US20110293590A1 - Pharmaceutical preparation - Google Patents

Pharmaceutical preparation Download PDF

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Publication number
US20110293590A1
US20110293590A1 US13/146,653 US200913146653A US2011293590A1 US 20110293590 A1 US20110293590 A1 US 20110293590A1 US 200913146653 A US200913146653 A US 200913146653A US 2011293590 A1 US2011293590 A1 US 2011293590A1
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US
United States
Prior art keywords
lipase
pharmaceutical preparation
liquid
type
solution
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.)
Abandoned
Application number
US13/146,653
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English (en)
Inventor
Christian Rämsch
Manfred Kurfürst
Rainer Friedel
Olaf Friedrich
Silke Hüttler
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 Arzneimittel GmbH and Co KG
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
Assigned to NORDMARK ARZNEIMITTEL GMBH & CO. KG reassignment NORDMARK ARZNEIMITTEL GMBH & CO. KG ASSIGNMENT OF ASSIGNORS INTEREST (SEE DOCUMENT FOR DETAILS). Assignors: FRIEDEL, RAINER, FRIEDRICH, OLAF, RAMSCH, CHRISTIAN, HUTTLER, SILKE, KURFURST, MANFRED
Publication of US20110293590A1 publication Critical patent/US20110293590A1/en
Abandoned legal-status Critical Current

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    • 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
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
    • 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

Definitions

  • the invention relates to pharmaceutical preparations for the treatment of pancreatic insufficiency, for example mucoviscidosis or other pancreatic illnesses.
  • this invention relates to liquid pharmaceutical preparations of digestive enzymes which have no coating and which are active in the aggressive environment of stomach and duodenum.
  • these liquid pharmaceutical preparations are stable and can be stored at high temperatures.
  • lipase enzymes most products on the base of porcine pancreas which has been unfatted, dried and crushed.
  • the corresponding product consists of several enzymes such as lipase, amylases, proteases, esterases etc.
  • administering forms are usually tablets, micro-tablets, micro-dragees, capsules, powder and granules coated with a film resistant to gastric juice.
  • the disadvantage of these administering forms consists in the discomfort of the administering to patients who have to swallow big tablets or capsules.
  • these administration forms can be applied only with difficulties. The crushing of the tablets cannot assure any homogeneous distribution of the enzymes to the chymus and the low solubility of the product can lead to the occlusion of the feeding tube.
  • the treatment on the base of easily available pancreatinic preparations has various disadvantages.
  • the lipase is considered as the main enzyme. Because of the low specific lipase activity a quantity of up to 5-10 g per day has to be taken by the patient. Moreover, the porcine lipase is active in a pH range of 5 to 9 and is thus inactive during the passage through the stomach.
  • the lipase activity has to be protected from the acid pH conditions in the stomach because of its sensitivity to a low pH value, for example by a coating of the tablets resistant to gastric juice.
  • the accompanying proteolytic or amylolytic enzyme activities are not desired.
  • the amylase content is not desired for children with mucoviscidosis while lipase is therapeutically necessary.
  • Proteases are contraindicated for patients with acute pancreatitis or active phases of chronic pancreatitis (see U.S. Pat. No. 5,645,832).
  • the availability of a lipase as single protein is advantageous.
  • a lipase obtained from bacteria has already been described in detail. Apart from the making available of a purified single protein, the lipase concentration of bacterial lipase is very high so that only low preparation quantities (approx. 0,2 g) have to be administered.
  • the pH value for the activity of the bacterial lipase is situated between 3 and 9 and thus overcomes the limitations of the stability and activity of porcine lipase/pancreatin. This means that the lipolytic effect of bacterial lipase can be applied with a better effect in the gastrointestinal tract than the products for the therapy of digestion disorders commonly sold on the market. Additionally, the bacterial lipase is a non-animal product which avoids the risk of possible viral infection originating from animal sources.
  • This invention provides a liquid pharmaceutical preparation which contains a digestive enzyme.
  • the preparation serves for the treatment of patients with pancreatic insufficiency, for example with mucoviscidosis or other pancreatic illnesses.
  • lipase without coating is active in the aggressive environment of stomach and duodenum and that the enzyme is stable in an aqueous solution over several months at ambient temperature. Additionally, it has been stated that bacterial lipase is able to reduce steatorrohea for mucoviscidosis patients.
  • FIG. 1 shows cumulated fat quantity in the patient's stool during the treatment with placebo or verum.
  • FIG. 2 shows the activity of lipase under conditions of a low pH value (imitation of the pH value in the stomach).
  • FIG. 3 shows stability of bacterial lipase in an aqueous solution.
  • the invention relates to a lipase which is produced in bacteria and its production is expressly described in U.S. Pat. No. 5,645,832.
  • the lipase application has been proved as an effective treatment of patients who suffer from pancreatitis or mucoviscidosis.
  • the reduction of steatorrohea has been observed during the exclusive application of lipase.
  • No other enzymes such as proteases, amylases or esterases were present (example 1).
  • Pure bacterial lipase can have specific activities of more than 3.5 U/g. Because of the high lipolytic activity, a lower quantity administered form (i.e. number of tablets or volume of solution) has to be administered to the patients.
  • This invention offers the lipase as a liquid pharmaceutical preparation in order to overcome the limitations of the usual formulae (tablets) of therapeutic digestion enzymes.
  • tablettes of therapeutic digestion enzymes.
  • the usual administering forms cannot be used or can only be used to a limited extent.
  • a liquid pharmaceutical product offers the possibility of a convenient dosage of the medicine, homogeneous distribution of the enzyme in the food and use with artificial feeding.
  • lipase without coating is active under pH conditions which imitate the aggressive environment of the stomach when taking in (example 2). Moreover, it has been shown that the bacterial lipase is stable in an aqueous solution for at least 3 months even at high temperatures (example 3). No chemical modification as it is described in U.S. 2006/0128587 was necessary.
  • the invention includes formulae which also use stabilizers such as salts organic acids
  • the matter can be, for the liquid formula, of: solutions, solution/drop; suspensions, suspension drops.
  • the invention is based on the advantages of liquid administering forms, in particular but not exclusively for children.
  • Liquid administering forms can be prepared either in hat the lipase is produced directly as a liquid solution or by dissolving the active constituent lipase in an aqueous or non aqueous solvent, by suspending the medicine in an appropriate medium or by adding the medicine into one of the two phases of an oil/water system.
  • Administering forms such as solutions, suspensions and emulsions of lipase are useful for many reasons. They can be formulated for different ways of administering: oral medication, insertion into body cavities or external use. The dosage can be adjusted by dilution and single drops can be administered for example with a dropping device. The liquid oral form can easily be administered to children or patients who are unable to swallow tablets, capsules or any other solid administering form.
  • the lipase solution is a homogeneous mixture which includes pharmaceutical forms which are designated as water, aromatic water, aqueous acids, solutions.
  • the lipase suspension refers to a two-phase system which consists of solid lipase which is dispersed in a liquid.
  • Bacterial lipase has been tested during a clinical study with mucoviscidosis patients. As shown in FIG. 1 and in the following table with the indication of coefficients of fat absorption of patients under placebo and verum, considerable differences are to be seen in the fat quantity in the stool of the patient under verum as well as the coefficient of fat absorption (CFA). The bacterial lipase significantly improves the resorption of fat during digestion.
  • Bacterial lipase has been dissolved and adjusted to the pH value of 1.0, 2.0, 3.0, 4.0 and 5.0. Lipase activities have been measured by applying the tributyrin test after 15, 30 minutes and 1, 2, 4 and 18 hours with the test pH value (8.0).
  • Bacterial lipase has been dissolved in water and incubated at 4° C., ambient temperature and 40° C. The activity has been measured after 1, 2, 3, 4, 5, 10 and 14 weeks. No considerable loss of activity has been stated during this time.

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  • Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Chemical & Material Sciences (AREA)
  • Engineering & Computer Science (AREA)
  • Veterinary Medicine (AREA)
  • Medicinal Chemistry (AREA)
  • Public Health (AREA)
  • General Health & Medical Sciences (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Gastroenterology & Hepatology (AREA)
  • Immunology (AREA)
  • Proteomics, Peptides & Aminoacids (AREA)
  • Epidemiology (AREA)
  • Organic Chemistry (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • General Chemical & Material Sciences (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
  • Medicinal Preparation (AREA)
  • Enzymes And Modification Thereof (AREA)
  • Medicines Containing Material From Animals Or Micro-Organisms (AREA)
US13/146,653 2009-01-29 2009-01-29 Pharmaceutical preparation Abandoned US20110293590A1 (en)

Applications Claiming Priority (1)

Application Number Priority Date Filing Date Title
PCT/EP2009/000566 WO2010085975A1 (de) 2009-01-29 2009-01-29 Pharmazeutisches präparat enthaltend lipase bakteriellen ursprungs

Related Parent Applications (1)

Application Number Title Priority Date Filing Date
PCT/EP2009/000566 A-371-Of-International WO2010085975A1 (de) 2009-01-29 2009-01-29 Pharmazeutisches präparat enthaltend lipase bakteriellen ursprungs

Related Child Applications (1)

Application Number Title Priority Date Filing Date
US15/182,779 Continuation US10596235B2 (en) 2009-01-29 2016-06-15 Pharmaceutical preparation

Publications (1)

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US20110293590A1 true US20110293590A1 (en) 2011-12-01

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Family Applications (2)

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US13/146,653 Abandoned US20110293590A1 (en) 2009-01-29 2009-01-29 Pharmaceutical preparation
US15/182,779 Active 2029-03-09 US10596235B2 (en) 2009-01-29 2016-06-15 Pharmaceutical preparation

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US15/182,779 Active 2029-03-09 US10596235B2 (en) 2009-01-29 2016-06-15 Pharmaceutical preparation

Country Status (13)

Country Link
US (2) US20110293590A1 (de)
EP (2) EP2391382B1 (de)
JP (1) JP5970189B2 (de)
CN (1) CN102231988A (de)
BR (1) BRPI0922653B8 (de)
CY (1) CY1115519T1 (de)
DK (1) DK2391382T3 (de)
ES (1) ES2488407T3 (de)
HR (1) HRP20140715T1 (de)
PL (1) PL2391382T3 (de)
PT (1) PT2391382E (de)
SI (1) SI2391382T1 (de)
WO (1) WO2010085975A1 (de)

Cited By (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US8691282B2 (en) 2011-02-17 2014-04-08 Nordmark Areneimittel GmbH & Co. KG Method for producing pancreatin pellets
US8999394B2 (en) 2009-08-28 2015-04-07 Thomas Moest Pancreatine pellets and method of producing same
US11439691B2 (en) 2017-03-03 2022-09-13 Nordmark Pharma Gmbh Aqueous solution of burlulipase comprising calciumions
US11464834B2 (en) * 2017-03-03 2022-10-11 Nordmark Pharma Gmbh Orodispersible tablet containing burlulipase and pharmaceutical composition produced therefrom

Families Citing this family (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP2165717A1 (de) 2008-08-27 2010-03-24 Nordmark Arzneimittel GmbH & Co.KG Verfahren zur Verringerung der viralen und mikrobiellen Belastung feststoffhaltiger biologischer Extrakte
US8268305B1 (en) 2011-09-23 2012-09-18 Bio-Cat, Inc. Method and compositions to reduce serum levels of triacylglycerides in human beings using a fungal lipase
WO2013146529A1 (ja) * 2012-03-28 2013-10-03 不二製油株式会社 ランダムエステル交換油脂の製造方法
DE102015114857A1 (de) 2015-09-04 2017-03-09 Nordmark Arzneimittel Gmbh & Co. Kg Getränk, enthaltend eine pharmazeutische Zusammensetzung
DE102017104482A1 (de) * 2017-03-03 2018-09-06 Nordmark Arzneimittel Gmbh & Co. Kg Pharmazeutische Zusammensetzung umfassend Pankreatin und einen lipasehaltigen Überzug
DE102017104501A1 (de) 2017-03-03 2018-09-06 Nordmark Arzneimittel Gmbh & Co. Kg Pharmazeutische Zusammensetzung umfassend einen Träger und einen Überzug enthaltend wenigstens eine Lipase

Citations (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5063160A (en) * 1989-03-16 1991-11-05 Olin Corporation Identification, characterization, and method of production of a novel microbial lipase
US5489530A (en) * 1991-07-01 1996-02-06 Basf Aktiengesellschaft Lipase from Pseudomonas and strain
US20010046493A1 (en) * 2000-02-24 2001-11-29 Alex Margolin Lipase-containing composition and methods of use thereof
US20050250817A1 (en) * 2004-03-22 2005-11-10 Solvay Pharmaceuticals Gmbh Pharmaceutical compositions of lipase-containing products, in particular of pancreation
US20060188636A1 (en) * 2002-11-26 2006-08-24 Choi Danette V Papaya puree and the use of the same
US20080299185A1 (en) * 2007-02-20 2008-12-04 Giovanni Ortenzi Stable digestive enzyme compositions

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CA2030581C (en) 1989-11-24 2000-06-27 Gunther Atzl Pancreatin preparations
DK173590D0 (da) 1990-06-06 1990-07-19 Novo Nordisk As Rekombinante terapeutiske lipaser
DE4227385A1 (de) 1992-08-19 1994-02-24 Kali Chemie Pharma Gmbh Pankreatinmikropellets
JPH08143469A (ja) * 1994-11-14 1996-06-04 Amano Pharmaceut Co Ltd 膵外分泌機能不全症治療剤
DE19724845A1 (de) 1996-08-28 1998-03-05 Solvay Pharm Gmbh Verwendung von komplexen Lipiden als stabilisierende Zusätze zu pharmazeutischen Zubereitungen von Verdauungsenzymgemischen
US6270723B1 (en) 1998-06-15 2001-08-07 Bbi Bioseq, Inc. Rapid cryobaric sterilization and vaccine preparation
KR100518139B1 (ko) 2000-04-06 2005-10-04 한나 리서치 인스티튜트 단백질 안정화된 유제
EP1486415A1 (de) 2003-06-12 2004-12-15 SSP Technology A/S Windturbinenflügel und Verfahren zur Herstellung einer Turbinenflügelwurzel
US6908789B1 (en) 2003-12-15 2005-06-21 Intel Corporation Method of making a microelectronic assembly
US7718169B2 (en) * 2004-10-14 2010-05-18 Cystic Fibrosis Foundations Therapeutics, Inc. Compositions and methods for treating pancreatic insufficiency
DE102004056340B4 (de) 2004-11-22 2010-11-18 Repower Systems Ag Vorrichtung und Verfahren zur Montage und/oder Demontage eines Bauteils einer Windkraftanlage
DE102005014868A1 (de) 2005-03-30 2006-10-05 Repower Systems Ag Offshore-Windenergieanlage mit rutschfesten Füßen
US11266607B2 (en) 2005-08-15 2022-03-08 AbbVie Pharmaceuticals GmbH Process for the manufacture and use of pancreatin micropellet cores
DE102006021982C5 (de) 2006-05-10 2010-10-07 Repower Systems Ag Gestaffelt abschaltbarer Windpark
DE102007014863A1 (de) 2007-03-26 2008-10-02 Repower Systems Ag Verfahren zum Betreiben einer Windenergieanlage
AU2008239737A1 (en) 2007-04-13 2008-10-23 Beth Israel Deaconess Medical Center, Inc. Novel nutritional food products for improved digestion and intestinal absorption
DE102008012664A1 (de) 2008-01-30 2009-08-06 Repower Systems Ag Windenergieanlage und ein Turm oder Turmsegment und eine Türzarge dafür
EP2165717A1 (de) 2008-08-27 2010-03-24 Nordmark Arzneimittel GmbH & Co.KG Verfahren zur Verringerung der viralen und mikrobiellen Belastung feststoffhaltiger biologischer Extrakte
PL2295039T5 (pl) 2009-08-28 2023-02-27 Nordmark Pharma Gmbh Sposób wytwarzania granulek zawierających pankreatynę, w szczególności mikrogranulek zawierających pankreatynę, oraz wytworzone tym sposobem granulki zawierające pankreatynę
EP2489349B1 (de) 2011-02-17 2014-05-28 Nordmark Arzneimittel GmbH & Co.KG Pankreatin-Pellets, insbesondere Pankreatin-Mikropellets, und Verfahren zu deren Herstellung

Patent Citations (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5063160A (en) * 1989-03-16 1991-11-05 Olin Corporation Identification, characterization, and method of production of a novel microbial lipase
US5489530A (en) * 1991-07-01 1996-02-06 Basf Aktiengesellschaft Lipase from Pseudomonas and strain
US20010046493A1 (en) * 2000-02-24 2001-11-29 Alex Margolin Lipase-containing composition and methods of use thereof
US20060188636A1 (en) * 2002-11-26 2006-08-24 Choi Danette V Papaya puree and the use of the same
US20050250817A1 (en) * 2004-03-22 2005-11-10 Solvay Pharmaceuticals Gmbh Pharmaceutical compositions of lipase-containing products, in particular of pancreation
US20080299185A1 (en) * 2007-02-20 2008-12-04 Giovanni Ortenzi Stable digestive enzyme compositions

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* Cited by examiner, † Cited by third party
Title
Dictionary term "aqueous solution" (accessed on 6/11/2015 at http://www.thefreedictionary.com/aqueous+solution) (of record). *
Dictionary term "aqueous solution" (accessed on 6/11/2015 at http://www.thefreedictionary.com/aqueous+solution). *
USPTO memo issued 3/4/2014 entitled: "Guidance For Determining Subject Matter Eligibility Of Claims Reciting Or Involving Laws of Nature, Natural Phenomena, & Natural Products (Guidance)." *

Cited By (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US8999394B2 (en) 2009-08-28 2015-04-07 Thomas Moest Pancreatine pellets and method of producing same
US8691282B2 (en) 2011-02-17 2014-04-08 Nordmark Areneimittel GmbH & Co. KG Method for producing pancreatin pellets
US11439691B2 (en) 2017-03-03 2022-09-13 Nordmark Pharma Gmbh Aqueous solution of burlulipase comprising calciumions
US11464834B2 (en) * 2017-03-03 2022-10-11 Nordmark Pharma Gmbh Orodispersible tablet containing burlulipase and pharmaceutical composition produced therefrom

Also Published As

Publication number Publication date
PT2391382E (pt) 2014-08-22
JP5970189B2 (ja) 2016-08-17
US10596235B2 (en) 2020-03-24
BRPI0922653B8 (pt) 2021-05-25
WO2010085975A1 (de) 2010-08-05
DK2391382T3 (da) 2014-08-25
EP2391382A1 (de) 2011-12-07
BRPI0922653A2 (pt) 2016-01-05
EP2786761A1 (de) 2014-10-08
BRPI0922653B1 (pt) 2021-04-13
EP2391382B1 (de) 2014-06-04
SI2391382T1 (sl) 2014-10-30
US20160287679A1 (en) 2016-10-06
JP2012516289A (ja) 2012-07-19
HRP20140715T1 (hr) 2014-09-26
CN102231988A (zh) 2011-11-02
ES2488407T3 (es) 2014-08-27
PL2391382T3 (pl) 2014-11-28
CY1115519T1 (el) 2017-01-04

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Owner name: NORDMARK ARZNEIMITTEL GMBH & CO. KG, GERMANY

Free format text: ASSIGNMENT OF ASSIGNORS INTEREST;ASSIGNORS:KURFURST, MANFRED;FRIEDEL, RAINER;FRIEDRICH, OLAF;AND OTHERS;SIGNING DATES FROM 20110719 TO 20110810;REEL/FRAME:026985/0398

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