with a 1% solution of sodium doxate) is lower than that of lot N8 (Table 15).

Example 11 Preparation of Pancreatin Microgranules with Selected Particle Size Range (> 250 μm) Several batches of pancreatine microgranules were made from pancreatin with a selected particle size range (> 250 μm) and 5% coacervated polymer weight. Prepare. These microgranules are produced using the same amount of ethylcellulose and polyethylene as used for the preparation of lot N7. The pancreatin microgranules are dried under vacuum at room temperature under a stream of nitrogen gas and sieved using a 500 μm sieve. The residual cyclohexane level is measured to be 500 ppm. The batch particle size distribution, dissolution rate and enzyme titer are then measured as described above.

Example 12 Preparation of Enteric Coated Pancreatin Microgranules Pancreatin Microgranules Lot N10 and Lot N11 (Example 11) were converted into a Glatt-GPCG1 fluid bed coater (4 inch Wurster insert and Munters ML 1350 dehumidifier). Equipped) and sprayed with a coating suspension (HP55: TEC: talc = 10: 1: 5) having the following composition (% w / w):

As shown in Table 19, three batches of enteric coated microgranules with different coating levels are prepared.

The final product is sieved through an 850 μm screen and the enzyme activity and dissolution rate is measured as shown in Tables 20-21.

  The resistance of the coated pancretin microgranule lot N13 is 43% at pH 5 (basin for 60 minutes at 37 ° C.), 90% at pH 5 (basket for 30 minutes at 37 ° C.), and resistance at pH 1.2 Is 100% after 30 minutes and 71% after 60 minutes.

Example 13 Stability Test of Enteric Coated Pancreatine Microgranules The stability of lot N14 under accelerated stability conditions is evaluated. The microgranules are sealed in a polyethylene sachet, which is then placed in a heat sealed NAPE bag. This product is subjected to a stability test at 40 ° C. and 75% relative humidity, and after 1 month of storage, enzyme activity and dissolution rate are measured (Table 23).

Example 14 Preparation and Stability of Coated Pancreatin Microgranules The particle size of the pancrelipase starting material (Lot M1, 100% pancreatin) is 300-700 μm (automatic sieve Octagon Digital equipped with a suitable sieve, Endecotte The calculated average geometric diameter is 355 μm. FIG. 14 shows the PSD of these micropellets loaded on the coating fluidized bed. The coating suspension has the following composition: HP-55 10%, talc 1%, triethyl citrate 1%, ethanol 80%, acetone 8%. Fluidized bed coating is performed using the following process parameters and equipment configurations. Wurster height 2 cm and length 15 cm, plate type B, spray nozzle 0.8 mm, spray speed 3.5 g / min, spray pressure 1.4 bar, inlet air temperature 50 ° C., inlet air speed 2.0 m / Second, drying temperature 50 ° C., drying time 15 minutes. The particles are uniformly round and light brown. These resulting pancrelipase particles are used to prepare dosage forms such as sachets and capsules. Packaging in a nialen sachet is obtained by manually filling 2 g of enteric coated particles and then bonding the sachet at 130 ° C. Dosage form capsules are obtained by filling each hard gelatin capsule with 500 mg of coated particles, and these capsules are stored in HDPE bottles. Intrinsic stability data is reported in Tables 24-25.

  From the stability data, it can be seen that enteric coated particles are assured of acceptable properties when dispensed into a nialen sachet. 25 ° C. and 60% R.D. H. The results after 12 months are quite satisfactory for both dosage forms. The nialen sachet packaging material appears to guarantee better properties in terms of enzymatic degradation. After 12 months at 25 ° C., the lipase activity of the coated particles packed in nialen sachets is virtually unchanged, but the same preparation packed in gelatin capsules and packed in HDPE bottles is Shows decreased activity. The stability of capsule dosage forms containing the same pancreatine enteric coated particles is improved when the coated particles are filled into HPMC (less than 3% moisture content) capsules instead of gelatin capsules.

  All these examples show that: That is, the particle size distribution is sufficiently small but the particle size distribution is narrow (for example, d (0.1) to d (0.9) of 400 to 800 μm when measured by laser diffraction, or about 400 μm A pharmaceutical composition or dosage form of a digestive enzyme comprising high dose particles (having a particle size of about 600 μm, more preferably from about 250 μm to about 500 μm) is suitable for oral or enteral administration, acceptable gastric resistance and It can be quite beneficial for pediatric, elderly and other patients who exhibit stability characteristics and who have difficulty swallowing conventional tablets or capsules due to dysphagia. Thus, these pharmaceutical compositions or dosage forms improve the digestion / absorption of nutrients and thereby improve patient compliance by allowing the digestive enzymes and food pieces to pass in better synchronization. . These compositions or dosage forms according to the present invention comprise a stable digestive enzyme mixture of high dose, small particle size particles.

Claims (39)

  A pharmaceutical composition comprising a plurality of particles comprising at least one digestive enzyme, wherein the particles have a low particle size dimension.   2. The pharmaceutical composition according to claim 1, wherein the particles have a volume diameter d (v, 0.1) of about 400 μm or more and a volume diameter d (v, 0.9) of about 800 μm or less. Pharmaceutical composition.   2. The pharmaceutical composition of claim 1, wherein the particles have a particle size of less than about 800 [mu] m.   4. The pharmaceutical composition according to claim 1 or 3, wherein the particles have a particle size of about 400 [mu] m to about 600 [mu] m.   4. A pharmaceutical composition according to claim 1 or claim 3, wherein the particles have a particle size of about 250 [mu] m to about 500 [mu] m.   6. The pharmaceutical composition according to any one of claims 1-5, wherein the particles have at least one coating and the particles comprise about 40-98% by weight digestive enzyme mixture, about 2-20. A pharmaceutical composition comprising weight percent polymer, optionally about 0-30 weight percent inert core, and optionally one or more pharmaceutically acceptable excipients.   7. The pharmaceutical composition of claim 6, wherein the particles comprise at least about 60% by weight digestive enzyme mixture.   7. The pharmaceutical composition according to claim 6, wherein the particles are micropellets, have at least one coating, and the particles comprise about 40-98% by weight digestive enzyme mixture, about 2-10% by weight. A water-soluble polymer, optionally from about 0 to 30% by weight of an inert core, and optionally one or more pharmaceutically acceptable excipients.   9. The pharmaceutical composition according to claim 8, wherein the polymer is a polymer binder.   The pharmaceutical composition according to claim 8 or 9, wherein the polymer binder is hydroxypropylcellulose, povidone, methylcellulose, hydroxypropylmethylcellulose, carboxyalkylcellulose, polyethylene oxide, vinylpyrrolidone-vinylacetate copolymer, polysaccharide and the like. A pharmaceutical composition characterized in that it is selected from the group consisting of:   7. The pharmaceutical composition of claim 6, wherein the particles are microgranules, have at least one coating, and the particles comprise about 80-95% by weight digestive enzyme mixture, about 5-20% by weight. A water-insoluble polymer and optionally one or more pharmaceutically acceptable excipients.   The pharmaceutical composition according to claim 11, wherein the water-insoluble polymer is a coacervated polymer.   The pharmaceutical composition according to claim 11 or 12, wherein the polymer is ethyl cellulose.   11. A pharmaceutical composition according to any one of claims 6 to 10, wherein the coating comprises one or more hydrophilic polymers, one or more plasticizers and an optional pharmaceutically acceptable hydrophobicity. A pharmaceutical composition comprising a material.   14. A pharmaceutical composition according to any one of claims 6 to 13, wherein the coating comprises one or more enteric polymers and one or more plasticizers.   16. The pharmaceutical composition according to any one of claims 1 to 15, wherein the at least one digestive enzyme is pancrelipase, lipase, trypsin, chymotrypsin, chymotrypsin B, pancreatopeptidase, carboxypeptidase A, carboxy. From the group consisting of peptidase B, glycerol ester hydrolase, phospholipase, phospholipase A2, sterol ester hydrolase, ribonuclease, deoxyribonuclease, α-amylase, papain, chymopapain, bromelain, ficin, β-amylase, cellulase, β-galactosidase and mixtures thereof A pharmaceutical composition characterized in that it is selected.   16. The pharmaceutical composition according to any one of claims 1 to 15, wherein the at least one digestive enzyme is a mixture comprising at least one lipase, at least one amylase and at least one protease. A pharmaceutical composition characterized by the above.   16. The pharmaceutical composition according to any one of claims 1 to 15, wherein the at least one digestive enzyme is derived from animal, bacterial, fungal, plant, recombinant origin or chemically modified. A pharmaceutical composition characterized by comprising:   15. The pharmaceutical composition according to claim 14, wherein the hydrophilic polymer comprises polyvinylpyrrolidone, polyethylene glycol, hydroxypropylmethylcellulose, hydroxypropylcellulose, low viscosity ethylcellulose, vinylpyrrolidone-vinylacetate copolymer, polyvinyl alcohol and mixtures thereof. A pharmaceutical composition, characterized in that it is selected from the group.   15. The pharmaceutical composition of claim 14, wherein the hydrophobic material comprises talc, colloidal silicon dioxide, and magnesium stearate, calcium stearate, zinc stearate, glyceryl fatty acid behenate, glyceryl palmitostearate, and their A pharmaceutical composition characterized in that it is selected from the group consisting of a mixture.   16. The pharmaceutical composition according to claim 15, wherein the enteric polymer is selected from the group consisting of cellulose acetate phthalate, hydroxypropylmethylcellulose phthalate, hydroxypropylmethylcellulose acetate succinate, polyvinyl acetate phthalate and mixtures thereof. A pharmaceutical composition characterized.   16. The pharmaceutical composition according to claim 15, wherein the plasticizer is triacetin, tributyl citrate, triethyl citrate, tri-n-butyl acetyl citrate, diethyl phthalate, dibutyl sebacate, polyethylene glycol, polypropylene glycol, castor oil. A pharmaceutical composition characterized in that it is selected from the group consisting of acetylated monoglycerides, acetylated diglycerides, cetyl alcohol and mixtures thereof.   16. The composition of claim 15, wherein the enteric coating further comprises an inorganic agent wherein the ratio of enteric polymer to inorganic agent is from about 4: 1 to about 1:25 by weight. Composition.   24. The pharmaceutical composition according to any one of claims 1 to 23, wherein the composition has a water content of about 3% or less as measured by loss on drying.   25. The pharmaceutical composition according to any one of claims 1 to 24, wherein the digestive enzyme exhibits a loss of digestive enzyme activity of about 20% or less after a 6 month accelerated stability test. Pharmaceutical composition.   26. The pharmaceutical composition of claim 25, wherein the accelerated stability test comprises storing the composition for 6 months in a sealed nialen bag at 40 ° C. and 75% relative humidity. Pharmaceutical composition.   24. A method for preparing a pharmaceutical composition according to any one of claims 1 to 23, comprising forming particles by controlled spheronization, powder stratification or coacervation.   28. The method of claim 27, wherein the controlled spheronization comprises at least one digestive enzyme having a volume median diameter d (v, 0.5) of about 25 [mu] m or less and optionally a polymer binder and flow. A process characterized in that it is carried out by directing a powder mixture containing the adjuvant into the powder layer of the product chamber simultaneously with spraying the polymer binder solution.   28. The method of claim 27, wherein the powder stratification comprises at least one digestive enzyme having a volume median diameter d (v, 0.5) of about 25 [mu] m or less, and optionally a polymer binder and a flow aid. A method comprising: directing a powder mixture comprising: an inert core suspended in a product chamber while spraying the polymer binder solution.   28. The method of claim 27, wherein the coacervation is performed using a water-insoluble polymer dissolved in a hydrophobic organic solvent in the presence of a phase separation agent.   31. The method according to claim 30, wherein the water-insoluble polymer is ethyl cellulose, the hydrophobic organic solvent is cyclohexane, and the phase separation agent is polyethylene. A method of preparing a pharmaceutical composition comprising:
a) forming particles comprising at least one digestive enzyme having a d (v, 0.1) -d (v, 0.9) particle size in the range of about 400-800 μm;
b) optionally coating the particles of step a) with a coating formulation comprising at least one hydrophilic polymer and at least one plasticizer;
c) applying an enteric coating comprising an enteric polymer and optionally a plasticizer to the particles of step a) or the particles of step b). A method for preparing a pharmaceutical composition comprising:
a) forming particles comprising at least one digestive enzyme having a particle size of about 250 μm to about 500 μm;
b) optionally coating the particles of step a) with a coating formulation comprising at least one hydrophilic polymer and at least one plasticizer;
c) applying an enteric coating comprising an enteric polymer and optionally a plasticizer to the particles of step a) or the particles of step b).   31. A method according to claim 29 or claim 30, characterized in that step a) is carried out by spheronization, powder stratification or coacervation.   24. A dosage form comprising the composition according to any one of claims 1-23.   36. A dosage form according to claim 35 which is a capsule, sachet or tablet.   37. The dosage form of claim 36, wherein the capsule comprises hydroxypropyl methylcellulose having a moisture content of about 3% or less.   A method of treating or preventing a patient with a disease associated with digestive enzyme deficiency for the treatment of digestive disease, pancreatic exocrine dysfunction, cystic fibrosis, type I diabetes and / or type II diabetes 24. A method comprising administering to a patient a pharmaceutical composition according to any one of 1-23.   A method for treating or preventing a patient having a disease associated with digestive enzyme deficiency, comprising combining the composition according to any one of claims 1 to 23 with an agent for increasing GI tract pH, Administering to a patient in need thereof.

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