CA2441260C - Insulin preparations, which do not contain any zinc or only a small quantity of zinc and which have an improved stability - Google Patents

Insulin preparations, which do not contain any zinc or only a small quantity of zinc and which have an improved stability Download PDF

Info

Publication number
CA2441260C
CA2441260C CA2441260A CA2441260A CA2441260C CA 2441260 C CA2441260 C CA 2441260C CA 2441260 A CA2441260 A CA 2441260A CA 2441260 A CA2441260 A CA 2441260A CA 2441260 C CA2441260 C CA 2441260C
Authority
CA
Canada
Prior art keywords
formulation
insulin
zinc
concentration
surfactant
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.)
Expired - Lifetime
Application number
CA2441260A
Other languages
French (fr)
Other versions
CA2441260A1 (en
Inventor
Peter Boderke
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.)
Sanofi Aventis Deutschland GmbH
Original Assignee
Sanofi Aventis Deutschland GmbH
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 Sanofi Aventis Deutschland GmbH filed Critical Sanofi Aventis Deutschland GmbH
Publication of CA2441260A1 publication Critical patent/CA2441260A1/en
Application granted granted Critical
Publication of CA2441260C publication Critical patent/CA2441260C/en
Anticipated expiration legal-status Critical
Expired - Lifetime legal-status Critical Current

Links

Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
    • A61K47/16—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing nitrogen, e.g. nitro-, nitroso-, azo-compounds, nitriles, cyanates
    • A61K47/18—Amines; Amides; Ureas; Quaternary ammonium compounds; Amino acids; Oligopeptides having up to five amino acids
    • 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
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
    • A61K47/08—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing oxygen, e.g. ethers, acetals, ketones, quinones, aldehydes, peroxides
    • A61K47/10—Alcohols; Phenols; Salts thereof, e.g. glycerol; Polyethylene glycols [PEG]; Poloxamers; PEG/POE alkyl ethers
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
    • A61K47/26—Carbohydrates, e.g. sugar alcohols, amino sugars, nucleic acids, mono-, di- or oligo-saccharides; Derivatives thereof, e.g. polysorbates, sorbitan fatty acid esters or glycyrrhizin
    • 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
    • A61K9/0012—Galenical forms characterised by the site of application
    • A61K9/0019—Injectable compositions; Intramuscular, intravenous, arterial, subcutaneous administration; Compositions to be administered through the skin in an invasive manner
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/08—Drugs for disorders of the metabolism for glucose homeostasis
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/08—Drugs for disorders of the metabolism for glucose homeostasis
    • A61P3/10—Drugs for disorders of the metabolism for glucose homeostasis for hyperglycaemia, e.g. antidiabetics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/10—Antimycotics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P5/00—Drugs for disorders of the endocrine system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P5/00—Drugs for disorders of the endocrine system
    • A61P5/48—Drugs for disorders of the endocrine system of the pancreatic hormones

Abstract

The invention relates to a pharmaceutical formulation containing: a polypeptide selected from a group containing insulin, an insulin metabolite, an insulin analog, an insulin derivative or combinations thereof; a surfactant or combinations of several surfactants; optionally, a preservative or combinations of several preservatives, and; optionally, an isotonizing agent, buffers or additional adjuvants or combinations thereof, whereby the pharmaceutical formulation does not contain any zinc or only a small quantity of zinc. The invention also relates to the production of insulin preparations of the aforementioned type.

Description

Description Insulin Preparations, Which Do Not Contain Any Zinc or Only a Small Quantity of Zinc and Which Have An Improved Stability The invention relates to stabilized pharmaceutical formulations comprising a polypeptide selected from a group comprising insulin (e.g. human insulin, bovine insulin or porcine insulin), an insulin analog, an insulin derivative, active insulin metabolites or combinations thereof; a surfactant or combinations of a number of surfactants and optionally a preservative or combinations of a number of preservatives and optionally an isotonicizing agent, buffer or further excipients or combinations thereof, the pharmaceutical formulation being low in zinc or free from zinc. These formulations can be employed for the treatment of diabetes and are particularly employable for use in insulin pumps, pens, injectors, inhalers or for preparations in which an increased physical stability is necessary. The invention likewise relates to parenteral preparations which contain such formulations and can be used in diabetes and to methods for producing the preparations and improving the stability of insulin preparations.

Worldwide, approximately 120 million people suffer from diabetes mellitus.
Among these, approximately 12 million are type I diabetics, for whom the substitution of the lacking endocrine insulin secretion is the only currently possible therapy.
The affected persons are dependent lifelong on insulin injections, as a rule a number of times daily. In contrast to type I diabetes, there is not basically a deficiency of insulin in type II diabetes, but in a large number of cases, especially in the advanced stage, treatment with insulin, optionally in combination with an oral antidiabetic, is regarded as the most favorable form of therapy.

In the healthy person, the release of insulin by the pancreas is strictly coupled to the concentration of the blood glucose. Elevated blood glucose levels, such as occur after meals, are rapidly compensated by a corresponding increase in insulin secretion. In the fasting state, the plasma insulin level falls to a basal value which is adequate to guarantee a continuous supply of insulin-sensitive organs and tissue with glucose and to keep hepatic glucose production low in the night. The replacement of the endogenous insulin secretion by exogenous, mostly'subcutaneous administration of insulin as a rule does not approximatey achieve the quality of the physiological regulation of the blood glucose described above. Often, deviations of the blood glucose upward or downward occur, which in their severest forms can be life-threatening. In addition, however, blood glucose levels which are increased for years without initial symptoms are a considerable health risk. The large-scale DCCT
study in the USA (The Diabetes Control and Complications Trial Research Group (1993) N.
Engl. J. Med. 329, 977-986) demonstrated clearly that chronically elevated blood glucose levels are essentially responsible for the development of diabetic late damage. Diabetic late damage is microvascular and macrovascular damage which is manifested, under certain circumstances, as retinopathy, nephropathy or neuropathy and leads to loss of sight, kidney failure and the loss of extremities and is moreover accompanied by an increased risk of cardiovascular diseases. It is to be derived from this that an improved therapy of diabetes is primarily to be aimed at keeping the blood glucose as closely as possible in the physiological range. According to the concept of intensified insulin therapy, this should be achieved by repeated daily injections of rapid- and slow-acting insulin preparations. Rapid-acting formulations are given at meals in order to level out the postprandial increase in the blood glucose.
Slow-acting basal insulins should ensure the basic supply with insulin, in particular during the night, without leading to hypoglycemia.

Insulin is a polypeptide of 51 amino acids, which are divided into 2 amino acid chains:
the A chain having 21 amino acids and the B chain having 30 amino acids. The chains are connected to one another by means of 2 disulfide bridges. Insulin preparations have been employed for diabetes therapy for many years. Not only naturally occurring insulins are used here, but recently also insulin derivatives and analogs.

Insulin analogs are analogs of naturally occurring insulins, namely human insulin or animal insulins, which differ by substitution of at least one naturally occurring amino acid residue with other amino acid residues and/or addition/removal of at least one amino acid residue from the corresponding, otherwise identical, naturally occurring insulin. The added and/or replaced amino acid residues can also be those which do not occur naturally.
3, Insulin derivatives are derivatives of naturally occurring insulin or an insulin analog which are obtained by chemical modification. The chemical modification can consist, for example, in the addition of one or more specific chemical groups to one or more amino acids.
As a rule, insulin derivatives and insulin analogs have a somewhat modified action compared with human insulin.

Insulin analogs having an accelerated onset of action are described in EP 0 214 826, EP 0 375 437 and EP 0 678 522. EP 0 124 826 relates, inter alia, to substitutions of B27 and B28. EP 0 678 522 describes insulin analogs which have various amino acids, preferably proline, in position B29, but not glutamic acid.
EP 0 375 437 includes insulin analogs with lysine or arginine in B28, which can optionally additionally be modified in B3 and/or A21.
In EP 0 419 504, insulin analogs are disclosed which are protected against chemical modifications, in which asparagine in B3 and at least one further amino acid in the positions A5, A15, Al 8 or A21 are modified.

In WO 92/00321, insulin analogs are described in which at least one amino acid of the positions B1-B6 is replaced by lysine or arginine. According to WO.92/00321, insulins of this type have a prolonged action.

The insulin preparations of naturally occurring insulins on the market for insulin substitution differ in the origin of the insulin (e.g. bovine, porcine, human insulin), and also the composition, whereby the profile of action (onset of action and duration of action) can be influenced. By combination of various insulin preparations, very different profiles of action can be obtained and blood sugar values which are as physiological as possible can be established. For some time, not only the naturally occurring insulins mentioned, but also preparations of insulin derivatives or insulin analogs have been on the market which show modified kinetics. Recombinant DNA
technology today makes possible the preparation of such modified insulins.
These include "monomeric insulin analogs" such as insulin LisproTM, insulin AspartTM
and HMR
1964 (Lys(B3), Glu(B29) human insulin) having a rapid onset of action, and also insulin GlarginTM having a prolonged duration of action.

In addition to the duration of action, the stability of the preparation is very important for the patients. Stabilized insulin formulations having increased physical long-term stability are needed 'in particular for preparations which are exposed to particular mechanical stresses or relatively high temperatures. These include, for example, insulins in administration systems such as pens, inhalation systems, needleless injection systems or insulin pumps. Insulin pumps are either worn on or implanted in the body of the patient. In both cases, the preparation is exposed to the heat of the body and movement and to the delivery motion of the pump and thus to a very high thermomechanical stress. Since insulin pens too (disposable and reutilizable pens) are usually worn. on the body, the same applies here. Previous preparations have only a limited stability under these conditions.
Insulin is present in neutral solution in pharmaceutical concentration in the form of stabilized zinc-containing hexamers, which are composed of 3 identical dimer units (Brange et al., Diabetes Care 13:923-954 (1990)). By modification of the amino acid sequence, the association of insulin can be decreased. Thus, the insulin analog Lispro, for example, mainly exists as a monomer and is thereby absorbed more rapidly and shows a shorter duration of action (HPT Ammon and C. Werning;
Antidiabetika [Antidiabetics]; 2. Ed.; Wiss. Verl.-Ges. Stuttgart; 2000; p.
94.f).
Especially the rapid-acting insulin analogs, which exist in the monomeric or dimeric form, show, however, a decreased stability and increased proneness to aggregation under thermal and mechanical stress. This makes itself noticeable in cloudiness and precipitates of insoluble aggregates. (Bakaysa et al, US patent no. 5474978).
These higher molecular weight transformation products (dimers, trimers, polymers) and aggregates decrease not only the dose of insulin administered but can also induce irritation or immune reactions in the patient. Moreover, such insoluble aggregates can affect and block the cannulas and tubing of the pumps. Since zinc leads to an additional stabilization of the insulin, zinc-free or low-zinc preparations of insulin and insulin analogs are particularly susceptible to instability. In particular, monomeric insulin analogs having a rapid onset of action are prone very rapidly to aggregation and physical instability, because the formation of insoluble aggregates proceeds via monomers of insulin. In order to guarantee the quality of an insulin preparation, it is necessary to avoi -t a formation of aggregates.

There are various approaches for stabilizing insulin formulations. Thus, in international patent application W098/56406 formulations stabilized by TRIS or arginine buffer have been described. US patent 5866538 describes an insulin preparation which contains glycerol and sodium chloride in concentrations of 5 5 mM and should have an increased stability. US patent 5948751 describes insulin preparations having increased physical stability, which is achieved by addition of mannitol or similar sugars. The addition of excess zinc to a zinc-containing insulin solution can likewise increase the stability (J. Brange et al., Diabetic Medicine, 3:
532-536, 1986). The influence of the pH and various excipients on the stability of insulin preparations has also been described in detail (J. Brange & L.
Langkjaer, Acta Pharm. Nordica 4:149-158).
Often, these stabilization methods are not adequate for increased demands (improvement in ability to be kept at room or body temperature and under mechanical stress) or for "monomeric" insulin analogs or rapid-acting insulins, which are particularly susceptible to physical stress. Moreover, all commercial insulin preparations contain zinc, which is added to stabilize the preparation. Thus, Bakaysa et al. in US patent 5474978 describes stabilized formulations of insulin complexes which consist of 6 insulin analog monomers, 2 zinc atoms and at least 3 molecules of a phenolic preservative. These formulations can additionally contain a physiologically acceptable buffer and a preservative. If it is wished, however, to prepare zinc-free or low-zinc insulin preparations, the stabilization methods mentioned are not adequate for a marketable preparation. For example, it was not possible to develop a zinc-free preparation of insulin Lispro on account of inadequate physical stability (Bakaysa et al., Protein Science (1996), 5:2521-2531). Low-zinc or zinc-free insulin formulations having adequate stability, in particular physical stability, are not described in the prior art.

The present invention was thus based on the object of finding zinc-free preparations for insulins and their derivatives and analogs, which are distinguished by a high stability.
It has now surprisingly been found that the addition of surfactants (emulsifiers) such as, for example, poloxamers or polysorbates (Tween ) can drastically increase the stability of insulin preparations and thus even zinc-free preparations can be prepared which have a superior stability, in order to be capable of being used in infusion pumps or other administration systems as well. These preparations show increased stability, particularly under stress conditions. This applies both to insulin, insulin analogs, insulin derivatives or mixtures thereof.

In neutral preparations, insulin forms complexes with zinc ions. Here, at an adequate zinc concentration, stable hexamers are formed from 6 insulin molecules and 2 zinc ions. For the formation of this structure, a zinc concentration of at least 0.4 % (w/w) relative to the insulin is necessary. This corresponds in the case of a preparation of 100 IU/ml of insulin to a concentration of about 13 Ng/ml of zinc. An excess of zinc (e.g. 4 zinc ions per hexamer) again markedly stabilizes the preparation against physical stress (J. Brange et al., Neutral insulin solutions physically stabilized by the addition of Zn2+. Diabetic Med. 3, 532-536 (1986)). In contrast to this, in preparations having lower zinc concentrations (< 0.4 percent by weight based on insulin), the formation of the hexamers is reduced. This leads to a dramatically reduced stability of the preparation (J. Brange and L. Langkjaer; Acta Pharm Nord, 4: 149-158 (1992)). "Zinc free " or "low-zinc " within the meaning of this application therefore means the presence of less than 0.4 percent by weight of zinc based on the insulin content of the preparation, preferably less than 0.2 percent by weight based on the insulin content. For a customary insulin preparation containing 100 units per milliliter (0.6 Nmol/ml), this means, for example, a concentration of less than 13 Ng/ml of Zn++
ions (0.2 Nmol/ml), preferably less than 6.5 Ng/ml of Zn' ions, in the pharmaceutical preparation, based on an insulin concentration of 100 units/ml. The freedom from zinc can also be achieved by addition of zinc-complexing substances, such as, for example, citrate or EDTA, so that sufficient zinc ions are not available for the formation of the insulin/zinc hexamer complex.

The pharmaceutical preparations contain 60-6000 nmol/ml, preferably 240-3000 nmol/ml, of an insulin, an insulin metabolite, an insulin analog or an insulin derivative.
Surfactants which can be used are, inter alia, nonionic or ionic (anionic, cationic or amphoteric) surfactants. In particular, pharmaceutically customary surfactants are preferred, such as, for example:
alkali metal soaps, amine soaps and alkaline earth metal soaps (stearates, palmitates, oleates, ricinoleates), alkylsulfates and alkylsulfonates (sodium laurylsulfate, sodium cetylsulfate, sodium stearylsulfate), natural surfactants (bile acid salts, saponins, gum arabic), cationic surfactants (alkonium bromides, cetylpyridinium chloride, cetrimide), fatty alcohols (cetyl alcohol, stearyl alcohol, cholesterol), partial and fatty acid esters of polyhydric alcohols such as of glycerol, sorbitol and the like (Span , Tween , Myrj , Brij ), Cremophor or poloxamers.
The surfactants are present in the pharmaceutical composition in a concentration of 0.1 pg/ml - 10000 pg/rl, preferably 1 Ng/ml - 1000 Ng/ml.

The preparation can additionally contain preservatives (e.g. phenol, cresol, parabens), isotonicizing agents (e.g. mannitol, sorbitol, lactose, dextrose, trehalose, sodium chloride, glycerol) buffer substances, salts, acids and alkalis, and further excipients.
These substances can in each case be present individually or alternatively as mixtures.
Glycerol, dextrose, lactose, sorbitol and mannitol are customarily present in the pharmaceutical preparation in a concentration of 100 - 250 mM, NaCl in a concentration of up to 150 mM. Buffer substances, such as, for example, phosphate, acetate, citrate, arginine, glycyiglycine or TRIS (i.e. 2-amino-2-hydroxymethyl-1,3-propanediol) buffer and corresponding salts, are present in a concentration of 250 mM, preferably 10 - 100 mM.
Further excipients can, inter alia, be salts, arginine, protamine, or Surfen .
The invention therefore relates to a pharmaceutical formulation comprising a polypeptide selected from a group comprising insulin, an insulin analog, an insulin derivative, an active insulin metabolite or combinations thereof; a surfactant or combinations of a number of surfactants; optionally a preservative or combinations of a number of preservatives; and optionally an isotonicizing agent, buffer substances and/or further excipients or combinations thereof, the pharmaceutical formulation being free from or low in zinc; such a pharmaceutical preparation is preferred where the surfactant is selected from a group comprising alkali metal soaps, amine soaps, alkaline earth metal soaps, alkylsulfates, alkylsulfonates, natural surfactants, cationic surfactants, fatty alcohols, partial and fatty acid esters of polyhydric alcohols such as of glycerol and sorbitol, polyols; where the soaps mentioned are selected from a group comprising stearates, palmitates, oleates, ricinoleates; where the alkylsulfates are selected from a group comprising sodium laurylsulfate, sodium cetylsulfate, sodium stearylsulfate; where the natural surfactants are selected from a group comprising bile acid salts, saponins, gum arabic, lecithins; where the cationic surfactants are selected from a group comprising alkonium bromides, cetylpyridinium chloride, Cetrimid ; where the fatty alcohols are selected from a group comprising cetyl alcohol, stearyl alcohol, cholesterol; where the partial and fatty acid esters and ethers of glycerol and sorbitol are selected from a group comprising Span , Tween , Myrj , Brij , Cremophor ; where the polyols are selected from the group comprising polypropylene glycols, polyethylene glycols, poloxamers, Pluronics, Tetronics;
where the preservative is selected from a group comprising phenol, cresol, parabens;
where the isotonicizing agent is-selected from a group comprising mannitol, sorbitol, sodium chloride, glycerol; where the excipients are selected from a group comprising buffer substances, acids, alkalis; where the insulin is an insulin occurring in nature, for example human, bovine or porcine insulin; where the insulin analog is selected from a group comprising GIy(A21)- Arg(B31)- Arg(B32) human insulin; Lys(B3)-Glu(B29) human insulin; LysB28ProB29 human insulin, B28 Asp human insulin, human insulin, in which proline in position B28 has been substituted by Asp, Lys, Leu, Val or Ala and where in position B29 Lys can be substituted by Pro; AlaB26 human insulin;
des(B28-B30) human insulin; des(B27) human insulin or des(B30) human insulin;
where the insulin derivative is selected from a group comprising B29-N-myristoyl-des(B30) human insulin, B29-N-palmitoyl-des(B30) human insulin, B29-N-myristoyl human insulin, B29-N-palmitoyl human insulin, B28-N-myristoyl LysB28Pro B29 human insulin, B28-N-palmitoyl-LysB28ProB29 human insulin, B30-N-myristoyl-ThrB29LysB30 human insulin, B30-N-palmitoyl- ThrB29LysB30 human insulin, B29-N-(N-palmitoyl-Y-glutamyl)-des(B30) human insulin, B29-N-(N-lithocholyl-Y-glutamyl)-des(B30) human insulin, B29-N-(w-carboxyheptadecanoyl)-des(B30) human insulin and 829-N-(w-carboxyheptadecanoyl) human insulin. , The invention further relates to a pharmaceutical formulation as described above, in which the insulin, the insulin analog, the active insulin metabolite and/or the insulin derivative is present in a concentration of 60 - 6000 nmol/ml, preferably in a concentration of 240 - 3000 nmol/ml (this corresponds approximately to a concentration of 1.4 - 35 mg/ml or 40 - 500 units/ml); in which the surfactant is present in a concentration of 0.1 - 10000 yg/ml, preferably in a concentration of I -1000 Ng/ml.
The invention further relates to a pharmaceutical formulation as mentioned above, in which glycerol and/or mannitol is present in a concentration of 100 - 250 mM, and/or chloride is preferably present in a concentration of up to 150 mM.

The invention further relates to a pharmaceutical formulation as mentioned above, in which a buffer substance is present in a concentration of 5 - 250 mM.
The invention further relates to a pharmaceutical insulin formulation which contains further additives such as, for example, salts, protamine or Surfen which delay the release of insulin. Mixtures of such delayed-release insulins with formulations as described above are also included therein.
The invention further relates to a method for the preparation of such pharmaceutical formulations. The invention further likewise relates to the administration of such formulations for the treatment of diabetes mellitus.
The invention further relates to the use or the addition of surfactants as stabilizer during the process for the preparation of insulin, insulin analogs or insulin derivatives or their preparations.

In the pharmaceutical formulations described comprising a polypeptide selected from a group comprising insulin, an insulin analog, an insulin derivative, an active insulin metabolite or combinations thereof, the pH is between 2 and 12, preferably between 6 and 8.5 and particularly preferably between 7 and 7.8.

The application is described below with the aid of some examples, which should in no case act in a restrictive manner.

Examples:
Comparison investigations: Various zinc-free preparations containing the insulin analog HMR1964 (Lys(B3), Glu(B29), human insulin) are prepared. To this end, zinc-free HMR1964 and the other constituents are dissolved in one part of water for injection purposes and the pH is adjusted to 7.3 +/- 0.2 with hydrochloric acid/NaOH
and made up to the final volume. The concentration of HMR 1964 in each of the experiments described below is 3.5 mg/ml (corresponds to 100 units/ml). A
second preparation is prepared identically, but a specific amount of a surfactant is additionally added. The solutions are dispensed into 5 ml or 10 ml glass vessels (vials) and fitted .
with crimp caps. These vessels are then exposed to stress conditions:
1. Rotation test: In each case 5 vessels of a batch and 5 vessels of the comparison 5 batch are subjected to a rotation test. To this end, the vessels are mounted in a rotator and rotated top over bottom (360 ) at 37 C at 60 rpm. After defined times, the turbidity of the preparations situated in the vessels is compared with turbidity standards or determined in formazine nephelometric units (FNU) using a laboratory turbidity photometer (nephelometer). The experiment is carried out 10 until a turbidity value of 18 FNU is exceeded in all vessels.

2. Shaking test: The vessels are placed on a laboratory shaker in an incubator and shaken at 30 C at 100 movements/min. After defined times, the turbidity value of the samples is determined by means of a laboratory turbidity photometer (nephelometer) in formazine nephelometric units (FNU).

Example 1: Stabilization of HMR1964 by addition of zinc in the rotation test a) Zinc-free HMR1964 (calculated such that a concentration of 3.5 mg/ml results in the finished formulation) is dissolved in an aqueous solution, which in the final formulation contains 2.7 mg/ml of m-cresol, 20 mg/ml of glycerol and 6 mg/ml of trometamol (tris), and the pH is adjusted to 7.2 - 7.4 (measured at room temperature) using 1 N hydrochloric acid/1 N NaOH. The solution is made up to the final volume with water and sterile-filtered through a 0.2 Nm filter. It is then filled into 5 ml injection vials and sealed using caps.
b) A comparison solution is prepared identically, but before making up with water a corresponding amount of a 0.1 % strength zinc chloride stock solution is added, so that a zinc content of 15 Ng/ml results in the finished formulation.

In each case, 5 samples are then stressed in the rotation test and the turbidity is determined after various periods of time. The results are shown in the following table.
Number of test samples with turbidi > 18 FNU after:
Description O h 8 h 16 h 32 h 40 h 56 h Without addition +15 Ng/ml of Zn The addition of zinc can markedly delay the resulting turbidity of the solution in terms of time and thereby stabilizes the HMR1964 formulation. Without addition of zinc, the preparation has a marked turbidity in the rotation test even after 8 hours.

Example 2: Stabilization of HMR1964 by addition of polysorbate 20 (Tween 20) in the rotation test a) Zinc-free HMR1964 (calculated such that a concentration of 3.5 mg/ml results in the finished formulation) is dissolved to an aqueous solution which contains 3.15 mg/
ml of m-cresol, 5 mg/ml of NaCl and 6 mg/ml of trometamol in the final formulation and the pH is adjusted to 7.2 - 7.4 (measured at room temperature) using 1 N
hydrochloric acid/1 N NaOH. The solution is made up to the final volume with water and sterile-filtered through a 0.2 Nm filter. It is then filled into 5 ml injection vials and . sealed using caps.

b) A comparison solution is prepared identically, but before making up with water a corresponding amount of a 0.1 % strength polysorbate 20 (Tween 20) stock solution is added, so that a concentration of 10 Ng/ml results in the finished formulation.

In each case 5 samples are then stressed in the rotation test and the turbidity is determined after various periods of time. The results are shown in the following table.
Number of test samples with turbidity > 18 FNU after:
Description 0 h 8 h 16 h 24 h 32 h 40 h Without addition + 10 erg/ml of Tween 0 0 0 0 .5 -The addition of polysorbate 20 delays the occurrence of turbidity very markedly.
Example 3: Stabilization of HMR1964 by addition of poloxamer in the rotation test a) Zinc-free HMR1964 (calculated such that a concentration of 3.5 mg/ml results in the finished formulation) is dissolved to an aqueous solution which contains 4.5 mg/
ml of phenol, 5 mg/ml of NaCl and 6 mg/ml of trometamol in the final formulation and the pH is adjusted to 7.2 - 7.4 (measured at room temperature) using 1 N
hydrochloric acid/1 N NaOH. The solution is made up to the final volume with water and sterile-filtered through a 0.2 Nm filter. It is then filled into 5 ml injection vials and sealed using caps.

b) A comparison solution is prepared identically, but before making up with water a corresponding amount of a 0.1 % strength poloxamer 171 (e.g. Genapol ) stock solution is added, such that a concentration of 10 Ng/ml results in the finished formulation.

In each case 5 samples are then stressed in the rotation test and the turbidity is determined after various periods of time. The results are shown in the following table.
Number of test samples with turbidity > 18 FNU
after:
Description 0 h 8 h 16 h 24 h 32 h 40 h Without addition + 0.01 mg/ml of poloxamer 0 0 0 2 5 -The addition of poloxamer 171 also delays the occurrence of turbidity markedly and stabilizes the preparation.
Example 4: Stabilization of HMR1964 by addition of polysorbate 20 or polysorbate.
80 in the shaking test a) Zinc-free HMR1964 (calculated such that a concentration of 3.5 mg/ml results in the finished formulation) is dissolved to an aqueous solution which contains 3.15 mg/
ml of m-cresol, 5 mg/ml of NaCl and 6 mg/ml of trometamol in the final formulation and the pH is adjusted to 7.2 - 7.4 (measured at room temperature) using 1 N
hydrochloric acid/1 N NaOH. The solution is made up to the final volume with water and sterile-filtered through a 0.2 Nm filter. It is then filled into 5 ml injection vials and sealed using caps.

b) A comparison solution is prepared identically, but before making up with water a corresponding amount of a 0.1 % strength polysorbate 20 (Tween 20) stock solution is added, such that a concentration of 10 Ng/ml results in the finished formulation.

c) A further comparison solution is prepared identically as in b), but this time polysorbate 80 (Tween 80) is used instead of polysorbate 20.

The samples are shaken at 30 C on a laboratory shaker (60 rpm) and the turbidity of the samples is measured after specific times. The results are shown in the following table.

Shaking test, turbidity after Addition Start 1 week 2 weeks 3 weeks 4 weeks Without 0.55 2.04 4.86 6.12 10.51 addition 0.01 mg/ml 1.75 2.60 2.44 2.44 3.80 of Tween 20 0.01 mg/ml 2.38 2.98 2.86 3.01 4.14 of Tween 80 -Both the addition of polysorbate 20 and of polysorbate 80 have a stabilizing effect on HMR1964 in the shaking test.

Example 5: Stabilization of HMR1964 by addition of zinc or poloxamer (Genapol ) in the shaking test a) Zinc-free HMR1964 (calculated such that a concentration of 3.5 mg/ml results in the finished formulation) is dissolved to an aqueous solution which contains 3.3 mg/
ml of phenol, 5 mg/ml of NaCl and 6 mg/ml of trometamol in the final formulation and the pH is adjusted to 7.2 - 7.4 (measured at room temperature) using 1 N
hydrochloric acid/1 N NaOH. The solution is made up to the final volume with water and sterile-filtered through a 0.2 Nm filter. It is then filled into 5 ml injection vials and sealed using caps.

b) A comparison solution is prepared identically, but before making up with water a corresponding amount of a 0.1 % strength poloxamer 171 (Genapol ) stock solution is added, such that a concentration of 10 pg/ml results in the finished formulation.

c) A further comparison solution is prepared as described in a), but instead of poloxamer, a corresponding amount of a 0.1 % strength zinc chloride stock solution is added to the solution before making up with water, so that a concentration of .15 Ng/
ml of zinc results in the finished formulation.

Shaking tes turbidity after Addition Start 1 week 2 weeks 3 weeks 4 weeks None 0.39 0.70 4.46 8.74 14.11 0.01 mg/ml of 0.36 0.57 0.52 1.59 0.89 poloxamer 0.015 mg/ml of 1.02 0.68 0.70 0.56 0.86 Zn Both an addition of zinc and the addition of poloxamer prevent the occurrence of turbidity in the shaking test.

Example 6: Stabilization of HMR1964 by addition of poloxamer in the rotation test a) Zinc-free HMR1964 (calculated such that a concentration of 3.5 mg/ml results in the finished formulation) is dissolved to an aqueous solution which contains 3.3. mg/
ml of phenol, 5 mg/ml of NaCl and 6 mg/ml of trometamol in the final formulation and the pH is adjusted to 7.2 - 7.4 (measured at room temperature) using 1 N
hydrochloric acid/1 N NaOH. The solution is made up to the final volume with water and sterile-filtered through a 0.2 ,um filter. It is then filled into 5 ml injection vials and sealed using caps.

b) A comparison solution is prepared identically, but before making up with water a corresponding amount of a 0.1 % strength poloxamer 171 (Genapol ) stock solution is added, such that a concentration of 100 pg/ml results in the finished formulation.

In each case 5 samples are then stressed in the rotation test and the turbidity is determined after various periods of time. The results are shown in the following table.

Number of test samples with turbidity > 18 FNU
after:

Description 0 h 8 h 16 h 24 h 32 h 40 h Without addition + 0.10 mg/ml of poloxamer 0 0 0 0 1 5 5 The addition of 100,ug/mI of poloxamer likewise stabilizes the HMR1964 preparation very markedly.

Claims (37)

What is claimed is:
1. A formulation comprising at least one insulin analog; and at least one surfactant;
wherein the at least one insulin analog is Lys(B3), Glu(B29) human insulin;
wherein the at least one surfactant is a polysorbate 20 or polysorbate 80; and wherein the formulation is free from zinc.
2. The formulation as claimed in claim 1 further comprising at least one preservative.
3. The formulation as claimed in claim 1 or 2 further comprising at least one of an isotonicizing agent, a buffer, and an excipient.
4. The formulation as claimed in any one of claims 1-3 further comprising at least one surfactant selected from alkali metal soaps, amine soaps, alkaline earth metal soaps, alkylsulfates, alkylsulfonates, natural surfactants, cationic surfactants, fatty alcohols, fatty acids, esters of polyhydric alcohols, ethers of polyhydric alcohols, and polyols.
5. The formulation as claimed in any one of claims 1-4 further comprising at least one surfactant comprising a soap selected from at least one of a stearate, a palmitate, an oleate, and a ricinoleate.
6. The formulation as claimed in claim 4, wherein the alkylsulfates are selected from at least one of sodium laurylsulfate, sodium cetylsulfate, and sodium stearylsulfate.
7. The formulation as claimed in claim 4, wherein the natural surfactants are selected from at least one of bile acid salts, saponins, gum arabic, and lecithins.
8. The formulation as claimed in claim 4, wherein the cationic surfactants are selected from at least one of alkonium halides, cetylpyndinium chloride, and Cetrimid~.
9. The formulation as claimed in claim 4, wherein the fatty alcohols are selected from at least one of cetyl alcohol, stearyl alcohol, and cholesterol.
10. The formulation as claimed in claim 4, wherein the esters of polyhydric alcohols are selected from at least one of esters of sorbitol, glycerol, sucrose, and polyethylene glycol.
11. The formulation as claimed in claim 4, wherein the esters of polyhydric alcohols are fatty acid esters.
12. The formulation as claimed in claim 4, wherein the ethers of polyhydric alcohols are selected from at least one of ethers of sorbitol, glycerol, sucrose, and polyethylene glycol.
13. The formulation as claimed in claim 10 or 12, wherein the fatty acid esters and ethers of polyhydric alcohols of glycerol and sorbitol are selected from at least one of Span~, Tween~(polysorbate), Myrj~, Brij~, Triton~, and Cremophor~.
14. The formulation as claimed in any one of claims 1-13 further comprising at least one surfactant selected from a polysorbate, a sorbitan ester, a polyoxyethylene stearate, a polyoxyethylene ether, and a polyethylene glycol ether.
15. The formulation as claimed in claim 4, wherein the polyols are selected from at least one of polypropylene glycols, polyethylene glycols, poloxamers, Pluronics.TM., and Tetronics.TM.
16. The formulation as claimed in any one of claims 2-15, wherein the preservative is selected from at least one of phenol, cresol, chlorocresol, benzyl alcohol, and parabens.
17. The formulation as claimed in any one of claims 3-16, wherein the isotonicizing agent is selected from at least one of mannitol, sorbitol, lactose, dextrose, trehalose, sodium chloride, and glycerol.
18. The formulation as claimed in any one of claims 3-17, wherein the excipient is selected from at least one of a buffer substance, an acid, an alkali, a salt, protamine, arginine, and Surfen®.
19. The formulation as claimed in claim 18, wherein the buffer substance is selected from TRIS, phosphate, citrate, acetate, and glycylglycine.
20. The formulation as claimed in any one of claims 1-19 further comprising at least one insulin analog selected from Gly(A21), Arg(B31), Arg(B32), human insulin; Asp(B28) human insulin, Lys(B28) Pro(B29) human insulin; and des(B30) human insulin.
21. The formulation as claimed in any one of claims 1-20, in which the at least one insulin analog is present in a concentration of 60-6000 nmol/ml.
22. The formulation as claimed in claim 21, wherein the insulin analog is present in a concentration of 240-3000 nmol/ml.
23. The formulation as claimed in any one of claims 1-22, in which the at least one surfactant is present in a concentration of 0.1-10000 µg/ml.
24. The formulation as claimed in claim 23, in which the surfactant is present in a concentration of 1-1000 µg/ml.
25. The formulation as claimed in any one of claims 1-24 further comprising at least one surfactant selected from glycerol and mannitol in a concentration of 100-250 mM.
26. The formulation as claimed in any one of claims 3-25, in which the isotonicizing agent comprises at least one of glycerol and mannitol in a concentration of 100-250 mM.
27. The formulation as claimed in claim 25 or 26 further comprising chloride as a buffer substance and/or isotonicizing agent in a concentration of up to 150 mM.
28. The formulation as claimed in any one of claims .3-27, in which the buffer substance is present in a concentration of 5-250 mM.
29. A process for the production of the formulation as claimed in any one of claims 1-28, wherein the components are mixed together in the form of aqueous solutions and the mixture is made up to the final volume with water.
30. The process for the production of the formulation as claimed in claim 29, the final concentration of 3.15 mg/ml of cresol, 3.5 mg/ml of HMR 1964, 6.0 mg/ml of trometamol, 5.0 mg/mi of NaCl, and 0.1 mg/ml of Tween~ 20 being achieved.
31. A formulation obtained from the process as claimed in claim 29 or 30.
32. The formulation of claim 1 further comprising cresol, trometamol, and NaCl.
33. A formulation comprising per milliliter:
(a) 1.4 to 35 mg of Lys(B3), Glu(B29) human insulin;
(b) 10 to 100 µg of polysorbate 20;

(c) 5 to 7 mg of tromethamine;
(d) 1 to 8 mg NaCl; and (e) water;

wherein the formulation is free from zinc; and wherein the pH of the formulation is 7.3+/-0.2.
34. A formulation comprising per milliliter:
(a) 3 to 5 mg of Lys(B3), Glu(B29) human insulin;
(b) 10 to 100 µg of polysorbate 20;
(c) 5 to 7 mg of tromethamine;
(d) 1 to 8 mg NaCl; and (e) water;

wherein the formulation is free from zinc; and wherein the pH of the formulation is 7.3+/-0.2.
35. The formulation of claim 33 or 34 further comprising m-cresol.
36. A formulation comprising per milliliter:
(a) 3 to 4 mg of Lys(B3), Glu(B29) human insulin;
(b) 0.01 mg of polysorbate 20;
(c) 3.15 mg m-cresol;
(d) 6 mg of tromethamine;
(e) 5 mg NaCl;
(f) water;

wherein the formulation is free from zinc; and wherein the pH of the formulation is 7.3+/-0.2.
37. Use of the formulation as claimed in any one of claims 1-28 and claims 31-36 for treating diabetes mellitus.
CA2441260A 2001-03-23 2002-03-09 Insulin preparations, which do not contain any zinc or only a small quantity of zinc and which have an improved stability Expired - Lifetime CA2441260C (en)

Applications Claiming Priority (3)

Application Number Priority Date Filing Date Title
DE10114178.5 2001-03-23
DE10114178A DE10114178A1 (en) 2001-03-23 2001-03-23 Zinc-free and low-zinc insulin preparations with improved stability
PCT/EP2002/002625 WO2002076495A1 (en) 2001-03-23 2002-03-09 Insulin preparations, which do not contain any zinc or only a small quantity of zinc and which have an improved stability

Publications (2)

Publication Number Publication Date
CA2441260A1 CA2441260A1 (en) 2002-10-03
CA2441260C true CA2441260C (en) 2011-04-26

Family

ID=7678654

Family Applications (1)

Application Number Title Priority Date Filing Date
CA2441260A Expired - Lifetime CA2441260C (en) 2001-03-23 2002-03-09 Insulin preparations, which do not contain any zinc or only a small quantity of zinc and which have an improved stability

Country Status (32)

Country Link
US (5) US6960561B2 (en)
EP (2) EP1381385B1 (en)
JP (1) JP4231292B2 (en)
KR (2) KR20100061868A (en)
CN (1) CN1273187C (en)
AR (2) AR033059A1 (en)
AT (1) ATE497777T1 (en)
AU (1) AU2002302409B2 (en)
BR (1) BRPI0208210B8 (en)
CA (1) CA2441260C (en)
CY (2) CY1111413T1 (en)
DE (2) DE10114178A1 (en)
DK (2) DK2289539T3 (en)
ES (2) ES2360505T3 (en)
HK (1) HK1061521A1 (en)
HR (1) HRP20030765B1 (en)
HU (1) HU228847B1 (en)
IL (2) IL158057A0 (en)
ME (1) ME00408B (en)
MX (1) MXPA03007942A (en)
MY (1) MY129417A (en)
NO (1) NO326780B1 (en)
NZ (1) NZ528335A (en)
PE (1) PE20020968A1 (en)
PL (1) PL205465B1 (en)
PT (2) PT2289539E (en)
RS (1) RS51579B (en)
RU (1) RU2311922C2 (en)
SI (1) SI1381385T1 (en)
TW (1) TWI301761B (en)
WO (1) WO2002076495A1 (en)
ZA (1) ZA200306637B (en)

Families Citing this family (78)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JP3764174B2 (en) * 1997-03-20 2006-04-05 ノボ ノルディスク アクティーゼルスカブ Zinc-free insulin crystals for use in pulmonary compositions
DE10114178A1 (en) 2001-03-23 2002-10-10 Aventis Pharma Gmbh Zinc-free and low-zinc insulin preparations with improved stability
US20050250676A1 (en) * 2001-11-19 2005-11-10 Aventis Pharma Deutschland Gmbh Method of activating insulin receptor substrate-2 to stimulate insulin production
DE10227232A1 (en) * 2002-06-18 2004-01-15 Aventis Pharma Deutschland Gmbh Sour insulin preparations with improved stability
DE10250297A1 (en) * 2002-10-29 2004-05-19 Aventis Pharma Deutschland Gmbh Insulin analog crystals and process for their preparation
US7193035B2 (en) 2002-10-29 2007-03-20 Sanofi-Aventis Deutschland Gmbh Crystals of insulin analogs and processes for their preparation
WO2004096266A1 (en) * 2003-05-02 2004-11-11 Novo Nordisk A/S Improved physical stability of insulin formulations
EP2264065B1 (en) 2003-08-05 2017-03-08 Novo Nordisk A/S Novel insulin derivatives
EP1711220A1 (en) * 2004-01-16 2006-10-18 Biodel, Inc. Sublingual drug delivery device
CA2555921A1 (en) * 2004-02-13 2005-09-15 Nod Pharmaceuticals, Inc. Therapeutic calcium phosphate particles and methods of making and using same
US20080096800A1 (en) * 2004-03-12 2008-04-24 Biodel, Inc. Rapid mucosal gel or film insulin compositions
US7279457B2 (en) * 2004-03-12 2007-10-09 Biodel, Inc. Rapid acting drug delivery compositions
US20080090753A1 (en) 2004-03-12 2008-04-17 Biodel, Inc. Rapid Acting Injectable Insulin Compositions
CA2910494C (en) 2004-07-19 2018-10-23 Biocon Limited Insulin-oligomer conjugates, formulations and uses thereof
JP2006087815A (en) * 2004-09-27 2006-04-06 Canon Inc Spraying method, and spraying apparatus based on the method
US20060194762A1 (en) * 2004-12-23 2006-08-31 Olaf Reer Composition comprising an epothilone and methods for producing a composition comprising an epothilone
US7713929B2 (en) 2006-04-12 2010-05-11 Biodel Inc. Rapid acting and long acting insulin combination formulations
US8084420B2 (en) 2005-09-29 2011-12-27 Biodel Inc. Rapid acting and long acting insulin combination formulations
ES2371361T3 (en) * 2005-12-28 2011-12-30 Novo Nordisk A/S COMPOSITIONS THAT INCLUDE AN INSULIN ACILADA AND ZINC AND METHOD OF PRODUCTION OF SUCH COMPOSITIONS.
US8927015B2 (en) 2006-04-12 2015-01-06 Emisphere Technologies, Inc. Formulations for delivering insulin
WO2007121256A2 (en) 2006-04-12 2007-10-25 Biodel, Inc. Rapid acting and long acting insulin combination formulations
US7714025B2 (en) * 2006-05-10 2010-05-11 Arizona Biomedical Research Commission Modified chalcone compounds as antimitotic agents
WO2008132229A2 (en) * 2007-04-30 2008-11-06 Novo Nordisk A/S Highly concentrated insulin solutions and compositions
ES2744384T3 (en) * 2007-06-13 2020-02-24 Novo Nordisk As Pharmaceutical formulation comprising an insulin derivative
US8642532B2 (en) * 2007-11-16 2014-02-04 Guohan Yang Excipients for protein stabilization
US20090186819A1 (en) * 2007-12-11 2009-07-23 Marieve Carrier Formulation of insulinotropic peptide conjugates
RU2524423C2 (en) 2008-01-09 2014-07-27 Санофи-Авентис Дойчланд Гмбх Novel insulin derivatives with extremely delayed time/action profile
KR101239008B1 (en) * 2008-03-31 2013-03-04 한양대학교 산학협력단 Bile acid derivatives and their applications
JP2010063762A (en) * 2008-09-12 2010-03-25 Yoshiharu Masui Antibacterial deodorant
ES2650621T3 (en) 2008-10-17 2018-01-19 Sanofi-Aventis Deutschland Gmbh Combination of an insulin and a GLP-1 agonist
RU2540922C2 (en) 2008-10-30 2015-02-10 Ново Нордиск А/С Treating diabetes mellitus by insulin injections as little as once day
US9060927B2 (en) 2009-03-03 2015-06-23 Biodel Inc. Insulin formulations for rapid uptake
WO2010149772A1 (en) * 2009-06-26 2010-12-29 Novo Nordisk A/S Preparation comprising insulin, nicotinamide and an amino acid
CN107080836A (en) * 2009-07-06 2017-08-22 赛诺菲-安万特德国有限公司 Aqueous insulin preparation containing methionine
PE20121362A1 (en) 2009-11-13 2012-10-17 Sanofi Aventis Deutschland PHARMACEUTICAL COMPOSITION INCLUDING DESPRO36EXENDIN-4 (1-39) -LYS6-NH2, INSULIN GLY (A21) -ARG (B31) -ARG (B32) AND METHIONINE
TWI468171B (en) 2009-11-13 2015-01-11 Sanofi Aventis Deutschland Pharmaceutical composition comprising a glp-1 agonist and methionine
CN101912600B (en) * 2010-01-11 2014-01-29 杨国汉 Method for improving stability of insulin in solution
RU2546520C2 (en) 2010-08-30 2015-04-10 Санофи-Авентис Дойчланд Гмбх Application of ave0010 for production of medication for treatment of type 2 diabetes mellitus
BR112013010345A2 (en) 2010-10-27 2017-07-25 Novo Nordisk As diabetes mellitus treatment using insulin injections administered at varying injection intervals
US9821032B2 (en) 2011-05-13 2017-11-21 Sanofi-Aventis Deutschland Gmbh Pharmaceutical combination for improving glycemic control as add-on therapy to basal insulin
CN103917241A (en) 2011-08-29 2014-07-09 赛诺菲-安万特德国有限公司 Pharmaceutical combination for use in glycemic control in diabetes type 2 patients
TWI559929B (en) 2011-09-01 2016-12-01 Sanofi Aventis Deutschland Pharmaceutical composition for use in the treatment of a neurodegenerative disease
AU2012328407A1 (en) 2011-10-27 2014-05-22 Case Western Reserve University Ultra-concentrated rapid-acting insulin analogue formulations
MX360107B (en) 2012-11-13 2018-10-23 Adocia Quick-acting insulin formulation including a substituted anionic compound.
TWI641381B (en) 2013-02-04 2018-11-21 法商賽諾菲公司 Stabilized pharmaceutical formulations of insulin analogues and/or insulin derivatives
HUE042381T2 (en) 2013-04-03 2019-06-28 Sanofi Sa Treatment of diabetes mellitus by long acting formulations of insulins
US10137172B2 (en) 2013-04-30 2018-11-27 Novo Nordisk A/S Administration regime
AR098168A1 (en) * 2013-10-25 2016-05-04 Sanofi Sa STABLE FORMULATION OF GLULISINE INSULIN
SG11201604706TA (en) 2014-01-09 2016-07-28 Sanofi Sa Stabilized pharmaceutical formulations of insulin aspart
MX2016008978A (en) 2014-01-09 2016-10-04 Sanofi Sa Stabilized glycerol free pharmaceutical formulations of insulin analogues and/or insulin derivatives.
RU2016132342A (en) 2014-01-09 2018-02-14 Санофи STABILIZED PHARMACEUTICAL COMPOSITIONS BASED ON INSULIN ANALOGUES AND / OR INSULIN DERIVATIVES
AR099569A1 (en) 2014-02-28 2016-08-03 Novo Nordisk As INSULIN DERIVATIVES AND THE MEDICAL USES OF THESE
US10314911B2 (en) 2014-04-08 2019-06-11 Healthpartners Research & Education Methods for protecting and treating traumatic brain injury, concussion and brain inflammation with intranasal insulin
RS64300B1 (en) 2014-12-12 2023-07-31 Sanofi Aventis Deutschland Insulin glargine/lixisenatide fixed ratio formulation
AR102869A1 (en) 2014-12-16 2017-03-29 Lilly Co Eli QUICK ACTION INSULIN COMPOSITIONS
TWI748945B (en) 2015-03-13 2021-12-11 德商賽諾菲阿凡提斯德意志有限公司 Treatment type 2 diabetes mellitus patients
TW201705975A (en) 2015-03-18 2017-02-16 賽諾菲阿凡提斯德意志有限公司 Treatment of type 2 diabetes mellitus patients
JP2018531899A (en) 2015-08-25 2018-11-01 ノヴォ ノルディスク アー／エス Novel insulin derivatives and their medical use
JP2018531900A (en) 2015-08-25 2018-11-01 ノヴォ ノルディスク アー／エス Novel insulin derivatives and their medical use
US20190010206A1 (en) 2015-08-25 2019-01-10 Novo Nordisk A/S Novel Insulin Derivatives and the Medical Uses Hereof
JO3749B1 (en) 2015-08-27 2021-01-31 Lilly Co Eli Rapid-acting insulin compositions
CN105749292A (en) * 2016-02-29 2016-07-13 苏州市贝克生物科技有限公司 Composition for promoting insulin absorption and preparation method of composition
GB201607918D0 (en) 2016-05-06 2016-06-22 Arecor Ltd Novel formulations
WO2018060736A1 (en) 2016-09-29 2018-04-05 Arecor Limited Novel formulations
GB201707189D0 (en) 2017-05-05 2017-06-21 Arecor Ltd Novel formulations
GB201707188D0 (en) 2017-05-05 2017-06-21 Arecor Ltd Novel formulations
GB201707187D0 (en) 2017-05-05 2017-06-21 Arecor Ltd Novel formulations
US11207384B2 (en) 2017-06-01 2021-12-28 Eli Lilly And Company Rapid-acting insulin compositions
CA3094237A1 (en) 2018-04-04 2019-10-10 Arecor Limited Medical infusion pump system for the delivery of an insulin compound
EP3773473A1 (en) 2018-04-04 2021-02-17 Arecor Limited Medical infusion pump system for the delivery of an insulin compound
US20210093775A1 (en) 2018-04-04 2021-04-01 Arecor Limited Medical infusion pump system for the delivery of an insulin compound
US10335464B1 (en) 2018-06-26 2019-07-02 Novo Nordisk A/S Device for titrating basal insulin
FR3083700B1 (en) * 2018-07-13 2021-03-12 Adocia THERMOSTABLE FORMULATION OF HUMAN INSULIN A21G
CN116726361A (en) 2018-11-19 2023-09-12 比奥拉治疗股份有限公司 Methods and devices for treating diseases with biologic therapeutic agents
WO2021081404A1 (en) 2019-10-25 2021-04-29 Cercacor Laboratories, Inc. Indicator compounds, devices comprising indicator compounds, and methods of making and using the same
EP4073097A1 (en) 2019-12-11 2022-10-19 Novo Nordisk A/S Novel insulin analogues and uses thereof
WO2021119482A1 (en) 2019-12-13 2021-06-17 Progenity, Inc. Ingestible device for delivery of therapeutic agent to the gastrointestinal tract
GB202004814D0 (en) 2020-04-01 2020-05-13 Arecor Ltd Novel formulations

Family Cites Families (101)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US3758683A (en) * 1971-04-30 1973-09-11 R Jackson Insulin product
US3868358A (en) * 1971-04-30 1975-02-25 Lilly Co Eli Protamine-insulin product
US4153689A (en) * 1975-06-13 1979-05-08 Takeda Chemical Industries, Ltd. Stable insulin preparation for nasal administration
GB1527605A (en) 1975-08-20 1978-10-04 Takeda Chemical Industries Ltd Insulin preparation for intranasal administration
US4783441A (en) * 1979-04-30 1988-11-08 Hoechst Aktiengesellschaft Aqueous protein solutions stable to denaturation
EP0018609B1 (en) 1979-04-30 1983-09-21 Hoechst Aktiengesellschaft Aqueous solutions of proteins stable against denaturization, process for their manufacture, and their utilization
JPS55153712A (en) 1979-05-18 1980-11-29 Kao Corp Insulin pharmaceutical preparation and its production
DE3033127A1 (en) 1980-09-03 1982-04-08 Hoechst Ag, 6000 Frankfurt NEW INSULIN ANALOG
AU558474B2 (en) 1981-07-17 1987-01-29 Nordisk Insulinlaboratorium A stable aqueous, therapeutic insulin preparation and a process for preparing it
NL193099C (en) * 1981-10-30 1998-11-03 Novo Industri As Stabilized insulin solution.
DE3316363A1 (en) 1983-05-05 1984-11-08 Deutsche Babcock Anlagen Ag, 4200 Oberhausen ROLLER GRID FOR WASTE COMBUSTION PLANTS
DE3326472A1 (en) 1983-07-22 1985-02-14 Hoechst Ag, 6230 Frankfurt NEW INSULIN DERIVATIVES, METHOD FOR THE PRODUCTION AND USE THEREOF AND PHARMACEUTICAL AGENTS FOR TREATING THE DIABETES MELLITUS
DE3326473A1 (en) * 1983-07-22 1985-01-31 Hoechst Ag, 6230 Frankfurt PHARMACEUTICAL AGENT FOR TREATING THE DIABETES MELLITUS
DE3327713A1 (en) 1983-07-29 1985-02-07 Hoechst Ag, 6230 Frankfurt WATER-SOLUBLE DISAZO COMPOUNDS, METHOD FOR THE PRODUCTION THEREOF AND THEIR USE AS DYES
DE3327709A1 (en) * 1983-07-29 1985-02-07 Hoechst Ag, 6230 Frankfurt INSULIN DERIVATIVE CRYSTAL SUSPENSIONS, METHOD FOR THE PRODUCTION AND USE THEREOF
CA1244347A (en) * 1984-05-29 1988-11-08 Eddie H. Massey Stabilized insulin formulations
US4839341A (en) * 1984-05-29 1989-06-13 Eli Lilly And Company Stabilized insulin formulations
DE3576120D1 (en) 1984-06-09 1990-04-05 Hoechst Ag INSULIN PREPARATIONS, METHOD FOR THE PRODUCTION AND USE THEREOF.
KR860001166B1 (en) * 1984-06-15 1986-08-20 곽성일 A method of manufacturing eyelets for footwears
DE3440988A1 (en) * 1984-11-09 1986-07-10 Hoechst Ag, 6230 Frankfurt METHOD FOR CLEAVING PEPTIDES AND PROTEINS ON THE METHIONYL BOND
DK113585D0 (en) 1985-03-12 1985-03-12 Novo Industri As NEW PEPTIDES
DK347086D0 (en) 1986-07-21 1986-07-21 Novo Industri As NOVEL PEPTIDES
US5008241A (en) * 1985-03-12 1991-04-16 Novo Nordisk A/S Novel insulin peptides
EP0200383A3 (en) * 1985-04-15 1987-09-02 Eli Lilly And Company An improved method for administering insulin
DE3526995A1 (en) 1985-07-27 1987-02-05 Hoechst Ag FUSION PROTEINS, METHOD FOR THEIR PRODUCTION AND THEIR USE
PH25772A (en) 1985-08-30 1991-10-18 Novo Industri As Insulin analogues, process for their preparation
DE3541856A1 (en) 1985-11-27 1987-06-04 Hoechst Ag EUKARYOTIC FUSION PROTEINS, THEIR PRODUCTION AND USE, AND MEANS FOR CARRYING OUT THE PROCESS
US5496924A (en) 1985-11-27 1996-03-05 Hoechst Aktiengesellschaft Fusion protein comprising an interleukin-2 fragment ballast portion
CA1275922C (en) 1985-11-28 1990-11-06 Harunobu Amagase Treatment of cancer
DE3544295A1 (en) * 1985-12-14 1987-06-19 Bayer Ag THERMOPLASTIC MOLDS WITH HIGH CROSS-CURRENT RESISTANCE
PH23446A (en) * 1986-10-20 1989-08-07 Novo Industri As Peptide preparations
AU612141B2 (en) 1987-02-25 1991-07-04 Novo Nordisk A/S Novel insulin derivatives
US5034415A (en) * 1987-08-07 1991-07-23 Century Laboratories, Inc. Treatment of diabetes mellitus
DE3726655A1 (en) * 1987-08-11 1989-02-23 Hoechst Ag METHOD FOR ISOLATING BASIC PROTEINS FROM PROTEIN MIXTURES CONTAINING SUCH BASIC PROTEINS
DK257988D0 (en) 1988-05-11 1988-05-11 Novo Industri As NEW PEPTIDES
US6875589B1 (en) * 1988-06-23 2005-04-05 Hoechst Aktiengesellschaft Mini-proinsulin, its preparation and use
DE3827533A1 (en) * 1988-08-13 1990-02-15 Hoechst Ag PHARMACEUTICAL PREPARATION FOR TREATING THE DIABETES MELLITUS
DE3837825A1 (en) * 1988-11-08 1990-05-10 Hoechst Ag NEW INSULIN DERIVATIVES, THEIR USE AND A PHARMACEUTICAL PREPARATION CONTAINING THEM
HUT56857A (en) 1988-12-23 1991-10-28 Novo Nordisk As Human insulin analogues
US4994439A (en) * 1989-01-19 1991-02-19 California Biotechnology Inc. Transmembrane formulations for drug administration
US5514646A (en) * 1989-02-09 1996-05-07 Chance; Ronald E. Insulin analogs modified at position 29 of the B chain
NZ232375A (en) 1989-02-09 1992-04-28 Lilly Co Eli Insulin analogues modified at b29
US5358857A (en) * 1989-08-29 1994-10-25 The General Hospital Corp. Method of preparing fusion proteins
US5397771A (en) * 1990-05-10 1995-03-14 Bechgaard International Research And Development A/S Pharmaceutical preparation
EP0532546B1 (en) 1990-05-10 1998-03-18 Bechgaard International Research And Development A/S A pharmaceutical preparation containing n-glycofurols and n-ethylene glycols
DK155690D0 (en) 1990-06-28 1990-06-28 Novo Nordisk As NEW PEPTIDES
DK10191D0 (en) * 1991-01-22 1991-01-22 Novo Nordisk As HIS UNKNOWN PEPTIDES
US5614219A (en) * 1991-12-05 1997-03-25 Alfatec-Pharma Gmbh Oral administration form for peptide pharmaceutical substances, in particular insulin
DK0615445T3 (en) * 1991-12-05 1996-06-03 Alfatec Pharma Gmbh Pharmaceutically manageable nanosol and method of preparation thereof
US6468959B1 (en) * 1991-12-05 2002-10-22 Alfatec-Pharm Gmbh Peroral dosage form for peptide containing medicaments, in particular insulin
DE59305396D1 (en) 1992-12-02 1997-03-20 Hoechst Ag Process for obtaining proinsulin with correctly connected cystine bridges
WO1994014461A1 (en) 1992-12-18 1994-07-07 Eli Lilly And Company Insulin analogs
DE4400709B4 (en) * 1993-01-13 2005-06-23 Denso Corp., Kariya Screw fastening device
US5606203A (en) * 1993-01-20 1997-02-25 Kabushiki Kaisha Toshiba Semiconductor device having Al-Cu wiring lines where Cu concentration is related to line width
US5506203C1 (en) * 1993-06-24 2001-02-06 Astra Ab Systemic administration of a therapeutic preparation
US5534488A (en) * 1993-08-13 1996-07-09 Eli Lilly And Company Insulin formulation
DE4405179A1 (en) 1994-02-18 1995-08-24 Hoechst Ag Method of obtaining insulin with correctly connected cystine bridges
US5474978A (en) 1994-06-16 1995-12-12 Eli Lilly And Company Insulin analog formulations
US5559094A (en) 1994-08-02 1996-09-24 Eli Lilly And Company AspB1 insulin analogs
ATE197398T1 (en) 1994-09-09 2000-11-11 Takeda Chemical Industries Ltd DELAYED RELEASE PREPARATION OF A METAL SALT OF A PEPTIDE
US5547929A (en) * 1994-09-12 1996-08-20 Eli Lilly And Company Insulin analog formulations
US5707641A (en) * 1994-10-13 1998-01-13 Pharmaderm Research & Development Ltd. Formulations comprising therapeutically-active proteins or polypeptides
US5824638A (en) * 1995-05-22 1998-10-20 Shire Laboratories, Inc. Oral insulin delivery
EP0831922A2 (en) 1995-06-08 1998-04-01 Therexsys Limited Improved pharmaceutical compositions for gene therapy
ATE268591T1 (en) * 1995-06-27 2004-06-15 Takeda Chemical Industries Ltd METHOD FOR PRODUCING DELAYED RELEASE PREPARATIONS
DE19545257A1 (en) * 1995-11-24 1997-06-19 Schering Ag Process for the production of morphologically uniform microcapsules and microcapsules produced by this process
US5985309A (en) * 1996-05-24 1999-11-16 Massachusetts Institute Of Technology Preparation of particles for inhalation
US5866538A (en) 1996-06-20 1999-02-02 Novo Nordisk A/S Insulin preparations containing NaCl
US5948751A (en) 1996-06-20 1999-09-07 Novo Nordisk A/S X14-mannitol
US5783556A (en) * 1996-08-13 1998-07-21 Genentech, Inc. Formulated insulin-containing composition
DE19707245A1 (en) * 1997-02-25 1998-08-27 Patent Treuhand Ges Fuer Elektrische Gluehlampen Mbh Method of making an electric light bulb
JP3764174B2 (en) * 1997-03-20 2006-04-05 ノボ ノルディスク アクティーゼルスカブ Zinc-free insulin crystals for use in pulmonary compositions
US6043214A (en) * 1997-03-20 2000-03-28 Novo Nordisk A/S Method for producing powder formulation comprising an insulin
US6310038B1 (en) * 1997-03-20 2001-10-30 Novo Nordisk A/S Pulmonary insulin crystals
ZA984697B (en) 1997-06-13 1999-12-01 Lilly Co Eli Stable insulin formulations.
DE19726167B4 (en) * 1997-06-20 2008-01-24 Sanofi-Aventis Deutschland Gmbh Insulin, process for its preparation and pharmaceutical preparation containing it
ZA989744B (en) * 1997-10-31 2000-04-26 Lilly Co Eli Method for administering acylated insulin.
CN1278737A (en) 1997-11-12 2001-01-03 阿尔萨公司 Method for decreasing self-association of polypeptides
WO1999034821A1 (en) * 1998-01-09 1999-07-15 Novo Nordisk A/S Stabilised insulin compositions
US6211144B1 (en) * 1998-10-16 2001-04-03 Novo Nordisk A/S Stable concentrated insulin preparations for pulmonary delivery
CA2346884A1 (en) 1998-10-16 2000-04-27 Novo Nordisk A/S Insulin preparations for pulmonary delivery containing menthol
US6635617B1 (en) * 1998-10-16 2003-10-21 Novo Nordisk A/S Insulin preparations for pulmonary delivery containing menthol
WO2000023098A1 (en) 1998-10-16 2000-04-27 Novo Nordisk A/S Stable concentrated insulin preparations for pulmonary delivery
EP1131089B1 (en) 1998-11-18 2004-02-18 Novo Nordisk A/S Stable aqueous insulin preparations without phenol and cresol
US6489292B1 (en) * 1998-11-18 2002-12-03 Novo Nordisk A/S Stable aqueous insulin preparations without phenol and cresol
DE19908041A1 (en) * 1999-02-24 2000-08-31 Hoecker Hartwig Covalently bridged insulin dimers
US6248363B1 (en) * 1999-11-23 2001-06-19 Lipocine, Inc. Solid carriers for improved delivery of active ingredients in pharmaceutical compositions
JP2003501404A (en) * 1999-06-04 2003-01-14 デルルックス ファーマシューティカル コーポレイション Preparation comprising dehydrated particles of drug and method of preparing same
WO2001000223A2 (en) * 1999-06-25 2001-01-04 Minimed Inc. Multiple agent diabetes therapy
US6309663B1 (en) 1999-08-17 2001-10-30 Lipocine Inc. Triglyceride-free compositions and methods for enhanced absorption of hydrophilic therapeutic agents
CN1174741C (en) 1999-09-21 2004-11-10 Rtp药品公司 Surface modified particulate compositions of biologically active substances
US6720001B2 (en) 1999-10-18 2004-04-13 Lipocine, Inc. Emulsion compositions for polyfunctional active ingredients
AU2001220765A1 (en) 2000-01-24 2001-07-31 Medtronic Minimed, Inc. Mixed buffer system for stabilizing polypeptide formulations
WO2001093837A2 (en) 2000-06-08 2001-12-13 Eli Lilly And Company Protein powder for pulmonary delivery
KR100508695B1 (en) 2001-02-13 2005-08-17 한국과학기술연구원 Formulation for oral delivery of insulin and preparation method thereof
DE10114178A1 (en) * 2001-03-23 2002-10-10 Aventis Pharma Gmbh Zinc-free and low-zinc insulin preparations with improved stability
CN1160122C (en) 2001-04-20 2004-08-04 清华大学 Method of preparing oil-phase oral insulin preparation
US20040265268A1 (en) * 2001-08-18 2004-12-30 Deepak Jain Compositions and methods for skin rejuvenation and repair
US20050123509A1 (en) 2001-10-19 2005-06-09 Lehrman S. R. Modulating charge density to produce improvements in the characteristics of spray-dried proteins
WO2003035051A2 (en) 2001-10-19 2003-05-01 Inhale Therapeutic Systems, Inc. The use of proton sequestering agents in drug formulations
US20060287221A1 (en) * 2003-11-13 2006-12-21 Novo Nordisk A/S Soluble pharmaceutical compositions for parenteral administration comprising a GLP-1 peptide and an insulin peptide of short time action for treatment of diabetes and bulimia

Also Published As

Publication number Publication date
WO2002076495A1 (en) 2002-10-03
ZA200306637B (en) 2004-05-07
BR0208210A (en) 2004-03-09
AR033059A1 (en) 2003-12-03
DE10114178A1 (en) 2002-10-10
ME00408B (en) 2011-10-10
HUP0303596A2 (en) 2004-01-28
CN1273187C (en) 2006-09-06
IL158057A0 (en) 2004-03-28
YU73503A (en) 2006-05-25
CA2441260A1 (en) 2002-10-03
AR096376A2 (en) 2015-12-23
EP2289539B1 (en) 2012-09-19
PT2289539E (en) 2012-11-20
PT1381385E (en) 2011-03-17
RU2311922C2 (en) 2007-12-10
US20030004096A1 (en) 2003-01-02
US7452860B2 (en) 2008-11-18
KR20040011483A (en) 2004-02-05
PL205465B1 (en) 2010-04-30
RS51579B (en) 2011-08-31
DK2289539T3 (en) 2013-01-14
EP1381385B1 (en) 2011-02-09
HRP20030765B1 (en) 2011-10-31
ES2360505T3 (en) 2011-06-06
TWI301761B (en) 2008-10-11
CY1113318T1 (en) 2016-04-13
KR20100061868A (en) 2010-06-09
EP1381385A1 (en) 2004-01-21
US20050187143A1 (en) 2005-08-25
US20050187142A1 (en) 2005-08-25
US7205276B2 (en) 2007-04-17
BRPI0208210B8 (en) 2021-05-25
US20090186807A1 (en) 2009-07-23
US20070155653A1 (en) 2007-07-05
US7696162B2 (en) 2010-04-13
ES2393180T3 (en) 2012-12-19
EP2289539A1 (en) 2011-03-02
ATE497777T1 (en) 2011-02-15
HK1061521A1 (en) 2004-09-24
JP2004523589A (en) 2004-08-05
NO20034125L (en) 2003-11-11
IL158057A (en) 2013-10-31
HU228847B1 (en) 2013-06-28
US7205277B2 (en) 2007-04-17
NZ528335A (en) 2005-03-24
CY1111413T1 (en) 2015-08-05
NO326780B1 (en) 2009-02-16
HRP20030765A2 (en) 2005-06-30
PL362800A1 (en) 2004-11-02
AU2002302409B2 (en) 2007-01-04
MXPA03007942A (en) 2004-04-02
DE50214903D1 (en) 2011-03-24
MY129417A (en) 2007-03-30
BRPI0208210B1 (en) 2018-05-02
US6960561B2 (en) 2005-11-01
NO20034125D0 (en) 2003-09-16
MEP60808A (en) 2011-05-10
HUP0303596A3 (en) 2005-11-28
PE20020968A1 (en) 2002-12-10
KR100987311B1 (en) 2010-10-13
SI1381385T1 (en) 2011-05-31
DK1381385T3 (en) 2011-06-06
JP4231292B2 (en) 2009-02-25
CN1498113A (en) 2004-05-19
RU2003131187A (en) 2005-03-10

Similar Documents

Publication Publication Date Title
CA2441260C (en) Insulin preparations, which do not contain any zinc or only a small quantity of zinc and which have an improved stability
KR101040029B1 (en) Acidic insulin preparations with improved stability
US8637458B2 (en) Insulin with a stable basal release profile
US20180036411A1 (en) Stable Formulation of Insulin Glulisine
US20100069292A1 (en) Insulin with a basal release profile
CA2487585A1 (en) Formulations for amylin agonist peptides
AU2013368990B2 (en) Pharmaceutical composition

Legal Events

Date Code Title Description
EEER Examination request
MKEX Expiry

Effective date: 20220309