WO1992019260A1 - Peptide hormone solution - Google Patents

Peptide hormone solution Download PDF

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Publication number
WO1992019260A1
WO1992019260A1 PCT/SE1992/000283 SE9200283W WO9219260A1 WO 1992019260 A1 WO1992019260 A1 WO 1992019260A1 SE 9200283 W SE9200283 W SE 9200283W WO 9219260 A1 WO9219260 A1 WO 9219260A1
Authority
WO
WIPO (PCT)
Prior art keywords
hormone
insulin
solution
peptide hormone
peptide
Prior art date
Application number
PCT/SE1992/000283
Other languages
French (fr)
Inventor
Tomas Moks
Original Assignee
Tomas Moks
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 Tomas Moks filed Critical Tomas Moks
Publication of WO1992019260A1 publication Critical patent/WO1992019260A1/en

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
    • A61K47/30—Macromolecular organic or inorganic compounds, e.g. inorganic polyphosphates
    • A61K47/42—Proteins; Polypeptides; Degradation products thereof; Derivatives thereof, e.g. albumin, gelatin or zein
    • 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
    • A61K38/2221—Relaxins
    • 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
    • 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
    • A61K38/30—Insulin-like growth factors (Somatomedins), e.g. IGF-1, IGF-2

Definitions

  • the present invention relates to peptide hormone solutions, such as for injection or infusion, containing a hormone in a biologically effective amount dissolved in an aqueous vehicle.
  • the invention also covers the use in a peptide hormone pump for the administration by injection or infusion of the peptide hormone solution of the inven ⁇ tion.
  • the invention involves a method of treating diabetes.
  • Peptide hormones are a class of substances that are involved in different control functions of the body, and examples are insulin, IGF-I, IGF-II, growth hormone, re- laxin, secretin, calcitonin etc. Common to all these sub ⁇ stances is the fact that they exert their action at very low concentrations and, therefore, their artificial use by administration through different routes are subject to problems. Quite frequently peptide hormones are to be sub ⁇ ject to long-term administration and in the past attempts have been made to develop sophisticated hormone delivery systems, such as systems based on implantable pumps. Among such pumps particularly so called micro infusion pumps are of interest in connection with the administration of very small amounts.
  • Insulin solutions for medical treatment were intro ⁇ quizzed as early as 1923.
  • the stability of insulin solutions has since been greatly improved but has not nearly reached any state of perfection.
  • a low pH of the solution was required to protect the insulin from degradation by contaminating pancreatic enzymes. It became later possible to remove such enzymes and the purity of insulin was improved to such an extent as to allow the manufacture of solutions of insulin having a physiological pH, the pH being around 7.
  • Neutral solu ⁇ tions are advantageous in use compared to acidic solu ⁇ tions.
  • Yet another possibility of providing stabilization of hormone solutions is to add amphiphilic surface-active substances to the protein solution. Such substances adsorb to the interface and transform the hydrophobic property of the protein into a hydrophilic one. However, such substan ⁇ ces interact with the insulin and tend to cause denatura ⁇ tion thereof when in solution.
  • the present invention has for its main object to pro ⁇ vide means for effective stabilization of peptide hormone solutions, such as solutions of insulin and insulin-like peptides.
  • Another object of the invention is to provide tech ⁇ niques enabling easy stabilization using a stabilizing additive that is tolerable for the intended purpose and also available at a relatively low cost.
  • Yet another object of the invention is to provide a method of medical treatment, particularly the treatment of diabetes using such stabilized hormone solution.
  • the invention resides in a peptide hormone solution, such as for injection or infu ⁇ sion, containing a hormone in a biologically effective amount dissolved in an aqueous vehicle.
  • the invention is based on the unexpected discovery that such a hormone so ⁇ lution can be effectively stabilized by introducing there ⁇ in a serum albumen in an active amount, such additive ef ⁇ fectively preventing precipitation of the hormone even at an elevated temperature (such as 37°C) and mechanical agi ⁇ tation.
  • the peptide hormone is preferably selected from insulin and insulin-like hor ⁇ mones, such as insulin, IGF-I, IGF-II, relaxin.
  • insulin and insulin-like hor ⁇ mones such as insulin, IGF-I, IGF-II, relaxin.
  • other peptide hormones are operable in the inventive con- cept as well, such as growth hormone, secretin, calci- tonin, etc.
  • HSA human serum albumin
  • the albumin is preferably used in a con ⁇ centration of at least about 0.1 mg/ml solution and expe ⁇ rimental work has indicated that it is preferred that the concentration of albumin does not substantially exceed that of the hormone. It is especially preferred that said concentration is lower than that of the hormone, such as half or even lower.
  • the invention also provides a method of treating dia ⁇ betes, such method comprising the step of administering to a patient in need of such treatment a blood glucose con ⁇ trolling amount of an insulin solution as outlined above.
  • Such method preferably involves the administration in a continuous or discontinuous manner by injection or infu ⁇ sion.
  • Stability was tested at different concentrations of albumin and without added albumin.
  • the different solutions used in the test were kept at 37 C C and the closed flasks containing the different samples were turned upside down at regular intervals i.e. around 30 turns per minute.
  • the degree of precipitation was measured by recording absor ⁇ saye at 600 nm which reflects turbidity and thus the de ⁇ gree of precipitation. The measurements were made in a spectrophotometer.
  • the diagram in the drawing further shows that at a concentration of 3 mg albumin per ml (curve 5) some pre ⁇ cipitation takes place after 40 days, although to a very small degree. However, at a concentration of albumin of 10 mg/ml (curve 6) precipitation starts at about 25 days, and at about 35 days there is a rapid increase in precipita ⁇ tion. The mechanism by which precipitation takes place at this relatively high concentration of albumin is unknown but a different mechanism seems to be involved as compared to that of using no albumin at all (curve 1).

Abstract

Peptide hormone solution such as for injection or infusion, containing a hormone in a biologically effective amount dissolved in an aqueous vehicle, said solution containing serum albumin (SA) in an amount capable of stabilizing the hormone to prevent precipitation thereof; the use of such solutions in hormone pumps; and a method of treating diabetes.

Description

Peptide hormone solution.
The present invention relates to peptide hormone solutions, such as for injection or infusion, containing a hormone in a biologically effective amount dissolved in an aqueous vehicle. The invention also covers the use in a peptide hormone pump for the administration by injection or infusion of the peptide hormone solution of the inven¬ tion. Finally, the invention involves a method of treating diabetes.
Peptide hormones are a class of substances that are involved in different control functions of the body, and examples are insulin, IGF-I, IGF-II, growth hormone, re- laxin, secretin, calcitonin etc. Common to all these sub¬ stances is the fact that they exert their action at very low concentrations and, therefore, their artificial use by administration through different routes are subject to problems. Quite frequently peptide hormones are to be sub¬ ject to long-term administration and in the past attempts have been made to develop sophisticated hormone delivery systems, such as systems based on implantable pumps. Among such pumps particularly so called micro infusion pumps are of interest in connection with the administration of very small amounts. Although the invention is not to be con¬ strued to be limited in any respect, to the subsequent ex¬ emplification of preferred embodiments of the invention, the following illustration will be made mainly with re¬ ference to the use of insulin for the treatment of diabe¬ tes. Insulin administration is a good example of the prob¬ lems associated with the administration of peptide hor¬ mones and is therefore a useful practical example of the problems involved.
It is well known that diabetes can be treated by con¬ trolling the blood glucose level in a patient in need of treatment. In using an insulin delivery system, such as one based on a micro infusion pump of the implantable type, one of the major problems is the instability of the insulin molecule itself. It is true that solutions of insulin can be stored for several years at room tempera¬ ture and with the insulin containers not moving around without significant physical change, whereas the condi¬ tions in for example an implanted insulin delivery pump puts much higher demands on the stability of the insulin solution. This is due to the fact that insulin contained in an implanted pump is exposed to elevated temperatures, motion and various more or less hydrophobic surfaces. These are conditions that will increase the incident of precipitation. Such precipitation of insulin incurs seve¬ ral problems, such as irregularities in administration by blocking the pump, inactivation of the insulin and may even cause the formation of antibodies.
Insulin solutions for medical treatment were intro¬ duced as early as 1923. The stability of insulin solutions has since been greatly improved but has not nearly reached any state of perfection. In the early years of insulin ma¬ nufacture a low pH of the solution was required to protect the insulin from degradation by contaminating pancreatic enzymes. It became later possible to remove such enzymes and the purity of insulin was improved to such an extent as to allow the manufacture of solutions of insulin having a physiological pH, the pH being around 7. Neutral solu¬ tions are advantageous in use compared to acidic solu¬ tions.
Experience with hormone pumps has shown that hydro¬ phobic interfaces may cause denaturation of the dissolved protein, which causes inactivation of the hormone and occ¬ lusion of the pump system. Many efforts have been made to develop stable insulin formulations, particularly for the purpose of making such formulations useful in implantable pumps.
Among techniques used for increasing stability there may be mentioned the addition of urea to lower the concen¬ tration of the dimeric form in the solution and direct the equilibrium to the monomeric form that has a better stabi- lity. However, such additional urea to useful concen¬ trations may cause denaturation of the insulin. Other additives are additives containing divalent metal ions also resulting in some stabilizing effect.
Yet another possibility of providing stabilization of hormone solutions is to add amphiphilic surface-active substances to the protein solution. Such substances adsorb to the interface and transform the hydrophobic property of the protein into a hydrophilic one. However, such substan¬ ces interact with the insulin and tend to cause denatura¬ tion thereof when in solution.
The present invention has for its main object to pro¬ vide means for effective stabilization of peptide hormone solutions, such as solutions of insulin and insulin-like peptides.
Another object of the invention is to provide tech¬ niques enabling easy stabilization using a stabilizing additive that is tolerable for the intended purpose and also available at a relatively low cost.
Yet another object of the invention is to provide a method of medical treatment, particularly the treatment of diabetes using such stabilized hormone solution.
For these and other objects that will be apparent from the following description the invention resides in a peptide hormone solution, such as for injection or infu¬ sion, containing a hormone in a biologically effective amount dissolved in an aqueous vehicle. The invention is based on the unexpected discovery that such a hormone so¬ lution can be effectively stabilized by introducing there¬ in a serum albumen in an active amount, such additive ef¬ fectively preventing precipitation of the hormone even at an elevated temperature (such as 37°C) and mechanical agi¬ tation.
In accordance with the invention the peptide hormone is preferably selected from insulin and insulin-like hor¬ mones, such as insulin, IGF-I, IGF-II, relaxin. However, other peptide hormones are operable in the inventive con- cept as well, such as growth hormone, secretin, calci- tonin, etc.
It goes without saying that when treating humans using a peptide hormone solution according to the present invention it is particularly preferred to use human serum albumin (HSA). The albumin is preferably used in a con¬ centration of at least about 0.1 mg/ml solution and expe¬ rimental work has indicated that it is preferred that the concentration of albumin does not substantially exceed that of the hormone. It is especially preferred that said concentration is lower than that of the hormone, such as half or even lower. A biologically effective amount of the insulin may be from about 1 mg/ml up to about 25 mg/ml. Within said range the biological activity may range from about 100 IU/ml up to about 500 IU/ml (IU = International Units).
In the administration of peptide hormones using a pump for continuous or discontinous supply by injection or infusion the use of the peptide hormone solution in accor¬ dance with the present invention is highly advantageous. Pumps of the implantable type, such as micro infusion pumps, operate well in the administration of hormone solu¬ tions in accordance with the present invention, since the improved stability of the solutions enable long-term ad¬ ministration without clogging or other malfunction of the pump while the hormone activity will be maintained essen¬ tially unchanged.
The invention also provides a method of treating dia¬ betes, such method comprising the step of administering to a patient in need of such treatment a blood glucose con¬ trolling amount of an insulin solution as outlined above. Such method preferably involves the administration in a continuous or discontinuous manner by injection or infu¬ sion.
The invention will in the following be further illu¬ strated by preferred embodiments thereof, which, however, are not to be construed to limit the scope of the inven- tion. This illustration will be made with reference to the appended drawing which shows a diagram on absorbance re¬ flecting turbidity as a function of time at varying con¬ centrations of albumin in a solution of insulin.
EXAMPLE
In the experiments insulin solutions at a concen¬ tration of 100 IU/ml (3.86 mg/ml), pH 7.4, were used (manufacturer: Hoechst, Frankfurt, Germany). Stability of the solutions was investigated using human serum albumin (Kabi, Sweden).
Stability was tested at different concentrations of albumin and without added albumin. The different solutions used in the test were kept at 37CC and the closed flasks containing the different samples were turned upside down at regular intervals i.e. around 30 turns per minute. The degree of precipitation was measured by recording absor¬ bance at 600 nm which reflects turbidity and thus the de¬ gree of precipitation. The measurements were made in a spectrophotometer.
The results of the experiments are illustrated in the appended drawing by the diagram therein, wherein OD is the absorbance at 600 nm shown as a function of storage time of the solutions in days. The different stability curves are designated by numbers from 1 to 6 and the correspon¬ ding albumin concentrations are as follows:
Curve No. Albumin concentration mg/ml
1 0
2 0.1
3 0.3
4 1
5 3
6 10 It can be seen from the diagram in the drawing that the insulin solution as delivered by the manufacturer and containing no albumin will be subject to sudden precipi¬ tation after about 12 days of storage at 37°C and with turning of the flask at regular intervals. At an albumin concentration of 0.1 mg/ml precipitation will be delayed for about 10 days followed by a rapid inset of precipi¬ tation (curve No. 2). Furthermore, at an albumin concen¬ tration of 0.3 (curve 3) precipitation is even further delayed up to about 30 days. At a concentration of 1 mg albumin per ml (curve 4) no precipitation has occurred after 40 days, at which stage the experiment was inter¬ rupted.
The diagram in the drawing further shows that at a concentration of 3 mg albumin per ml (curve 5) some pre¬ cipitation takes place after 40 days, although to a very small degree. However, at a concentration of albumin of 10 mg/ml (curve 6) precipitation starts at about 25 days, and at about 35 days there is a rapid increase in precipita¬ tion. The mechanism by which precipitation takes place at this relatively high concentration of albumin is unknown but a different mechanism seems to be involved as compared to that of using no albumin at all (curve 1).
Adding albumin to the hormone solution has an asto¬ nishing effect on stability as the above experiments clearly show. Particularly when used in implanted pumps for the administration the stability obtained by practi¬ cing the concept of the present invention is of utmost importance and enables efficient use of such implanted pump. It is to be noted that the present invention is in no way limited to solutions containing insulin or insulin¬ like substances but that the inventive concept of the in¬ vention is applicable to other hormone peptides as well. The invention is therefore limited as to its scope only as reflected by the scope of the appended patent claims.

Claims

1. Peptide hormone solution such as for injection or infusion, containing a hormone in a biologically effective amount dissolved in an aqueous vehicle, said solution con¬ taining serum albumin (SA) in an amount capable of stabi¬ lizing the hormone to prevent precipitation thereof.
2. Peptide hormone solution according to claim 1, wherein the serum albumin is HSA.
3. Peptide hormone solution according to claim 1 or 2, wherein said SA is used in a concentration of at least about 0.1 mg/ml.
4. Peptide hormone solution according to any prece¬ ding claim, wherein said hormone is selected from insulin and insulin-like hormones.
5. Peptide hormone solution according to claim 4, wherein said hormone is insulin.
6. Peptide hormone solution according to claim 5, wherein said biologically effective amount is from about 1 mg/ml up to about 25 mg/ml.
7. The use in a peptide hormone pump for the admini¬ stration by injection or infusion of the peptide hormone solution of any preceding claim.
8. The use according to claim 7, wherein the hormone pump is of the implantable type.
9. The use according to claim 8, wherein the hormone pump is of the micro infusion type.
10. A method of treating diabetes comprising the step of administering to a patient in need of such treatment a blood glucose controlling amount of an insulin solution according to any of claims 2 to 6.
11. A method according to claim 10, wherein the ad¬ ministration is made continuously or discontinuously by injection or infusion.
PCT/SE1992/000283 1991-05-07 1992-04-29 Peptide hormone solution WO1992019260A1 (en)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
SE9101381A SE9101381D0 (en) 1991-05-07 1991-05-07 PEPTIDE HORMONE SOLUTION
SE9101381-3 1991-05-07

Publications (1)

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WO1992019260A1 true WO1992019260A1 (en) 1992-11-12

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Cited By (17)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2005049061A2 (en) * 2003-11-20 2005-06-02 Novo Nordisk A/S Propylene glycol-containing peptide formulations which are optimal for production and for use in injection devices
WO2011051486A2 (en) 2009-11-02 2011-05-05 Novo Nordisk A/S Pharmaceutical solution of non covalently bound albumin and acylated insulin
US8114959B2 (en) 2003-06-03 2012-02-14 Novo Nordisk A/S Stabilized pharmaceutical peptide compositions
US8614181B2 (en) 2003-06-03 2013-12-24 Novo Nordisk A/S Stabilized pharmaceutical peptide compositions
US8710181B2 (en) 2004-08-31 2014-04-29 Novo Nordisk A/S Use of tris(hydroxymethyl) aminomethane for the stabilization of peptides, polypeptides and proteins
US8748376B2 (en) 2004-11-12 2014-06-10 Novo Nordisk A/S Stable formulations of peptides
WO2014096440A2 (en) 2012-12-21 2014-06-26 Novozymes Biopharma Dk A/S Composition
US8846618B2 (en) 2001-06-28 2014-09-30 Novo Nordisk A/S Stable formulation of modified GLP-1
US9233204B2 (en) 2014-01-31 2016-01-12 Aseko, Inc. Insulin management
US9483619B2 (en) 2012-09-11 2016-11-01 Aseko, Inc. Means and method for improved glycemic control for diabetic patients
US9486580B2 (en) 2014-01-31 2016-11-08 Aseko, Inc. Insulin management
US9886556B2 (en) 2015-08-20 2018-02-06 Aseko, Inc. Diabetes management therapy advisor
US9892234B2 (en) 2014-10-27 2018-02-13 Aseko, Inc. Subcutaneous outpatient management
US9897565B1 (en) 2012-09-11 2018-02-20 Aseko, Inc. System and method for optimizing insulin dosages for diabetic subjects
US11081226B2 (en) 2014-10-27 2021-08-03 Aseko, Inc. Method and controller for administering recommended insulin dosages to a patient
US11318191B2 (en) 2020-02-18 2022-05-03 Novo Nordisk A/S GLP-1 compositions and uses thereof
US11752198B2 (en) 2017-08-24 2023-09-12 Novo Nordisk A/S GLP-1 compositions and uses thereof

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EP0308725A2 (en) * 1987-09-25 1989-03-29 SCLAVO S.p.A. Pharmaceutical composition for intrarectal administration of a calcitonin and unit dosage forms prepared therefrom
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US8846618B2 (en) 2001-06-28 2014-09-30 Novo Nordisk A/S Stable formulation of modified GLP-1
US8114959B2 (en) 2003-06-03 2012-02-14 Novo Nordisk A/S Stabilized pharmaceutical peptide compositions
US8614181B2 (en) 2003-06-03 2013-12-24 Novo Nordisk A/S Stabilized pharmaceutical peptide compositions
WO2005049061A3 (en) * 2003-11-20 2005-10-20 Novo Nordisk As Propylene glycol-containing peptide formulations which are optimal for production and for use in injection devices
EP2394656A3 (en) * 2003-11-20 2012-01-18 Novo Nordisk A/S Propylene Glycol-containing peptide formulations which are optimal for production and for use in injection devices
US8114833B2 (en) 2003-11-20 2012-02-14 Novo Nordisk A/S Propylene glycol-containing peptide formulations which are optimal for production and for use in injection devices
WO2005049061A2 (en) * 2003-11-20 2005-06-02 Novo Nordisk A/S Propylene glycol-containing peptide formulations which are optimal for production and for use in injection devices
US8710181B2 (en) 2004-08-31 2014-04-29 Novo Nordisk A/S Use of tris(hydroxymethyl) aminomethane for the stabilization of peptides, polypeptides and proteins
US8748376B2 (en) 2004-11-12 2014-06-10 Novo Nordisk A/S Stable formulations of peptides
WO2011051486A2 (en) 2009-11-02 2011-05-05 Novo Nordisk A/S Pharmaceutical solution of non covalently bound albumin and acylated insulin
WO2011051486A3 (en) * 2009-11-02 2011-12-22 Novo Nordisk A/S Pharmaceutical solution of non covalently bound albumin and acylated insulin
US8865647B2 (en) 2009-11-02 2014-10-21 Novo Nordisk A/S Pharmaceutical solution of non covalently bound albumin and acylated insulin
US10102922B2 (en) 2012-09-11 2018-10-16 Aseko, Inc. Means and method for improved glycemic control for diabetic patients
US9897565B1 (en) 2012-09-11 2018-02-20 Aseko, Inc. System and method for optimizing insulin dosages for diabetic subjects
US11733196B2 (en) 2012-09-11 2023-08-22 Aseko, Inc. System and method for optimizing insulin dosages for diabetic subjects
US9483619B2 (en) 2012-09-11 2016-11-01 Aseko, Inc. Means and method for improved glycemic control for diabetic patients
US11131643B2 (en) 2012-09-11 2021-09-28 Aseko, Inc. Method and system for optimizing insulin dosages for diabetic subjects
US10629294B2 (en) 2012-09-11 2020-04-21 Aseko, Inc. Means and method for improved glycemic control for diabetic patients
US10410740B2 (en) 2012-09-11 2019-09-10 Aseko, Inc. Means and method for improved glycemic control for diabetic patients
US9773096B2 (en) 2012-09-11 2017-09-26 Aseko, Inc. Means and method for improved glycemic control for diabetic patients
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US9965596B2 (en) 2012-09-11 2018-05-08 Aseko, Inc. Means and method for improved glycemic control for diabetic patients
WO2014096440A3 (en) * 2012-12-21 2014-08-14 Novozymes Biopharma Dk A/S Albumin composition for preventing and/or reducing formation of peptide fibrils
WO2014096440A2 (en) 2012-12-21 2014-06-26 Novozymes Biopharma Dk A/S Composition
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US11081226B2 (en) 2014-10-27 2021-08-03 Aseko, Inc. Method and controller for administering recommended insulin dosages to a patient
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