EP3589275A1 - Compositions pharmaceutiques comprenant de la pancréatine et un enrobage contenant de la lipase - Google Patents

Compositions pharmaceutiques comprenant de la pancréatine et un enrobage contenant de la lipase

Info

Publication number
EP3589275A1
EP3589275A1 EP18711042.4A EP18711042A EP3589275A1 EP 3589275 A1 EP3589275 A1 EP 3589275A1 EP 18711042 A EP18711042 A EP 18711042A EP 3589275 A1 EP3589275 A1 EP 3589275A1
Authority
EP
European Patent Office
Prior art keywords
coating
pharmaceutical composition
pancreatin
lipase
composition according
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Pending
Application number
EP18711042.4A
Other languages
German (de)
English (en)
Inventor
Jan Lüdemann
Richard Fuhrherr
Jörn Tonne
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Nordmark Pharma GmbH
Original Assignee
Nordmark Arzneimittel GmbH and Co KG
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Nordmark Arzneimittel GmbH and Co KG filed Critical Nordmark Arzneimittel GmbH and Co KG
Publication of EP3589275A1 publication Critical patent/EP3589275A1/fr
Pending legal-status Critical Current

Links

Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/20—Pills, tablets, discs, rods
    • A61K9/2004—Excipients; Inactive ingredients
    • A61K9/2022—Organic macromolecular compounds
    • A61K9/205—Polysaccharides, e.g. alginate, gums; Cyclodextrin
    • A61K9/2054—Cellulose; Cellulose derivatives, e.g. hydroxypropyl methylcellulose
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides
    • A61K38/16—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
    • A61K38/43—Enzymes; Proenzymes; Derivatives thereof
    • A61K38/46—Hydrolases (3)
    • A61K38/465—Hydrolases (3) acting on ester bonds (3.1), e.g. lipases, ribonucleases
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides
    • A61K38/16—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
    • A61K38/43—Enzymes; Proenzymes; Derivatives thereof
    • A61K38/54—Mixtures of enzymes or proenzymes covered by more than a single one of groups A61K38/44 - A61K38/46 or A61K38/51 - A61K38/53
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/20—Pills, tablets, discs, rods
    • A61K9/2072—Pills, tablets, discs, rods characterised by shape, structure or size; Tablets with holes, special break lines or identification marks; Partially coated tablets; Disintegrating flat shaped forms
    • A61K9/2086—Layered tablets, e.g. bilayer tablets; Tablets of the type inert core-active coat
    • A61K9/209—Layered tablets, e.g. bilayer tablets; Tablets of the type inert core-active coat containing drug in at least two layers or in the core and in at least one outer layer
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/20—Pills, tablets, discs, rods
    • A61K9/28—Dragees; Coated pills or tablets, e.g. with film or compression coating
    • A61K9/2806—Coating materials
    • A61K9/2833—Organic macromolecular compounds
    • A61K9/286—Polysaccharides, e.g. gums; Cyclodextrin
    • A61K9/2866—Cellulose; Cellulose derivatives, e.g. hydroxypropyl methylcellulose
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/20—Pills, tablets, discs, rods
    • A61K9/28—Dragees; Coated pills or tablets, e.g. with film or compression coating
    • A61K9/2806—Coating materials
    • A61K9/2833—Organic macromolecular compounds
    • A61K9/2873—Proteins, e.g. gelatin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
    • A61P1/14—Prodigestives, e.g. acids, enzymes, appetite stimulants, antidyspeptics, tonics, antiflatulents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
    • A61P1/18—Drugs for disorders of the alimentary tract or the digestive system for pancreatic disorders, e.g. pancreatic enzymes
    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12N—MICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA
    • C12N9/00—Enzymes; Proenzymes; Compositions thereof; Processes for preparing, activating, inhibiting, separating or purifying enzymes
    • C12N9/94—Pancreatin

Definitions

  • composition comprising pancreatin
  • the present invention relates to a pharmaceutical composition
  • a pharmaceutical composition comprising pancreatin having a coating containing at least one lipase.
  • the at least one lipase is burlulipase.
  • pharmaceutical compositions comprising such a pharmaceutical composition.
  • a process for producing such a pharmaceutical composition is also part of the present invention.
  • the pancreas also called the pancreas, is a simultaneously endocrine and exocrine-acting gland. It forms digestive enzymes, which are released into the duodenum (exocrine gland), which split fats, carbohydrates and proteins of the food in the gut into a form that can be absorbed by the intestinal mucosa.
  • "digestive enzymes” are usually enzymes which are preferably derived from the three classes of enzymes required for the digestion of the three basic components of the diet - lipases for fats, amylases for carbohydrates, proteases for proteins contained in exocrine pancreatic secretions.
  • a disease that affects the exocrine part is, for example, pancreatitis.
  • pancreatitis or inflammation of the pancreas the release of digestive enzymes leads to self-digestion of the organ and thus to a strong inflammatory reaction.
  • the insufficient formation of pancreatic enzymes is called exocrine pancreatic insufficiency. It is a decline in the formation of digestive enzymes, which means that the food can no longer be sufficiently digested. This can be caused, for example, by loss of pancreatic tissue in chronic ⁇ Pancreatic cancer acquired, but also in genetically-related diseases, such as cystic fibrosis, be congenital.
  • the exocrine pancreatic insufficiency causes digestive problems with steatorrhea (fat loss) and other symptoms and is usually treated with meals by administering pancreatin.
  • Cystic fibrosis is an autosomal recessive metabolic disease in which the composition of all secretions of exocrine glands is altered. Due to an altered gene on the chromosome number 7 (CFTR gene), the salt and water transport of the cells is disturbed. Therefore, u. a. the digestive juices produced by the pancreas are tougher than normal and obstruct the ducts of the gland. The accumulating digestive juices cause irritation and eventually damage to the pancreas. Furthermore, the lack of digestive enzymes in the intestine makes the absorption of nutrients more difficult. Malnutrition and stunted growth are the result. Cystic fibrosis-induced exocrine pancreatic insufficiency is usually treated with the known enzyme therapy by administration of pancreatin.
  • pancreatin monographed in the European Pharmacopoeia (Ph. Eur.) As “pancreatic powder” (Pancreas Powder), in the US Pharmacopoeia (USP) as “pancreatin” or “pancrelipase” - is obtained by extraction from pigs -Pancreas and contains a mixture of active digestive enzymes.
  • the main ingredients of pancreatin are lipases, amylases and various proteases.
  • the most important therapeutic component of pancreatin are the lipases, which cause the breakdown of dietary fats, improve the nutritional status of a patient and at the same time help to avoid unpleasant side effects of a lack of fat digestion, such as fatty stools.
  • pancreatic lipases the specific enzyme activities, especially those of the pancreatic lipases, are relatively low. For the patient, this leads in the therapeutic practice to the unpleasant requirement to have to swallow a significant number of usually very large-sized pancreatin-containing dosage forms for each meal. This is inherently burdensome in itself and leads to further limitations in the quality of life of patients in the already serious diseases.
  • infants, infants and elderly patients have significant additional hurdles to administer.
  • the crushing of the solid administration form as otherwise usual in such cases option is here to omit, because it leads to the destruction of the protective enteric film, so that the enzymes are exposed to the acidic gastric juice unprotected and can be inactivated in this milieu.
  • the capsules containing, for example, pancreatic enzyme preparations are opened and the solid, enteric coated, multiparticulate units contained therein on or in the meal, e.g. Apple porridge, distributed.
  • the integrity of the functional enteric coating can be destroyed by chewing and the enzymes are released, denatured and thus rendered ineffective at the wrong place, especially before the passage of the stomach.
  • individual multiparticulate units can get stuck in the cheek pouches and lead to irritation and damage to the mucous membrane, in the worst case to ulcers (ulcerations).
  • pancreatic lipases are acid-labile. Therefore, pancreatin-containing drugs are usually enteric-coated to protect the enzymes from stomach acid.
  • the commonly available forms of administration of pancreatin are usually, in particular enteric-coated film coated tablets, microtablets, micropellets / granules, microdrugs and capsules, and powders. After the gastric passage and the increase in pH when entering the small intestine, the enteric protective film then dissolves and releases the active ingredient, which can then develop its enzymatic action in the dietary pulp. Pancreatin-containing medicines must be taken directly with the meal so that they can arrive in the small intestine together with the ingested food in order to work there.
  • acid-suppressing drugs such as proton pump inhibitors (PPIs) or H2-receptor antagonists, to inhibit gastric acid secretion. These cause a higher pH in the stomach and subsequently in the intestinal lumen and cause d Release of active ingredient from the usually functional enteric-coated pancreatin preparations.
  • PPIs proton pump inhibitors
  • H2-receptor antagonists to inhibit gastric acid secretion.
  • WO 2010/085975 A1 discloses liquid preparation forms of burlulipase for the treatment of indigestion, in particular of pancreatitis and cystic fibrosis.
  • Burlulipase International Freename, INN
  • Burlulipase is the lipase of the bacterial species Burkholderia plantarii.
  • Burlulipase is a triacylglycerol acyl hydrolase (EC 3.1.1.3) which has an amino acid sequence consistent with the lipases produced by Burkholderia plantarii and Burkholderia glumae.
  • Burlulipase is produced by a traditional fermentation process using Burkholderia plantarii, a non-recombinant Gram-negative bacterium as a production strain. Pure burlulipase may have a specific activity of more than 3,500 TBU / mg (tributyrin units per milligram of protein). Due to its high lipolytic activity, Burlulipase is particularly suitable for supporting digestive performance in healthy and sick people. Burlulipase can be obtained in very high drug densities with high specific activity, so that only small amounts of substance (i.e., a small mass or a small volume of solution) have to be administered. Burlulipase, however, has disadvantages that have hitherto prevented its practical use in medicines. It is unstable under a variety of conditions. For example, activity in uncooled liquids on storage decreases, and tableting of burlulipase-containing compositions results in unacceptable loss of activity (unpublished results).
  • these medicaments should Prevent and / or treat these diseases.
  • the additional administration of drugs to inhibit gastric acid secretion or to control the acid in the stomach and / or duodenum should be unnecessary, or at least its administration should be reduced.
  • the medicament is said to be capable of being administered to patients who have difficulty taking large volume dosage forms such as infants, infants and elderly patients. Also, it should be possible to mix the preparation form for administration with food, without the effectiveness is impaired.
  • pancreatin characterized in that it comprises a coating containing at least one lipase.
  • a pharmaceutical composition comprising pancreatin having a coating containing at least one lipase, the pharmaceutical composition comprising a core containing pancreatin on which the coating is applied, characterized in that it is the one used in the coating at least one lipase is a different lipase than the pancreatin occurring lipases.
  • the effect that such a composition has over conventional administration of pancreatin is that the amount of lipase in the coating can be chosen such that the combined activity of the lipases in the pharmaceutical composition is sufficient to meet the need for lipolytic activity.
  • pancreatin The lipolytic activity of pancreatin is often inadequate and must be ensured by the administration of large amounts of pancreatin or additional administration of drugs. Not infrequently, however, the administration of the largest possible amount of pancreatin does not ensure the sufficient lipolytic activity.
  • This problem can be solved by the use of at least one further lipase which is applied in the form of a coating.
  • Lipases, proteases and amylases occur in pancreatin in predetermined proportions.
  • the pancreatin is usually and as much as possible Patients are provided enough lipases. Since proteases and annylases are usually present in excess in pancreatin, they are often overdosed.
  • the ratio of lipases to proteases and amylases can be optimally adjusted and the sufficient supply of the patient with lipases, proteases and amylases ensured. The absolute amount (mass) of the drug is thereby reduced.
  • the spatial separation of the lipase from the pancreatin causes the activity of the lipase is not affected by the enzymes of pancreatin.
  • the degradation by proteases is omitted.
  • the use of a coating means that there is no separation of the pancreatin and the at least one lipase in the coating.
  • the activity of the at least one lipase in the coating is preferably stable to the action of gastric acid in vivo. In particular, it is preferably more stable to the action of gastric acid than the lipases of pancreatin.
  • the at least one lipase used in the coating is preferably a different lipase than the lipases occurring in the pancreatin. Most preferably it is a microbial lipase. Microwave lipases are easy to produce on an industrial scale and can be made sure they do not contain harmful microbial contaminants. Most preferably, the at least one lipase is a bacterial lipase. Bacterial lipases usually have higher lipolytic activity than pancreatin and are more acid-stable.
  • the at least one lipase is burlulipase. Because of the high specific activity of burlulipase, the use of a small amount (mass) of burlulipase relative to the amount of pancreatin is sufficient to ensure sufficient lipolytic activity. Furthermore, the activity of burlulipase is stable under the action of gastric acid. The preparation of solid formulations of the Burlulipase how et T '' ''''' usually associated with a large loss of burlulipase activity. Typically, only about 60% of the original activity (measured in TBU units) of the burlulipase used remains in the tablets, and often less than 60%. The extent of the loss of activity also depends on the process conditions.
  • burlulipase appears to be sensitive to some of the excipients used in tablets.
  • the loss of activity is so great that the use of such tablets as a drug is usually not possible. This is also true because the difference in activity between two different batches can be very high.
  • burlulipase is surprisingly not or only slightly inactivated. Also, the activity is reproducible in different batches. Furthermore, the pharmaceutical composition according to the invention is surprisingly storage-stable at room temperature. In the preparation of the compositions of the invention, the loss of burlulipase activity is so low that practical application of the pharmaceutical composition of the present invention as a drug becomes possible.
  • the pharmaceutical composition according to the invention can be easily prepared and allows storage at room temperature for a period of time usual for pharmaceuticals. Even when stored for several years, the activity of the lipases contained therein decreases only to a pharmaceutically acceptable extent. Also, an artificial stabilization of the lipase can be dispensed with. The use of crystalline lipase becomes unnecessary. Also a cross-linking of the lipase is not necessary.
  • the pharmaceutical composition according to the invention is therefore preferably characterized in that the lipase contained therein is not chemically modified. It is further preferably characterized in that the lipase contained therein is not in crystalline form, that is amorphous. Most preferably, the lipase is chemically unmodified and is in an amorphous form.
  • any solid pharmaceutical preparations of pancreatin can be used in this invention.
  • the pharmaceutical composition of the invention comprises a core containing pancreatin on which the coating is applied. This allows the use of the previously known medicaments and their precursors as a core for the preparation of the pharmaceutical composition according to the invention.
  • the proportion of lipase and in particular Burlulipase can be adjusted in all embodiments by the layer thickness of the coating and so different ratios between pancreatin and lipase, in particular burlulipase, can be adjusted.
  • the pharmaceutical composition of the invention may be free of enteric coatings. This is preferred. Gastric juice-resistant coatings are virtually indispensable for conventional medicines containing pancreatin, as the lipase in the pancreatin is decomposed by the gastric juice.
  • the enteric coatings are designed to dissolve at the pH usually prevalent in the duodenum and release the pancreatin. Paradoxically, the effect of pancreatin to cure indigestion is based on the fact that at least part of the digestion works smoothly, namely the pH regulation in the stomach and especially in the duodenum. This is not or not always the case with many patients. The duodenum often has too low a pH, which results in the enzymes of pancreatin not or not completely or not released in time.
  • the pharmaceutical composition of the present invention preferably contains at least one lipase which is stable upon contact with gastric acid. An enteric coating is therefore not necessary. The release of the lipase from the coating and the lipases, proteases and amylases from the pancreatin therefore already in the stomach for the beginning of the decomposition, which favors a sufficient digestion. The inactivation of the lipases of pancreatin in the stomach can be easily compensated by a larger amount of at least one lipase in the coating.
  • the composition according to the invention therefore guarantees a satisfactory supply of digestive enzymes even in patients with disturbances of acid regulation in the stomach and / or duodenum. Also a temporary hyperacidity ('' acid or alkaline food does not affect the effect.
  • the pharmaceutical composition according to the invention without an enteric coating can therefore solve the disadvantages of pancreatin in conjunction with the acidity of stomach and duodenum. Because the applied bacterial lipase is acid stable, it provides sufficient lipolytic activity and eliminates or reduces the need to administer additional drugs to control acidity. Surprisingly, therefore, when administering the pharmaceutical composition according to the invention to the additional administration of drugs for the inhibition of gastric acid secretion can be dispensed with as a rule. The otherwise associated with these preparations otherwise severe side effects are avoided.
  • the digestive enzymes can already work in the stomach and improve digestion.
  • the pharmaceutical composition according to the invention may also have an enteric coating.
  • This enteric coating may simultaneously contain the at least one lipase.
  • the at least one lipase may also be contained in a further coating or in both coatings.
  • Embodiments of the pharmaceutical composition according to the invention provided with an enteric coating have a high lipase activity and are storage-stable under customary conditions.
  • a pancreatin-containing core is surrounded by at least one enteric coating on which in turn a further coating containing the at least one lipase is applied.
  • This embodiment also exhibits sufficient lipolytic activity in the event of disturbance of gastric acid secretion. It causes an improved digestion, since the lipase of the coating is already released in the stomach.
  • the lipase in the coating is such a lipase, whose lipolytic activity against the in vitro simulated action of gastric acid is stable. Particularly preferred is burlulipase.
  • pancreatin-containing cores as they are already contained in commercial preparations, such as the capsule filling in drug "Cotazym ®” by the company CHEPLAPHARM Arzneistoff GmbH in Mesekenhagen, Germany, as an example of enterically coated pellets pancreatin without adjuvants.
  • the capsule filling in drug "Creon ®” by the company Mylan HealthCare GmbH in Hanover, Germany as an example of enterically coated pellets containing pancreatin and auxiliaries.
  • pancreatin-containing cores without enteric coating examples include the drug "Eurobiol ® 12500, granules” of the company Laboratoires Mayoly Spindler in Chatou, France, where it is loose, to be administered with a dosing spoon microtablets from pancreatin with excipients with are provided film coating, as well as “Viokace ®” by the company Allergan USA, Inc. in Irvine (CA), USA, as an example of non-coated tablets - one - but not enteric.
  • Embodiments of the pharmaceutical composition according to the invention provided with an enteric coating have a high lipase activity and are storage-stable under customary conditions. They provide improved digestion because the lipase of the coating is already released in the stomach, and they can be mixed with food and administered to toddlers, infants, and elderly patients, as partial destruction of the enteric coating has no effect on the activity of the coated lipase Has. It is advantageous if the pharmaceutical composition according to the invention comprises a core which consists of pancreatin. The absence of excipients in the core enhances the specific activity of the formulation and allows administration of the same activity by smaller size preparations.
  • the core can take different forms. For example, it may be selected from the group consisting of tablets, microtablets, rapidly disintegrating microtablets, granules, pellets and powders. Preferably, a rapidly disintegrating micro-tablet (FDMT, fast disintegrating (or dissolving) micro-tablet) is used as the core.
  • FDMT rapidly disintegrating micro-tablet
  • Such formulations allow the rapid and complete release of the enzymes. This can already happen in the stomach or even in the mouth.
  • solutions, emulsions or suspensions which can be administered in liquid form, for example by stomach probes, by dissolving the coated, rapidly disintegrating microtablets.
  • all embodiments of the preparation according to the invention can be administered in this way.
  • Liquid formulations of burlulipase are thermally unstable and can only be marketed in the form of chilled solutions, with all the problems associated with a continuous cold chain.
  • the pharmaceutical composition according to the invention can be used successfully here in order to avoid the storage of liquid preparation forms. The packaging is easier than with liquids.
  • a further preferred embodiment of the pharmaceutical composition according to the invention is characterized in that it contains a pancreatin whose content of lipase and viruses is reduced.
  • Swine pancreas contains a variety of viruses.
  • the number of active viruses can be reduced by exposure to heat and other methods. In such a virus reduction or inactivation, a part of the lipases of pancreatin is usually inactivated.
  • Such a pancreatin may ideally be used in the pharmaceutical composition of the present invention without the risk of the lipolytic activity being insufficient.
  • the amount of lipase in the coating is used in such compositions to remove the inactive 'T of pancreatin. At the same time a largely virus-free pharmaceutical composition is obtained.
  • a pharmaceutical composition according to the invention which is characterized in that it has in its coating a lipolytic activity in the range of 10,000 to 500,000 TBU / g.
  • the enzymatic activity of the at least one lipase, preferably a bacterial lipase, more preferably burlulipase, in the coating of the pharmaceutical composition of the present invention as described herein is preferably from 10,000 to 500,000 TBU / g in the case of multiparticulate preparations such as pellets or miniproposits 50,000 to 400,000 TBU / g.
  • the range is from 100,000 to 200,000 TBU / g, in the case of slightly larger pellets (in the range from 1.4 to 2.4 mm), the range is from 200,000 to 300,000 TBU / g. and in the case of slightly smaller pellets (in the range of 1.0 to 1.6 mm) the range of 225,000 to 375,000 TBU / g.
  • the enzymatic activity of the at least one lipase, preferably a bacterial lipase, particularly preferably burlulipase, in the coating of the pharmaceutical composition according to the invention as described herein in the case of monolithic preparations such as tablets is preferably from 10,000 to 200,000 TBU / g, more preferably from 20,000 to 150,000 TBU / g. and most preferably from 50,000 to 100,000 TBU / g.
  • the core of the pharmaceutical composition of the invention contains pancreatin, which in turn contains the three enzyme fractions of the lipases, amylases and proteases.
  • pancreatin which in turn contains the three enzyme fractions of the lipases, amylases and proteases.
  • pancreatin-containing units - in the respective ranges of the pancreatin-containing products on the market Examples of such products, their pancreatin-containing pharmaceutical forms of the type can be used as a pancreatin-containing cores in the inventive pharmaceutical composition have already been mentioned above.
  • the commercially available Pankreatan ® 10000 has a lipolytic activity of 10 nnn " amylolytic activity of 7.500 Ph. Eur.-E. and a proteolytic activity of 450 Ph. Eur.-E. on.
  • the corresponding contents for capsule contents - in this example microfilm tablets - are in the range of about 52,000 - 62,500 Ph. Eur.-E./g for the lipolytic activity, 39,000 - 47,000 Ph. Eur.-E./g for the amylolytic activity and 2,300-2,800 Ph. Eur.-E./g for total proteolytic activity.
  • the pharmaceutical composition according to the invention may also contain auxiliaries in the coating.
  • auxiliaries are all auxiliaries which are customarily used in pharmaceutical compositions. Active substances, in particular enzymes, are not adjuvants within the meaning of this application. Suitable excipients are listed, for example, in the "Handbook of Pharmaceutical Excipients" of the American Pharmaceutical Association.
  • the pharmaceutical composition according to the invention as described herein may contain, in addition to the enzymes contained in the pancreatin and the further lipases contained in the coating, also further enzymes, in particular further digestive enzymes.
  • Suitable digestive enzymes are, in particular, enzymes which are selected from the group consisting of proteases and amylases.
  • a pharmaceutical composition of the invention containing both protease and amylase forms part of the present invention.
  • the pancreatin used in the pharmaceutical composition of the present invention may be any pancreatin in solid form, even in the form described in, for example, Ph. Eur. Pancreatin can be purchased. A method for the gentle recovery of pancreatin is described in DE 32 48 588 AI. A pancreatin so produced is preferred. A method for producing pancreatin micropellets is described, for example, in EP 0 583 726 A2.
  • EP 0 436 110 A1 describes a process for the preparation of spherical particles comprising pancreatin.
  • EP 2 295 039 Bl describes pancreatin pellets and micropellets containing exclusively pancreatin. The pancreatin products described in these references are useful in the pharmaceutical composition of the present invention.
  • the core used in this invention may be any known solid pharmaceutical preparation of pancreatin.
  • the coating may consist exclusively of the at least one lipase. It can also consist exclusively of Burlulipase. However, it is preferred that the coating comprises pharmacologically acceptable excipients. Suitable excipients are listed, for example, in the "Handbook of Pharmaceutical Excipients" of the American Pharmaceutical Association.
  • the coating may contain one or more adjuvants selected from the group consisting of binders, plasticizers, release agents, fillers, carriers, humectants, disintegrants and colorants. This list is not exhaustive, but other, known in the art auxiliaries can be used.
  • Suitable pharmacologically acceptable binders which may be present in the coating are, for example, compounds selected from the group comprising hydroxypropylmethylcellulose, polyethylene glycols, polyoxyethylene, polyoxyethylene-polyoxypropylene copolymers and mixtures thereof. This list is not exhaustive, but other, known in the art binders can be used. Suitable dyes are, for example, food dyes, in particular food dyes, which are described in the German Drugs Dye Regulation. If an enteric coating is to be used, the materials and methods known to the person skilled in the art can be used for this purpose, in particular for the abovementioned materials and methods. Such materials and methods are also described, for example, in EP 2 295 039 Bl in paragraphs [0028] to [0033].
  • compositions comprising a pharmaceutical composition according to the invention. It is preferably a medicament for the prevention and / or treatment of indigestion, in particular exocrine pancreatic insufficiency and more preferably a medicament for the prevention and / or treatment of exocrine pancreatic insufficiency in patients with cystic fibrosis, in infants and children and in elderly and bedridden patients.
  • a further aspect of the present invention is a process for the preparation of the pharmaceutical composition according to the invention, comprising the steps:
  • pancreatin
  • the at least one lipase in the coating composition is a microbial lipase, more preferably a bacterial lipase, and most preferably, at least one lipase in the coating composition is burlulipase.
  • the pancreatin and the ingredients of the coating, and thus the coating composition are described above.
  • Preferred as the coating composition is a solution of the components necessary for the coating in water.
  • Preferred is a method of the invention wherein the pancreatin is provided in the form of a core of a rapidly disintegrating microtablet containing pancreatin, and the coating composition is a solution of burlulipase, hydroxypropylmethylcellulose, and optionally further adjuvants in water.
  • the formation of the coating can be carried out by known techniques, for example in a fluidized bed system with Wurster column or a Kugelcoater.
  • the pancreatin is introduced into the respective plant and sprayed a previously prepared mixture of the at least one lipase for the coating and the excipients and optionally a solvent.
  • burlulipase and other lipases can be inactivated by pressure, increased pressures should be avoided as much as possible. Preference is therefore given to a production process according to the invention for the pharmaceutical composition according to the invention, in which pressing operations after introduction of the least one lipase for the coating and in particular the burlulipase is dispensed with. Particular preference is given to production processes according to the invention for the pharmaceutical compositions according to the invention, t ' ' mechanical pressure for compaction or solidification of the pharmaceutical composition according to the invention after introduction of the at least one lipase for the coating and in particular the burlulipase is dispensed with.
  • the analytical determination of the lipolytic activity is carried out by the so-called tributyrin assay according to Erlanson, Ch. & Borgström, B .: "Tributyrins as a Substrate for Determination of Lipase Activity of Pancreatic Juice and Small Intestinal Content”; Scand. J. Gastroent. 5, 293-295 (1970).
  • TBU-E Partly shortened to TBU
  • TBU-U Partly shortened to TBU
  • An enzymatic activity of 1 unit (1 enzyme unit) corresponds to a substance conversion of 1 ⁇ of substrate per minute.
  • spherical pancreatin micropellets consisting of pancreatin prepared by the process according to claim 1 of EP 2 295 039 B1 having a mean particle diameter of about 0.6 mm, are prepared in a Wurster spray-coating system of the Glatt-GPCG-5 type with Wurster column coated with 4.500 g of burlulipase solution.
  • the following parameters are used: atomizing air pressure 1.5 bar, air flow 50-55 m 3 / h, supply air temperature 47.3 - 49.7 ° C, product temperature 30.6 - 31.8 ° C, spray rate 4.9 - 6 , 0 g / min, spray time 160 min.
  • the yield is 96.7%.
  • the loss of activity (in TBU) of burlulipase in the coated micropellets by the spray process is 22.2%. This includes loss due to attachment of the enzyme to the apparatus.
  • the corrected loss of activity due to inactivation of burlulipase is 20.8%. After storage at 25 ° C for 8 months in polyethylene bags no further change in activity is detectable.
  • pancreatin micropellets which were prepared according to Example 2 of EP 0 436 110 Al, gives very similar results.
  • the loss of activity is 17.4% due to spraying and 13.2% corrected loss due to inactivation of burlulipase.
  • 5,000 g of magnesium stearate are added via a 0.25 mm sieve to 495.0 g of a microcrystalline cellulose (proper name: "Avicel PH101", available from “FMC Corporation", Philadelphia, USA) and placed in a Zoller free fall mixer at 25 rpm for 10 min. mixed.
  • 300 mg of the carrier mixture thus prepared are mixed with 150 ⁇ l of a solution of burlulipase in water having an activity of 50,050 TBU / ml and incorporated with a spatula until the solution is completely absorbed. Subsequently, the resulting mixture is dried in a vacuum oven at room temperature ( ⁇ 25 ° C) and 50 mbar for 1.5 hours.
  • the mixture thus obtained is compressed into tablets with the aid of a Korz EKO eccentric press and 10 mm diameter punching machine, dragee-curved, with a pressing pressure of 21.0 kN.
  • the finished tablets are added to water and the TBU activity is determined.
  • the loss of activity of burlulipase (TBU) is 41.5%.
  • the present pharmaceutical composition is therefore superior to normal tableting.
  • burlulipase is added to the carrier mixture in the form of a solid lyophilisate, similar losses of activity are obtained.

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Abstract

La présente invention concerne une composition pharmaceutique comprenant de la pancréatine, et présentant d'un enrobage qui contient au moins une lipase. L'au moins une lipase est de préférence la burlulipase. L'invention concerne en outre un médicament comprenant une telle composition pharmaceutique. L'invention s'étend également à un procédé de fabrication d'une telle composition pharmaceutique.
EP18711042.4A 2017-03-03 2018-03-05 Compositions pharmaceutiques comprenant de la pancréatine et un enrobage contenant de la lipase Pending EP3589275A1 (fr)

Applications Claiming Priority (2)

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DE102017104482.5A DE102017104482A1 (de) 2017-03-03 2017-03-03 Pharmazeutische Zusammensetzung umfassend Pankreatin und einen lipasehaltigen Überzug
PCT/EP2018/055351 WO2018158465A1 (fr) 2017-03-03 2018-03-05 Compositions pharmaceutiques comprenant de la pancréatine et un enrobage contenant de la lipase

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DE3248588A1 (de) 1982-12-30 1984-07-12 Nordmark-Werke Gmbh, 2000 Hamburg Verfahren zur gewinnung von pankreatin von hohem schuettgewicht
PH30058A (en) * 1989-11-24 1996-11-08 Biochemie Gmbh Pancreation preparations
DE4227385A1 (de) 1992-08-19 1994-02-24 Kali Chemie Pharma Gmbh Pankreatinmikropellets
KR19990072826A (ko) * 1998-02-26 1999-09-27 우재영 판크레아틴장용코팅과립의제조방법
ES2320174T3 (es) * 2005-08-15 2009-05-19 Solvay Pharmaceuticals Gmbh Microesferas de pancreatina adecuadas para el revestimiento enterico.
CN101242812B (zh) * 2005-08-15 2012-12-26 雅培产品有限公司 适合肠溶包衣的胰酶微丸芯
US20090117180A1 (en) * 2007-02-20 2009-05-07 Giovanni Ortenzi Stable digestive enzyme compositions
PT2079445E (pt) * 2007-02-20 2016-02-29 Allergan Pharmaceuticals Internat Ltd Composições de enzimas digestivas estáveis
WO2009083607A1 (fr) * 2008-01-03 2009-07-09 Solvay Pharmaceuticals Gmbh Compositions pharmaceutiques comprenant des granules de lipase microbienne purifiée et procédés de prévention ou de traitement des troubles digestifs
PL2391382T3 (pl) * 2009-01-29 2014-11-28 Nordmark Arzneimittel Gmbh & Co Kg Preparat farmaceutyczny zawierający lipazę pochodzenia bakteryjnego
EP2295039B2 (fr) 2009-08-28 2022-10-26 Nordmark Pharma GmbH Pellets de pancréatine, notamment micro-pellets de pancréatine et leur procédé de fabrication
CN102883712A (zh) 2010-03-19 2013-01-16 加拿大阿普塔利斯制药公司 耐胃液酶药物组合物
CN102946872A (zh) 2010-05-03 2013-02-27 阿普塔利斯制药有限公司 包含含有胰酶的消化酶混合物的微丸组合物
EP2489349B1 (fr) * 2011-02-17 2014-05-28 Nordmark Arzneimittel GmbH & Co.KG Granules de pancréatine, notamment micro-granules de pancréatine et leur procédé de fabrication
DE202011000728U1 (de) * 2011-03-30 2011-06-09 Nordmark Arzneimittel GmbH & Co. KG, 25436 Pankreatin-Pellets, insbesondere Pankreatin-Mikropellets
US20140127307A1 (en) * 2012-11-02 2014-05-08 Aptalis Pharma Limited Micropellet compositions comprising pancreatin containing digestive enzyme mixture

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WO2018158465A9 (fr) 2020-04-23
JP7184789B2 (ja) 2022-12-06
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CA3055118A1 (fr) 2018-09-07
US20200121766A1 (en) 2020-04-23
CN110650731A (zh) 2020-01-03
WO2018158465A1 (fr) 2018-09-07
DE102017104482A1 (de) 2018-09-06
CN110650731B (zh) 2022-12-13
JP2023018079A (ja) 2023-02-07

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