WO1996010417A1 - PREPARATIONS CONTAINING AspB28 HUMAN INSULIN AND NICOTINAMIDE - Google Patents
PREPARATIONS CONTAINING AspB28 HUMAN INSULIN AND NICOTINAMIDE Download PDFInfo
- Publication number
- WO1996010417A1 WO1996010417A1 PCT/DK1995/000395 DK9500395W WO9610417A1 WO 1996010417 A1 WO1996010417 A1 WO 1996010417A1 DK 9500395 W DK9500395 W DK 9500395W WO 9610417 A1 WO9610417 A1 WO 9610417A1
- Authority
- WO
- WIPO (PCT)
- Prior art keywords
- insulin
- nicotinamide
- preparations
- preparation
- human insulin
- Prior art date
Links
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
- the present invention relates to insulin preparations containing Asp ⁇ 2 *- * human insulin and nicotinamide or a salt thereof.
- the preparations exhibit interesting therapeutic properties.
- rapidly acting preparations are neutral solutions of zinc containing insulin which, inter alia, are known under the trade marks Actrapid* and Velosulin*.
- Faster absorption of insulin compared to that obtained with the last-mentioned preparations can be effected by using monomeric or dimeric insulin analogs, vide European patent application No. 86306721, or by formulating insulin with magnesium salts, vide European patent application No. 87309229.
- Diabetic Medicine 6 (1989) diabetic patients have been treated orally with nicotinamide and they have been injected with insulin.
- the object of the study was to investigate whether small oral doses of nicotin ⁇ amide would improve metabolic control.
- nicotinamide and insulin was not mixed before administration.
- a similar study is described in Diabe- tologia 22 (1989), 160.
- compositions for application to the hair and scalp which may con ⁇ tain nicotinamide and/or isophane insulin has been suggested in British patent No. 1,603,639. No compositions containing both nicotinamide and isophane insulin are described therein. This composition is for use in stimulating hair growth and in treating alopecia and excessive hair loss.
- preparations con ⁇ taining Asp B28 human insulin and nicotinamide or a salt thereof have superior properties.
- the superiority of such preparations is, for example, the very rapid onset of insulin action when such preparations are administered to humans.
- the present invention relates to preparations containing Asp B28 human insulin and nicotinamide or a salt thereof. Such preparations can be used for parenteral administration to diabetics.
- the preparations of this invention may, if desired, furthermore con ⁇ tain precipitated insulin or a precipitated insulin derivative having protracted action. By adding such precipitates, a suspension is obtained.
- the ab ⁇ sorption of Asp B28 human insulin was surprisingly found to be faster than that of the reference insulin used in the example below. This property is useful for a rapidly acting insulin, in particular in connection with a multiple injection regimen where insulin is given before each meal. With quicker onset of action, the insulin can conveniently be taken closer to the meal than with conventional rapidly acting insulin solutions. Furthermore, a faster disappearance of insulin probably di ⁇ minishes the risk of post meal hypoglycemia.
- preparations of this invention are believed to be well suited for application in fountain pen like devices used for multiple injection insulin therapy.
- the preparations according to this invention containing Asp B28 human insulin and nicotinamide or a salt thereof are present as a solution thereof, prefer- ably in an aqueous solution.
- Asp B28 human insulin of high purity is used.
- the content of Asp B28 human insulin in solutions of this invention may be in the range of 20 to 500 international units (IU) per ml, preferably in the range of 40 to 100 lU/ml, in preparations for injection. However, for other purposes of parenteral administration, the content of Asp B28 human insulin may be higher.
- the solution of Asp B28 human insulin may be mixed with a solid insulin material such as zinc insulin crystals or zinc protamine insulin crystals.
- the preferred concentration of nicotin ⁇ amide plus salts thereof is in the range from about 0.01 to about 1 M, preferably from about 0.05 to about 0.5 M.
- the preservative present in the insulin preparation of this invention may be as in the heretofore conventional insulin preparations, for example phenol, m-cresol and methylparaben.
- the preparations of this invention have a pH value in the range from about 3 to about 8.5.
- a slightly acidic solution of Asp B28 human insulin can be mixed with a solution containing all the other components of the final preparation. Then follows adjustment of pH value, if required, stirring until a clear solution is ob ⁇ tained and finally sterile filtration. If desired, a sterile, protracted acting insulin suspension may be added to the sterile insulin solution yielding a preparation with biphasic action.
- stabilising agents such as phospholipids, may be included.
- composition of this invention also contains precipitated insulin or a precipi ⁇ tated insulin derivative
- a biphasic preparation may be obtained.
- the biphasic preparations according to this invention have a more rapid onset of blood sugar lowering effect.
- E ⁇ xamples of precipitated insulin are zinc insulin crystals and protamine zinc insulin crystals.
- the insulin preparations of this invention can be used in the treatment of diabe ⁇ tics by parenteral administration, tt is recommended that the dosage of the insulin preparations of this invention which is to be administered to the patient be selected by a physician similarly to the selection of the dosage of known insulin preparations for injection to human beings.
- This invention is further illustrated in the following examples which, however, are not to be construed as limiting.
- test and reference preparations (all solutions) were made from 1 5 l-labelled human insulin or Asp B28 human insulin derivative. 6 IU (0.036 ⁇ mol) of the test preparation was injected at one side of the neck and 6 IU of the reference preparation at the other side in each of a number of pigs. The absorption was followed by external monitoring of the radioactivity remaining at the site of injection. The injections were performed by NovoPenTM, US j n g _ normal needle, inserted to a depth of 5 mm (subcutaneously). Terms used in the examples
- Zn + + /hexamer Number of zinc ions per insulin hexamer.
- 125-l-labelled Asp B28 human insulin was used for the absorption study. 0.06 ml of a reference solution (0.6 mmol/l Asp 528 , 3 Zn/hexamer, 16 g/l glycerol, 3 g/l
- test solution 10 phenol, pH value 7.4
- 0.06 ml of test solution prepared by substituting 0.26 mol/l nicotinamide for glycerol, were injected contralaterally in the neck of 6 pigs followed by counting over the injection sites. A cross-over was made 6 days after.
- the T 75% averages ( ⁇ SEM) were: 21 ⁇ 1 and 36 ⁇ 4 minutes for test and reference, respectively (p ⁇ 0.01).
- the T5Q% averages ( ⁇ SEM) were 52 ⁇ 3 and
Abstract
Preparations containing AspB28 human insulin and nicotinamide or a salt thereof show superior pharmacological properties.
Description
PREPARATIONS CONTAINING AspB28 HUMAN IN INSULIN AND NICOTINAMIDE.
The present invention relates to insulin preparations containing Asp^2*-* human insulin and nicotinamide or a salt thereof. The preparations exhibit interesting therapeutic properties.
BACKGROUND OF THIS INVENTION
For decades, insulin has been used for the treatment of diabetics. Among the commercially available insulin preparations, rapidly acting, intermediately acting and prolonged acting preparations can be mentioned. Examples of rapidly acting preparations are neutral solutions of zinc containing insulin which, inter alia, are known under the trade marks Actrapid* and Velosulin*. Faster absorption of insulin compared to that obtained with the last-mentioned preparations can be effected by using monomeric or dimeric insulin analogs, vide European patent application No. 86306721, or by formulating insulin with magnesium salts, vide European patent application No. 87309229. According to Diabetic Medicine 6 (1989), 568, diabetic patients have been treated orally with nicotinamide and they have been injected with insulin. The object of the study was to investigate whether small oral doses of nicotin¬ amide would improve metabolic control. In this known study, nicotinamide and insulin was not mixed before administration. A similar study is described in Diabe- tologia 22 (1989), 160.
A composition for application to the hair and scalp which may con¬ tain nicotinamide and/or isophane insulin has been suggested in British patent No. 1,603,639. No compositions containing both nicotinamide and isophane insulin are described therein. This composition is for use in stimulating hair growth and in treating alopecia and excessive hair loss.
International Patent Application No. WO 91/09617 relates to insulin preparations containing nicotinamide or nicotinic acid or a salt thereof and insulin
or an insulin derivative. In this known application, there is no mentioning of AspB28 human insulin. Compared with this known invention, the present invention is a so-called selection invention.
BRIEF DISCUSSION OF THIS INVENTION
According to this invention, it has, surprisingly, been found that preparations con¬ taining AspB28 human insulin and nicotinamide or a salt thereof have superior properties. The superiority of such preparations is, for example, the very rapid onset of insulin action when such preparations are administered to humans.
Thus, the present invention relates to preparations containing AspB28 human insulin and nicotinamide or a salt thereof. Such preparations can be used for parenteral administration to diabetics.
The preparations of this invention may, if desired, furthermore con¬ tain precipitated insulin or a precipitated insulin derivative having protracted action. By adding such precipitates, a suspension is obtained.
ATTRIBUTES OF THIS INVENTION
Absent retarding substances in the insulin preparations of this invention, the ab¬ sorption of AspB28 human insulin was surprisingly found to be faster than that of the reference insulin used in the example below. This property is useful for a rapidly acting insulin, in particular in connection with a multiple injection regimen where insulin is given before each meal. With quicker onset of action, the insulin can conveniently be taken closer to the meal than with conventional rapidly acting insulin solutions. Furthermore, a faster disappearance of insulin probably di¬ minishes the risk of post meal hypoglycemia.
As an example, the preparations of this invention are believed to be well suited for application in fountain pen like devices used for multiple injection
insulin therapy.
DETAILED DISCUSSION OF THIS INVENTION
Preferably, the preparations according to this invention containing AspB28 human insulin and nicotinamide or a salt thereof are present as a solution thereof, prefer- ably in an aqueous solution.
Preferably, AspB28 human insulin of high purity is used.
The content of AspB28 human insulin in solutions of this invention may be in the range of 20 to 500 international units (IU) per ml, preferably in the range of 40 to 100 lU/ml, in preparations for injection. However, for other purposes of parenteral administration, the content of AspB28 human insulin may be higher. The solution of AspB28 human insulin may be mixed with a solid insulin material such as zinc insulin crystals or zinc protamine insulin crystals.
According to this invention, the preferred concentration of nicotin¬ amide plus salts thereof is in the range from about 0.01 to about 1 M, preferably from about 0.05 to about 0.5 M.
Known to the art stabilizers and preservatives may be present in the insulin preparations of this invention.
The preservative present in the insulin preparation of this invention may be as in the heretofore conventional insulin preparations, for example phenol, m-cresol and methylparaben.
As an example, the preparations of this invention have a pH value in the range from about 3 to about 8.5.
For the preparation of aqueous insulin preparations according to this invention, a slightly acidic solution of AspB28 human insulin can be mixed with a solution containing all the other components of the final preparation. Then follows adjustment of pH value, if required, stirring until a clear solution is ob¬ tained and finally sterile filtration. If desired, a sterile, protracted acting insulin
suspension may be added to the sterile insulin solution yielding a preparation with biphasic action. In order to protect the preparations from the denaturation that may take place by occasional heating and shaking, known stabilising agents, such as phospholipids, may be included.
If the composition of this invention also contains precipitated insulin or a precipi¬ tated insulin derivative, a biphasic preparation may be obtained. Compared with the known biphasic insulin preparations, the biphasic preparations according to this invention have a more rapid onset of blood sugar lowering effect. EΞxamples of precipitated insulin are zinc insulin crystals and protamine zinc insulin crystals.
The insulin preparations of this invention can be used in the treatment of diabe¬ tics by parenteral administration, tt is recommended that the dosage of the insulin preparations of this invention which is to be administered to the patient be selected by a physician similarly to the selection of the dosage of known insulin preparations for injection to human beings. This invention is further illustrated in the following examples which, however, are not to be construed as limiting.
Absorption studies
The experiments described in the following examples were performed as ab¬ sorption studies in pigs. Test and reference preparations (all solutions) were made from 1 5l-labelled human insulin or AspB28 human insulin derivative. 6 IU (0.036 μmol) of the test preparation was injected at one side of the neck and 6 IU of the reference preparation at the other side in each of a number of pigs. The absorption was followed by external monitoring of the radioactivity remaining at the site of injection. The injections were performed by NovoPen™, USjng _ normal needle, inserted to a depth of 5 mm (subcutaneously).
Terms used in the examples
Zn+ +/hexamer: Number of zinc ions per insulin hexamer.
'75% Time until 75% of initial radioactivity remaining.
' 50% Time until 50% of initial radioactivity remaining.
5 F75% T75% (test)/T75oi (reference). F50% τ50% (test)^50% (reference).
Example 1
125-l-labelled AspB28 human insulin was used for the absorption study. 0.06 ml of a reference solution (0.6 mmol/l Asp528, 3 Zn/hexamer, 16 g/l glycerol, 3 g/l
10 phenol, pH value 7.4) and 0.06 ml of test solution, prepared by substituting 0.26 mol/l nicotinamide for glycerol, were injected contralaterally in the neck of 6 pigs followed by counting over the injection sites. A cross-over was made 6 days after. The T75% averages (± SEM) were: 21 ± 1 and 36 ± 4 minutes for test and reference, respectively (p < 0.01). The T5Q% averages (± SEM) were 52 ± 3 and
15 68 ± 5 minutes, respectively (p < 0.02). In a cross-over study in four fasted pigs (mean weight 103 kg), each pig was injected with 0.06 ml of the test solution on one day and 0.06 ml of the reference solution on the other day. Plasma glucose was measured at various times after injection.
The results (minutes/mean decrease in mmol/l glucose for test/reference) were:
Time after injection Decrease in plasma Decrease in plasma Minutes glucose glucose Reference, mmol/l
0 0 0
20 2.3 0.9
40 2.6 2.4
60 2.7 2.4
80 2.4 2.5
100 2.4 2.6
120 2.5 2.5
150 1.8 2.3
180 1.4 2.1
210 1.3 1.7
240 1.0 1.4
270 0.7 1.1
300 0.5 0.8
Based upon these results, it can be concluded that formulation of AspB28 human insulin with nicotinamide results in initially faster absorption of AspB28 human insulin after subcutaneous injection in pigs and earlier onset of action. The mono- meric insulin analog formulated with nicotinamide may therefore be more appropriate as an ultra short acting preparation, given just before meals, than the analog in conventional formulation.
Claims
1. Insulin preparations for injection or infusion, characterized in that it comprises AspB28 human insulin and nicotinamide or a salt thereof.
2. Preparation according to Claim 1 , characterized in that the con- tent of nicotinamide plus salts thereof is in the range from about 0.01 to about 1
M, preferably from about 0.05 to about 0.5 M.
3. Preparation according to any one of the preceding claims, char¬ acterized in that the preparation is to be used as a preparation for the treatment of diabetics.
4. Preparation according to any one of the preceding claims, char¬ acterized in that it, additionally, comprises zinc ions, preferably less than about 6 zinc ions per hexamer insulin or insulin derivative, more preferred less than about 4 zinc ions per hexamer insulin or insulin derivative.
5. Preparation according to any one of the preceding claims, char- acterized in that the pH value is above about 3, preferably in the range from about 5 to about 8.5, more preferred from about 6 to about 8, most preferred from about 6.5 to about 7.5.
6. Preparation according to any one of the preceding claims, char¬ acterized in that it has an activity in the range below about 500 IU per ml, prefer- ably from about 20 to 200 IU per ml, most preferred from about 40 to about 150 IU per ml.
7. Preparation according to any one of the preceding claims, char¬ acterized in that it is rapidly acting. 8
8. The use as a preparation for the treatment of diabetics with a preparation comprising AspB28 human insulin and nicotinamide or a salt thereof.
9. Any novel feature or combination of features described herein.
Novo Nordisk A/S
5 1995-09-22, ToN/KGF 4182.204-WO
Priority Applications (1)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
AU35621/95A AU3562195A (en) | 1994-10-04 | 1995-10-03 | Preparations containing aspb28 human insulin and nicotinamide |
Applications Claiming Priority (2)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
DK1145/94 | 1994-10-04 | ||
DK114594 | 1994-10-04 |
Publications (1)
Publication Number | Publication Date |
---|---|
WO1996010417A1 true WO1996010417A1 (en) | 1996-04-11 |
Family
ID=8101519
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
PCT/DK1995/000395 WO1996010417A1 (en) | 1994-10-04 | 1995-10-03 | PREPARATIONS CONTAINING AspB28 HUMAN INSULIN AND NICOTINAMIDE |
Country Status (2)
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AU (1) | AU3562195A (en) |
WO (1) | WO1996010417A1 (en) |
Cited By (14)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
EP0880968A1 (en) * | 1997-05-28 | 1998-12-02 | Applied Research Systems ARS Holding N.V. | Pharmaceutical compositions of peptides having low solubility in physiological medium |
EP0880969A1 (en) * | 1997-05-28 | 1998-12-02 | Applied Research Systems ARS Holdings N.V. | Pharmaceutical compositions of peptides having low solubility in physiological medium |
US6852694B2 (en) | 2001-02-21 | 2005-02-08 | Medtronic Minimed, Inc. | Stabilized insulin formulations |
WO2010149772A1 (en) | 2009-06-26 | 2010-12-29 | Novo Nordisk A/S | Preparation comprising insulin, nicotinamide and an amino acid |
WO2012080362A1 (en) | 2010-12-14 | 2012-06-21 | Novo Nordisk A/S | Preparation comprising insulin, nicotinamide and an amino acid |
WO2012080320A1 (en) | 2010-12-14 | 2012-06-21 | Novo Nordisk A/S | Fast-acting insulin in combination with long-acting insulin |
US8828923B2 (en) | 2003-08-05 | 2014-09-09 | Novo Nordisk A/S | Insulin derivatives |
US9034818B2 (en) | 2007-06-13 | 2015-05-19 | Novo Nordisk A/S | Pharmaceutical formulations comprising an insulin derivative |
US9603904B2 (en) | 2008-10-30 | 2017-03-28 | Novo Nordisk A/S | Treating diabetes melitus using insulin injections with less than daily injection frequency |
US10137172B2 (en) | 2013-04-30 | 2018-11-27 | Novo Nordisk A/S | Administration regime |
US10335464B1 (en) | 2018-06-26 | 2019-07-02 | Novo Nordisk A/S | Device for titrating basal insulin |
US10596229B2 (en) | 2010-10-27 | 2020-03-24 | Novo Nordisk A/S | Method of treating diabetes mellitus by administration, at specifically defined intervals, of a derivative of a naturally occurring insulin or insulin analogue, the derivative having a prolonged profile of action |
US11167035B2 (en) | 2005-12-28 | 2021-11-09 | Novo Nordisk A/S | Insulin compositions and method of making a composition |
US11278624B2 (en) | 2016-05-06 | 2022-03-22 | Arecor Limited | Formulations |
Citations (4)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
GB1603639A (en) * | 1978-05-26 | 1981-11-25 | Haggar H | Composition for application to the hair and scalp |
EP0214826A2 (en) * | 1985-08-30 | 1987-03-18 | Novo Nordisk A/S | Insulin analogues and method of preparing the same |
WO1990007522A1 (en) * | 1988-12-23 | 1990-07-12 | Novo Nordisk A/S | Human insulin analogues |
WO1991009617A1 (en) * | 1989-12-21 | 1991-07-11 | Novo Nordisk A/S | Insulin preparations containing nicotinic acid or nicotinamide |
-
1995
- 1995-10-03 AU AU35621/95A patent/AU3562195A/en not_active Abandoned
- 1995-10-03 WO PCT/DK1995/000395 patent/WO1996010417A1/en active Application Filing
Patent Citations (4)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
GB1603639A (en) * | 1978-05-26 | 1981-11-25 | Haggar H | Composition for application to the hair and scalp |
EP0214826A2 (en) * | 1985-08-30 | 1987-03-18 | Novo Nordisk A/S | Insulin analogues and method of preparing the same |
WO1990007522A1 (en) * | 1988-12-23 | 1990-07-12 | Novo Nordisk A/S | Human insulin analogues |
WO1991009617A1 (en) * | 1989-12-21 | 1991-07-11 | Novo Nordisk A/S | Insulin preparations containing nicotinic acid or nicotinamide |
Cited By (27)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
EP0880969A1 (en) * | 1997-05-28 | 1998-12-02 | Applied Research Systems ARS Holdings N.V. | Pharmaceutical compositions of peptides having low solubility in physiological medium |
BG64668B1 (en) * | 1997-05-28 | 2005-11-30 | Applied Research Systems Ars Holding N.V. | Pharmaceutical compositions of peptides having little solubility in a physiological medium |
EP0880968A1 (en) * | 1997-05-28 | 1998-12-02 | Applied Research Systems ARS Holding N.V. | Pharmaceutical compositions of peptides having low solubility in physiological medium |
US6852694B2 (en) | 2001-02-21 | 2005-02-08 | Medtronic Minimed, Inc. | Stabilized insulin formulations |
US8828923B2 (en) | 2003-08-05 | 2014-09-09 | Novo Nordisk A/S | Insulin derivatives |
US11167035B2 (en) | 2005-12-28 | 2021-11-09 | Novo Nordisk A/S | Insulin compositions and method of making a composition |
US9034818B2 (en) | 2007-06-13 | 2015-05-19 | Novo Nordisk A/S | Pharmaceutical formulations comprising an insulin derivative |
US9603904B2 (en) | 2008-10-30 | 2017-03-28 | Novo Nordisk A/S | Treating diabetes melitus using insulin injections with less than daily injection frequency |
AU2010264636B2 (en) * | 2009-06-26 | 2013-06-27 | Novo Nordisk A/S | Preparation comprising insulin, nicotinamide and an amino acid |
JP2012530768A (en) * | 2009-06-26 | 2012-12-06 | ノボ・ノルデイスク・エー/エス | Formulation containing insulin, nicotinamide and amino acid |
CN104667264B (en) * | 2009-06-26 | 2018-09-07 | 诺沃—诺迪斯克有限公司 | Include the preparation of insulin, niacinamide and amino acid |
EP2612677A1 (en) | 2009-06-26 | 2013-07-10 | Novo Nordisk A/S | Preparation comprising insulin, nicotinamide and an amino acid |
US8324157B2 (en) | 2009-06-26 | 2012-12-04 | Novo Nordisk A/S | Preparation comprising insulin, nicotinamide and an amino acid |
TWI459962B (en) * | 2009-06-26 | 2014-11-11 | Novo Nordisk As | Preparation comprising insulin, nicotinamide and an amino acid |
RU2533217C2 (en) * | 2009-06-26 | 2014-11-20 | Ново Нордиск А/С | Preparation containing insulin, nicotinamide and amino acid |
JP2015071608A (en) * | 2009-06-26 | 2015-04-16 | ノボ・ノルデイスク・エー/エス | Preparation comprising insulin, nicotinamide and amino acid |
CN102470165A (en) * | 2009-06-26 | 2012-05-23 | 诺沃-诺迪斯克有限公司 | Preparation comprising insulin, nicotinamide and an amino acid |
CN104667264A (en) * | 2009-06-26 | 2015-06-03 | 诺沃—诺迪斯克有限公司 | Preparation comprising insulin, nicotinamide and an amino acid |
WO2010149772A1 (en) | 2009-06-26 | 2010-12-29 | Novo Nordisk A/S | Preparation comprising insulin, nicotinamide and an amino acid |
KR101775000B1 (en) * | 2009-06-26 | 2017-09-04 | 노보 노르디스크 에이/에스 | Preparation comprising insulin, nicotinamide and an amino acid |
US10596229B2 (en) | 2010-10-27 | 2020-03-24 | Novo Nordisk A/S | Method of treating diabetes mellitus by administration, at specifically defined intervals, of a derivative of a naturally occurring insulin or insulin analogue, the derivative having a prolonged profile of action |
WO2012080362A1 (en) | 2010-12-14 | 2012-06-21 | Novo Nordisk A/S | Preparation comprising insulin, nicotinamide and an amino acid |
CN103328006A (en) * | 2010-12-14 | 2013-09-25 | 诺沃—诺迪斯克有限公司 | Preparation comprising insulin, nicotinamide and an amino acid |
WO2012080320A1 (en) | 2010-12-14 | 2012-06-21 | Novo Nordisk A/S | Fast-acting insulin in combination with long-acting insulin |
US10137172B2 (en) | 2013-04-30 | 2018-11-27 | Novo Nordisk A/S | Administration regime |
US11278624B2 (en) | 2016-05-06 | 2022-03-22 | Arecor Limited | Formulations |
US10335464B1 (en) | 2018-06-26 | 2019-07-02 | Novo Nordisk A/S | Device for titrating basal insulin |
Also Published As
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