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WO1999048520A1 - Nouvelle preparation d'insuline humaine a action prolongee - Google Patents

Nouvelle preparation d'insuline humaine a action prolongee Download PDF

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Publication number
WO1999048520A1
WO1999048520A1 PCT/DK1999/000157 DK9900157W WO9948520A1 WO 1999048520 A1 WO1999048520 A1 WO 1999048520A1 DK 9900157 W DK9900157 W DK 9900157W WO 9948520 A1 WO9948520 A1 WO 9948520A1
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WO
WIPO (PCT)
Prior art keywords
insulin
preparation
suspended
human
human insulin
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.)
Ceased
Application number
PCT/DK1999/000157
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English (en)
Inventor
Klavs Holger JØRGENSEN
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.)
Individual
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Individual
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 Individual filed Critical Individual
Priority to AU28271/99A priority Critical patent/AU2827199A/en
Publication of WO1999048520A1 publication Critical patent/WO1999048520A1/fr
Anticipated expiration legal-status Critical
Ceased legal-status Critical Current

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Classifications

    • 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
    • A61K38/17—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
    • A61K38/22—Hormones
    • A61K38/28—Insulins

Definitions

  • ⁇ P ⁇ contains tetragonal crystals of zinc, insulin and the basic polypeptide protamine in an amount just sufficient for the positive charge of protamine to neutralise the negative charge of the insulin, thereby lowering the solubility of the crystals to produce a protracted acting drug.
  • the formation of the crystals is dependent on the presence of phenolic substances. In fact, only phenol and m-cresol are used in practise.
  • the ratio between the amounts of protamine and insulin (in the order of 10 % by weight on the basis of insulin) is called the isophane ratio and is determined as the ratio giving minimum solubility of both insulin and protamine.
  • the isophane ratio varies with different protamine preparations, p ⁇ , zinc and auxiliaries.
  • ⁇ P ⁇ preparations could be mixed with neutral soluble insulin without loss of the fast action of the soluble insulin part and of the protracted action of the ⁇ P ⁇ part.
  • Such preparations in a premixed state, with the insulin components in different proportions have found widespread use for twice a day injections. This also goes for mixed preparations of human insulin (examples: Mixtard® 50/50 ⁇ ovo ⁇ ordisk and ⁇ umulin® 30/70 Lilly).
  • the preparation contains protamine, zinc and insulin (human, porcine or bovine).
  • the crystals have a claimed length below 20 ⁇ m and a claimed insulin concentration in the range of from 20 to 500 IU/ml.
  • a particularly prolonged action is obtained by ratios between the amounts of protamine and insulin and between the amounts of zinc and insulin being extremely higher than those of therapeutically applied human NPH.
  • the preparation according to Application WO 88/02633 has never been made available for general use and is outside the scope of the present invention.
  • an injectable short-acting suspension of amorphous porcine zinc insulin was introduced under the name of Semilente.
  • an intermediate-acting 3:7 mixture of Semilente and Ultralente was introduced under the name of Lente.
  • the size of the individual amorphous particles in Semilente is about 1 ⁇ m allowing unhindered passage of the particles through the finest injection needles.
  • Semilente is more protracted acting than soluble insulin, it is less protracted acting than NPH.
  • Human Semilente is a component in a 3:7 mixture with human Ultralente under the name of Monotard® Novo Nordisk (Brange et al., in Galenics of Insulin, pp 36-38, Springer-Verlag, Berlin (1987))
  • Insulin analogues have been prepared for use as long-acting preparations and may be well suited for administration by insulin pen once per day. Recently, two promising candidates have been described.
  • B-3 l-B32-Di-Arg-human insulin has shown a flat insulin profile between 1 and 24 hours and a more slow absorption than NPH after subcutaneous injection in healthy subjects (Coates et al., Diabetes 44 (Suppl 1) 130A (1995)).
  • Soluble fatty acid acylated insulin, capable of binding to albumin has shown a slower absorption and a more flat profile of action than NPH after subcutaneous injection in pigs (Markussen et al., Diabetologia 39, 281-288 (1996)).
  • insulin analogs can always be suspected of having unwanted effects such as mitogenesis and immunogenicity, until long term clinical trials have confirmed whether an analog is safe (Johannesen et al., Diabetologia 40, B89-B93 (1997)). Indeed, serious side effects have been found unexpectedly, both with the rapid-acting insulin analog, Asp B1 ° (showing in vitro mitogenic and in vivo carcinogenic properties in rats), and with the long-acting insulin analog, Novo Sol Basal (showing a local inflammatory reaction and increasing dosage requrements), as described by Barnett and Owens (Lancet 349, 47-51 (1997)). Another rapid-acting analog, insulin lispro, appears safe and efficient after long term clinical trials, vide the last quoted paper. The rapid-acting analog, insulin aspart, also appears promising so far (Home et al., 4
  • the long-acting insulin analogs await more thorough investigations and long term trials before it can be decided, whether or not they are safe and efficient. Insulin analogs are outside the scope of the present invention.
  • the main technical problem addressed by the present invention is the too fast absorption of current human insulin suspension preparations capable of being injected by means of an insulin pen comprising a fine injection needle without problems of clogging of the needle.
  • the object of the invention is to provide an injectable, protracted acting preparation comprising a liquid carrier and suspended therein human insulin containing particles, which regarding their kind and size of less than 15 ⁇ m are known for use in conventional insulin therapy, in which preparation the concentration of suspended human insulin is between about 200 and about 1200 IU/ml
  • an injectable, protracted acting preparation comprising a liquid carrier and suspended therein tetragonal crystals containing human insulin, protamine and zinc, which crystals regarding their kind and size of less than 15 ⁇ m are known for use in conventional insulin therapy in the form of human NPH , in which preparation the concentration of suspended human insulin is between about 200 and about 1200 IU/ml.
  • the preparation according to Claim 4 is new and useful, since the invention is based on the discovery that, when the insulin concentration in human NPH is strongly increased, preparations are obtained, which combine the advantages of the two prior art products NPH and Ultralente (both having a strength of maxJOO IU/ml), i.e. a small particle size of lower than 15 ⁇ m, and a slow onset of action combined with a long duration of action, respectively. It is surprising that the protraction properties are substantially improved by the increase of insulin concentration.
  • the preparation preferably exhibits such a slow onset of action, that the risk of hypoglycaemia is reduced, and such a high degree of protraction that appropriate control of the basal blood glucose level can be provided by one injection per day only.
  • the higher insulin strength (at least twice the normal) in the preparation of the present invention is advantageous per se, in that the smaller volume thus obtained for a given insulin dose might be less painful for the patient to inject.
  • the insulin particles in the preparation of the present invention are small enough to allow free flow without fractionation through the finest needles available today.
  • the concentration of suspended human insulin is between about 500 and about 1100 IU/ml, more preferred about 1000 IU/ml.
  • the particles are tetragonal protamine zinc insulin crystals, as in NPH.
  • the suspended crystals are admixed with dissolved human insulin in the concentration range of from about 20 to about 1200 IU/ml.
  • the particles are amorphous, as in Semilente. It is preferred, that the preparation according to the invention is contained in a cartridge for insertion into an insulin pen.
  • the present invention further relates to a preparation as defined in claim 1 for use as a medicament for treating or preventing diabetes mellitus.
  • the present invention relates to the use of a preparation as defined in claim 1 for the manufacture of a medicament for treating or preventing diabetes mellitus.
  • the present invention relates to a method of treating or preventing diabetes mellitus, which comprises administering subcutaneously to an individual in need of such treatment or intervention the preparation of the invention.
  • the auxiliaries and their concentrations can be chosen to be similar to those of a current human NPH preparation. However, changes can be made on condition that the kind of the crystals is not changed, and that their size is still less than 15 ⁇ m.
  • the ratio between the amounts of protamine and insulin 6 should be close to the isophane ratio determined as known in the art, e.g. as described by Krayenbuhl and Rosenberg (Rep Steno Mem Hosp Nord Insulinlab 1, 60-73(1946)).
  • the preparation according to Claim 4 can be produced by removing so much of the liquid carrier from a human NPH preparation (by filtration or by suction of supernatant after sedimentation or centrifugation), that the desired degree of concentration is obtained, as illustrated in Example 1.
  • the preparation is preferably produced in such a way that the desired strength of insulin is obtained directly, as illustrated in Example 5.
  • the premixed preparation according to Claim 5 is made in analogy to a method known in the art of producing of a current premixed preparation.
  • the preparation according to Claim 6 can be produced by removing so much of the liquid carrier from a human Semilente U100, (by filtration or by suction of supernatant after sedimentation or centrifugation), that the desired degree of concentration is obtained, as illustrated in Example 2.
  • the preparation is preferably produced in such a way that the desired strength of insulin is obtained directly, as illustrated in Example 7.
  • the concentration of total zinc has to be adjusted, as it is exemplified for Lente preparations with strengths from 40 to 100 IU/ml by Brange et al.
  • the preparation should preferably be injected by a reusable or rather a disposable insulin pen with a cartridge different from conventional cartridges, in order to avoid interchange, and with a pen adapted for the special use.
  • the cartridge should contain a ball that could easily be moved from one end to the other, when the insulin pen is turned upside down in order to ensure that an even distribution of crystals is obtained at the time of injection.
  • a solution of 85.5 mg/ml human insulin (2311 IU/ml) with a pH of 7.8 was prepared by dissolving 1.05 g human monocomponent insulin containing 2.2 zinc atoms/insulin hexamer in 9.5 ml water and 0.8 ml 1 mol/1 HCl, followed by pH adjustment with 1.2 ml 1 mol 1 NaOH. 216 ⁇ l of this insulin solution (500 IU) was mixed with 4 ml water, 500 ⁇ l 1.6 g/1 methyl-p- hydroxybenzoate, 150 ⁇ l 4 mol 1 NaCl and 12.5 ⁇ l 4 mol/1 sodium acetate.
  • the pH of AIL was adjusted to 7.3 with HCl just before use.
  • 125 ⁇ l of NPH UlOO and NPH U1000 from Example 1 and 125 ⁇ l AS UlOO and AS U1000 from Example 2 were pipetted into 4 tubes.
  • 125 ⁇ l AIL was added to each tube that was of such a size, that just a small air bubble was left in the tube after it was stoppered.
  • the tubes were then rotated for 3 hours at 37 °C, the movement of air bubbles up and down allowing the particles to be kept evenly suspended.
  • the tubes were centrifuged and the insulin contents of the supernatants determined by HPLC on a C4 column effecting a complete separation of insulin and albumin. The found percentages of insulin dissolved in the 1:1 mixtures of preparation and AIL are shown in the table below.
  • NPH UlOO Insulatard® Novo Nordisk, 5 zinc atoms/insulin hexamer
  • the preparation so prepared was named *NPH UlOO and used as a reference in all of the 14 pig experiments. 7 ml of the *NPH UlOO was centrifuged in a tube. 5.6 ml of the supernatant was removed, and the precipitate suspended in the residual supernatant. This preparation was named *NPH
  • the labelled preparations were filled into 1.5 ml NovoPen cartridges, each containing a glass ball. Each cartridge was then inserted in a NovoPen® 1.5.
  • 100 ml of an injectable preparation of human NPH U500, for use in insulin therapy, according to the present invention, is prepared in the following way.
  • An amount of dry, crystallized human insulin (about 1.85 g), corresponding to 50000 IU, is dissolved in 20 ml of water and 1.38 ml 1 mol/1 HCl.
  • An amont of protamine sulphate determined beforehand to provide the isophane ratio together with 50000 IU human insulin, is added in the form a 10 mg/ml protamine sulphate solution.
  • a solution of 1 mol/1 ZnCl is added in a volume that gives a total content of 5 zinc atoms per insulin hexamer (inclusive the zinc content in the applied dry insulin). Finally the volume is adjusted to 50 ml with water.
  • HSL UlOO and HSL U500 were labelled with trace amounts of mono- 125 I-(Tyr A19- insulin, in the following way.
  • human insulin with 2.2 zinc atoms/insulin hexamer and with a pH of 7.8 (described in Example 4) 287 ⁇ l (700 IU) was pipetted into a tube and mixed with 4.375 ml 1.6 g/1 methyl-p-hydroxybenzoate, 1.875 ml water and 30 ⁇ l 1 mol/1 HCl.
  • I-insulin was then added to the acid solution thus obtained.
  • the two tables below show the mean values in % of the value at zero time and the T75%, T50 % and T25 % values, respectively.
  • 100 ml of an injectable preparation of human HSL U1000, for use in insulin therapy, according to the present invention, is prepared in the following way.

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  • Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Zoology (AREA)
  • Gastroenterology & Hepatology (AREA)
  • Chemical & Material Sciences (AREA)
  • Engineering & Computer Science (AREA)
  • Diabetes (AREA)
  • Immunology (AREA)
  • Medicinal Chemistry (AREA)
  • Endocrinology (AREA)
  • Proteomics, Peptides & Aminoacids (AREA)
  • Epidemiology (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)

Abstract

L'invention concerne une préparation injectable d'insuline humaine à action prolongée sous forme de suspension, dans laquelle la concentration d'insuline a été fortement augmentée. Cette préparation est conçue pour être injectée au moyen d'un stylo injecteur d'insuline et présente des avantages thérapeutiques potentiels.
PCT/DK1999/000157 1998-03-24 1999-03-23 Nouvelle preparation d'insuline humaine a action prolongee Ceased WO1999048520A1 (fr)

Priority Applications (1)

Application Number Priority Date Filing Date Title
AU28271/99A AU2827199A (en) 1998-03-24 1999-03-23 Novel preparation of protracted acting human insulin

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
DK41498 1998-03-24
DK0414/98 1998-03-24

Publications (1)

Publication Number Publication Date
WO1999048520A1 true WO1999048520A1 (fr) 1999-09-30

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Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/DK1999/000157 Ceased WO1999048520A1 (fr) 1998-03-24 1999-03-23 Nouvelle preparation d'insuline humaine a action prolongee

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AU (1) AU2827199A (fr)
WO (1) WO1999048520A1 (fr)

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2017163159A1 (fr) 2016-03-21 2017-09-28 Wockhardt Limited Composition pharmaceutique biphasique d'insuline humaine

Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5547929A (en) * 1994-09-12 1996-08-20 Eli Lilly And Company Insulin analog formulations
WO1996030040A1 (fr) * 1995-03-31 1996-10-03 Eli Lilly And Company Formulations d'analogues monomeres d'insuline
WO1997048413A1 (fr) * 1996-06-20 1997-12-24 Novo Nordisk A/S Preparations a base d'insuline contenant des glucides

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5547929A (en) * 1994-09-12 1996-08-20 Eli Lilly And Company Insulin analog formulations
WO1996030040A1 (fr) * 1995-03-31 1996-10-03 Eli Lilly And Company Formulations d'analogues monomeres d'insuline
WO1997048413A1 (fr) * 1996-06-20 1997-12-24 Novo Nordisk A/S Preparations a base d'insuline contenant des glucides

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2017163159A1 (fr) 2016-03-21 2017-09-28 Wockhardt Limited Composition pharmaceutique biphasique d'insuline humaine

Also Published As

Publication number Publication date
AU2827199A (en) 1999-10-18

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