Treating diabetes melitus using insulin injections with less than daily injection frequency

The present invention relates to novel insulin administration regimens that are particularly useful in the treatment of diabetes mellitus and hyperglycemia, in particular insulin-dependent diabetes mellitus. Insulin administration and insulin involves the use of analogs with a sustained action profile in new dosing regimens.

Diabetes mellitus often requires insulin treatment to establish appropriate metabolic regulation (mainly hyperglycemic regulation, but including other metabolic parameters for which insulin treatment is beneficial). The established practice of insulin treatment is to administer insulin preparations once or more times per day, sometimes in combination with other treatment regimens, as described in the available treatment guidelines. Is. Intravenous and subcutaneous insulin infusions have also been used in clinical practice.

One of the widely used insulin treatment options is to administer a long-acting insulin agent, also called basal insulin, to supplement the patient's insulin needs in whole or in part. Long-acting insulin is given once or more often per day and is used for both type 1 and type 2 diabetes mellitus and other forms of insulin-requiring disease conditions (hyperglycemia of any cause). ing.

Currently, the treatment of diabetes in both type 1 and type 2 diabetes is increasingly dependent on so-called intensive insulin therapy. In this treatment, patients supplement their diet-related insulin requirements with multiple daily insulin injections, including one or two daily injections of long-acting insulin to supplement their basal insulin requirements. Receive treatment supplemented with a bolus injection of fast-acting insulin.

Current practices in the management of diabetes and hyperglycemia are described, for example: --IDF Clinical Guidelines Task Force. Global Guideline for Type 2 Diabetes. Brussels: International Diabetes Federation, 2005, http://www.idf.org/webdata/docs/IDF%20GGT2D.pdf --IDF Clinical Guidelines Task Force. Guideline for Management of PostMeal Glucose. Brussels: International Diabetes Federation, 2007, http://www.idf.org/webdata/docs/Guideline_PMG_final.pdf --DM Nathan, JB Buse, MB Davidson, E. Ferrannini, RR Holman, R. Sherwin, and B. Zinman. Management of hyperglycemia in type 2 diabetes: a consensus algorithm for the initiation and adjustment of therapy: update regarding thiazolidinediones: a consensus statement from the American Diabetes Association and the European Association for the Study of Diabetes. Diabetes care 31 (1): 173-175, 2008,

An overview of basal insulin analogues and their properties and current clinical use can be found, among other things: --T. Heise and TR Pieber. Towards peakless, reproducible and long-acting insulins. An assessment of the basal analogues based on isoglycaemic clamp studies. Diabetes Obes Metab 9 (5): 648-659, 2007 --AH Barnett. A review of basal insulins. Diabet Med 20 (11): 873-885, 2003.

<figref num="1">The glucose infusion rate plotted against the time after administration of the investigational drug is shown.</figref><figref num="2">The blood glucose level plotted against the time after administration of the investigational drug is shown.</figref><figref num="3">Clinical trial flow</figref>

Description of the invention

The present invention is based on the surprising finding that diabetes and hyperglycemia can be treated by administering insulin at increased intervals. For example, it has been demonstrated that a satisfactory diabetes treatment plan can be achieved at intervals longer than 24 hours. Many benefits come directly from such a simplified treatment plan: Convenience for patients is improved because less dosing is required than daily dosing Dosing less than twice daily for part of the week further improves convenience Improved convenience potentially improves patient compliance and ultimately improves patient long-term outcomes If the dosing device is used less than daily, the cost of treatment can be lower due to less consumption of needles and auxiliary components of the device.

In its most general aspect, the present invention comprises administering an effective dosage of a naturally occurring insulin or insulin analog insulin derivative to a patient in need thereof, a condition in which insulin administration is beneficial or With respect to the method of treating the disease, the insulin derivative exhibits a sustained action profile, wherein the dosage is administered at intervals longer than 24 hours.

The present invention also relates to the use of such insulin derivatives in the therapeutic methods discussed herein, and the present invention also relates to the use of such insulin derivatives in the preparation of pharmaceutical compositions for the treatment of the diseases and conditions discussed herein. Also related.

Diseases and symptoms that are the primary targets of this method are prediabetes (type 1 or 2) or other symptoms characterized by hyperglycemia, such as prediabetes, glucose tolerance disorders, metabolic syndrome, obesity, cahexy. Of general interest are metabolic disorders and conditions in which the metabolic effects of insulin are clinically relevant, such as in vivo β-cell depletion / death, excess appetite, and inflammation. For all of these types of symptoms, it is known or believed that stable metabolic status in patients with the disease / symptom is beneficial.

Any treatment regimen mediated by insulin administration can be modified by the practice of this teaching, which provides here with insulin, insulin analogs or derivatives of any of these therapies with a sustained action profile. It means to include administration according to the instructions given.

Invention treatment plan The present invention is best used at the convenience of the patient. Therefore, a particular dosing interval is sought for each insulin agent that exhibits a long enough action profile to allow the dosing regimen disclosed herein in which the dosage is administered less frequently each day. Therefore, the final mode of use depends on both the efficacy of the product and the patient's qualities and preferences. This is because the effect of any insulin depends on the individual patient's insulin needs and susceptibility to the pharmacodynamic effects of insulin and ultimately also on the patient's preference under the given circumstances. These conditions can change over time, both for longer periods (years) and in terms of daily life.

However, the present invention provides many embodiments of general dosing regimens. In one embodiment of the method of the invention, the dosage is administered at intervals of at least 36 hours. In one embodiment of the method of the invention, the dosage is administered at intervals of at least 42 hours. The interval can be even longer, depending in particular on the duration of action of the insulin, analog or derivative used. Thus, in one embodiment, the dosage is administered at intervals of at least 48 hours, in another embodiment, the dosage is administered at intervals of at least 96 hours, and in yet another embodiment, the dosage is administered. Is administered at least at intervals of 120 hours.

In other embodiments, the dosage is administered at intervals of at least 144 hours, but longer intervals can be used in the present invention, which means that the dosage can be administered at intervals of at least 168 hours. Means, and even long intervals of up to 336 hours constitute embodiments of the present invention.

In some embodiments, the dosage is administered at intervals of up to 312 hours. In other embodiments, the dosage is administered at intervals of up to 288 hours. In yet another embodiment, the dosage is administered at intervals of up to 264 hours. In a further embodiment, the dosage is administered at intervals of up to 240 hours. In yet another further embodiment, the dosage is administered at intervals of up to 216 hours. One embodiment requires the dosage to be administered at intervals of up to 192 hours, the other embodiment requires the dosage to be administered at intervals of up to 168 hours.

In a series of embodiments of the invention, the dosage is administered at regular intervals. For example, in one of these embodiments, the dosage is administered every other day. In other of these embodiments, the dosage is administered every two days, and in yet other of these embodiments, the dosage is administered every three days. In other embodiments, the dosage is administered every 4 days, the dosage is administered every 5 days, the dosage is administered every 6 days, the dosage is 14 However, the present invention also includes those administered daily, but the invention also administers the above dosages every 7 days, every 8 days, every 9 days, every 10 days, every 1 day, or every 12 days. Also includes embodiments.

As an alternative to administration at regular intervals, one embodiment of the invention is that the dosage is administered on a fixed weekday. This has the advantage seen from the patient's side for the simple reason that it is easy to remember a fixed weekly plan. Thus, in one embodiment, the dosage is administered on a fixed 3 week day. In another embodiment, the dosage is administered on a fixed 2 week day.

In one embodiment, none of the fixed weekdays are in close proximity to each other. For dosing plans that include 3 week days, this means that the following plans are possible: Monday-Wednesday-Friday; Monday-Wednesday-Saturday; Monday-Thursday-Saturday; Tuesday-Thursday-Saturday; Tuesday -Thursday-Saturday; and Tuesday-Friday-Sunday. In embodiments that use fixed two weekdays, these are by more specific embodiments that are separated by only two and three other weekdays, that is, the following plans are possible: Monday-Thursday; Monday. -Friday; Tuesday-Friday; Tuesday-Saturday; Wednesday-Saturday; Wednesday-Sunday; and Thursday-Sunday.

In the method according to any one of the claims, substantially no other naturally occurring insulin, insulin analog or derivative of naturally occurring insulin or insulin analog is administered to the patient.

Insulin with a sustained action useful in the present invention Interesting derivatives with a sustained action profile are disclosed in WO 2005/012347 (Novo Nordisk), all of which are considered to be particularly useful for practicing the present invention. It is called "'347 derivative".

Use of '347 derivatives in the methods of the invention The method of the present invention comprises an embodiment in which the derivative is a '347 derivative. That is, naturally occurring insulin or insulin analog derivatives have a side chain attached to the α-amino group of the N-terminal amino acid residue of the parent insulin B chain or the ε-amino group of the Lys residue present in the B chain. The side chain has the general formula: -WXYZ [In the above formula, W is The residue is along with one of its carboxylic acid groups, along with the α-amino group of the N-terminal amino acid residue of the B chain of the parent insulin or the ε-amino group of the Lys residue present in the B chain. Α-amino acid residue having a carboxylic acid group in the side chain to form an amide group; -A chain consisting of 2, 3 or 4 α-amino acid residues linked together via an amide bond, and the chain via the amide bond is the N-terminal amino acid residue of the B chain of the parent insulin. It is linked to the α-amino group or the ε-amino group of the Lys residue present in the B chain, and the amino acid residue of W is at least one amino acid residue in which W has a carboxylic acid group in the side chain. To have, it is selected from the group of amino acid residues having a neutral side chain and amino acid residues having a carboxylic acid group in the side chain; -Covalent bond from X to the α-amino group of the N-terminal amino acid residue of the B chain of the parent insulin or the ε-amino group of the Lys residue present in the B chain Is; X is -CO-; -COCH (COOH)<u style="single">C</u>O-; -CON (CH)₂COOH) CH₂<u style="single">C</u>O-; -CON (CH)₂COOH) CH₂CON (CH₂COOH) CH₂<u style="single">C</u>O-; -CON (CH)₂CH₂COOH) CH₂CH₂<u style="single">C</u>O-; -CON (CH)₂CH₂COOH) CH₂CH₂CON (CH₂CH₂COOH) CH₂CH₂<u style="single">C</u>O-; -CONHCH (COOH) (CH₂)₄NH<u style="single">C</u>O-; -CON (CH)₂CH₂COOH) CH₂<u style="single">C</u>O-; or -CON (CH)₂COOH) CH₂CH₂<u style="single">C</u>O-and a) When W is an amino acid residue or a chain of amino acid residues, it forms an amide bond with an amino group in W through a bond from the underlined carbonyl carbon, or b) When W is a covalent bond, the α-amino group of the N-terminal amino acid residue of the B chain of the parent insulin or the ε- of the Lys residue present in the B chain via the bond from the underlined carbonyl carbon. Form an amide bond with an amino group; Y is · M is an integer in the range 6-32-(CH₂)_m-; 1, 2 or 3 -CH = CH-groups and enough -CH to provide a total number of carbon atoms in the range 10-32 in the chain₂-A divalent hydrocarbon chain containing groups; Expression-(CH₂)_vC₆H₄(CH₂)_W-(In the equation, v and w are integers such that the sum of v and w is in the range of 6 to 30, or one of them is zero). Is; Z is -COOH; -CO-Asp; -CO-Glu; -CO-Gly; -CO-Sar; -CH (COOH)₂; -N (CH)₂COOH)₂; -SO₃H; or -PO₃H Is] What is and its Zn²⁺It is a complex, where Z is different from -COOH when W is a covalent bond and X is -CO-.

In one embodiment, the side chain-WXYZ is attached to the α-amino group of the N-terminal amino acid residue of the B chain of the parent insulin. In another embodiment of the invention, the side chain-WXYZ is attached to the ε-amino group of the Lys residue present in the B chain of the parent insulin. In a more specific embodiment of this embodiment, the side chain-WXYZ is attached to the ε-amino group of the Lys residue located at position 28 of the B chain. In a more specific embodiment of this embodiment, the side chain-WXYZ is attached to the ε-amino group of the Lys residue located at position 29 of the B chain. In a more specific embodiment of this embodiment, the side chain-WXYZ is attached to the ε-amino group of the Lys residue located at position 30 of the B chain.

The partial structure W of the side chain-WXYZ can be a covalent bond. Alternatively, W can be a residue of an α-amino acid having a carboxylic acid group in the side chain and a total of 4 to 10 carbon atoms. That is, W can be a residue of α-amino acid that can be encoded by the genetic code. Thus, W can be selected, for example, from the group consisting of α-Asp, β-Asp, α-Glu, and γ-Glu. Further options for W are, for example, α-hGlu and δ-hGlu.

In a further embodiment, W has two α-amino acid residues, one having 4 to 10 carbon atoms and a carboxylic acid group and the other having 2 to 11 carbon atoms but no free carboxylic acid group. It is a chain consisting of. An α-amino acid residue that does not have a free carboxylic acid group can be a neutral codeable α-amino acid residue. Examples of W according to this embodiment are α-Asp-Gly; Gly-α-Asp; β-Asp-Gly; Gly-β-Asp; α-Glu-Gly; Gly-α-Glu; γ-Glu- Gly; Gly-γ-Glu; α-hGlu-Gly; Gly-α-hGlu; δ-hGlu-Gly; and Gly-δ-hGlu.

In a further embodiment, W is a chain consisting of two α-amino acid residues having 4 to 10 carbon atoms independently and both having a carboxylic acid group in the side chain. One or both of these α-amino acid residues can be encoded α-amino acid residues. Examples of W according to this embodiment are α-Asp-α-Asp; α-Asp-α-Glu; α-Asp-α-hGlu; α-Asp-β-Asp; α-Asp-γ-Glu; α-Asp-δ-hGlu; β-Asp-α-Asp; β-Asp-α-Glu; β-Asp-α-hGlu; β-Asp-β-Asp; β-Asp-γ-Glu; β- Asp-δ-hGlu; α-Glu-α-Asp; α-Glu-α-Glu; α-Glu-α-hGlu; α-Glu-β-Asp; α-Glu-γ-Glu; α-Glu- δ-hGlu; γ-Glu-α-Asp; γ-Glu-α-Glu; γ-Glu-α-hGlu; γ-Glu-β-Asp; γ-Glu-γ-Glu; γ-Glu-δ- hGlu; α-hGlu-α-Asp; α-hGlu-α-Glu; α-hGlu-α-hGlu; α-hGlu-β-Asp; α-hGlu-γ-Glu; α-hGlu-δ-hGlu; δ-hGlu-α-Asp; δ-hGlu-α-Glu; δ-hGlu-α-hGlu; δ-hGlu-β-Asp; δ-hGlu-γ-Glu; and δ-hGlu-δ-hGlu. ..

In a further embodiment, W is a chain consisting of three α-amino acid residues independently having 4 to 10 carbon atoms, the amino acid residue of the chain having a carboxylic acid group in the side chain. It is selected from the group of residues having a carboxylic acid group in the side chain and residues having a neutral side chain so as to have at least one residue having. In one embodiment, the amino acid residue is a codeable residue. In a further embodiment, W is a chain consisting of four α-amino acid residues independently having 4 to 10 carbon atoms, the amino acid residues of the chain having a carboxylic acid group in the side chain. It is selected from the group having a residue having a carboxylic acid group in the side chain and a neutral side chain so as to have at least one residue having. In one embodiment, the amino acid residue is a codeable residue. In one embodiment, W can be linked to the ε-amino group of the Lys residue in the B chain via a urea derivative.

The partial structure X of the side chain-WXYZ is an amino group in W via a bond from the underlined carbonyl carbon, or when W is a covalent bond, the N-terminal α-amino group of the B chain of the parent insulin or Formula that forms an amide bond with the ε-amino group of the Lys residue present in the B chain-<u style="single">C</u>Can be the basis of O-. In a further embodiment, the side chain partial structure X is covalently attached to an amino group in W via a bond from the underlined carbonyl carbon, or when W is a covalent bond, the N-terminal α of the B chain of the parent insulin. -Formula that forms an amide bond with the ε-amino group of the Lys residue present in the amino group or B chain-CH (COOH)<u style="single">C</u>Can be the basis of O-.

In a further embodiment, the side chain partial structure X is covalently attached to an amino group in W via a bond from the underlined carbonyl carbon, or when W is a covalent bond, the N-terminal α of the B chain of the parent insulin. -The formula that forms an amide bond with the ε-amino group of the Lys residue present in the amino group or B chain-CON (CH)₂COOH) CH₂<u style="single">C</u>Can be the basis of O-. In a further embodiment, the side chain partial structure X is covalently attached to an amino group in W via a bond from the underlined carbonyl carbon, or when W is a covalent bond, the N-terminal α of the B chain of the parent insulin. -The formula that forms an amide bond with the ε-amino group of the Lys residue present in the amino group or B chain-CON (CH)₂CH₂COOH) CH₂<u style="single">C</u>Can be the basis of O-.

In a further embodiment, the side chain partial structure X is covalently attached to an amino group in W via a bond from the underlined carbonyl carbon, or when W is a covalent bond, the N-terminal α of the B chain of the parent insulin. -The formula that forms an amide bond with the ε-amino group of the Lys residue present in the amino group or B chain-CON (CH)₂COOH) CH₂CH₂<u style="single">C</u>Can be the basis of O-. In a further embodiment, the side chain partial structure X is covalently attached to an amino group in W via a bond from the underlined carbonyl carbon, or when W is a covalent bond, the N-terminal α of the B chain of the parent insulin. -The formula that forms an amide bond with the ε-amino group of the Lys residue present in the amino group or B chain-CON (CH)₂COOH) CH₂CON (CH₂COOH) CH₂<u style="single">C</u>Can be the basis of O-.

In a further embodiment, the side chain partial structure X is covalently attached to an amino group in W via a bond from the underlined carbonyl carbon, or when W is a covalent bond, the N-terminal α of the B chain of the parent insulin. -The formula that forms an amide bond with the ε-amino group of the Lys residue present in the amino group or B chain-CON (CH)₂CH₂COOH) CH₂CH₂<u style="single">C</u>Can be the basis of O-. In a further embodiment, the side chain partial structure X is covalently attached to an amino group in W via a bond from the underlined carbonyl carbon, or when W is a covalent bond, the N-terminal α of the B chain of the parent insulin. -The formula that forms an amide bond with the ε-amino group of the Lys residue present in the amino group or B chain-CON (CH)₂CH₂COOH) CH₂CH₂CON (CH₂CH₂COOH) CH₂CH₂<u style="single">C</u>Can be the basis of O-.

The side chain-partial structure Y of WXYZ is given by the equation-(CH₂)_m-(In the equation, m is an integer in the range 6 to 32, 8 to 20, 12 to 20, or 12-16). In another embodiment, Y imparts 1, 2 or 3 -CH = CH- groups and a total number of carbon atoms in the range 6 to 32, 10 to 32, 12 to 20, or 12-16 in the chain. Enough to do-CH₂-A divalent hydrocarbon chain containing a group. In other embodiments, Y is the expression-(CH₂)_vC₆H₄(CH₂)_W-(In the equation, v and w are integers such that the sum of v and w is in the range 6 to 30, 10 to 20, or 12-16, or one of them is zero). It is a hydrocarbon chain. In one embodiment, the partial structure Z of the side chain -WXYZ is -COOH, except that Z is -COOH if W is a covalent bond and X is -CO-.

In another embodiment, Z is -CO-Asp. In another embodiment, Z is -CO-Glu. In another embodiment, Z is -CO-Gly. In another embodiment, Z is -CO-Sar. In other embodiments, Z is -CH (COOH).₂Is. In other embodiments, Z is -N (CH).₂COOH)₂Is. In other embodiments, Z is -SO₃H. In other embodiments, Z is -PO₃H.

In a further embodiment, W is selected from the group consisting of α-Asp, β-Asp, α-Glu, and γ-Glu; X is -CO- or -CH (COOH) CO; Y is-( CH₂)_m-(In the equation, m is an integer in the range 12-18) and Z is -COOH or -CH (COOH)₂Is.

The insulin portion of the '347 derivative, also referred to herein as parent insulin, can be naturally occurring insulin, such as human insulin or porcine insulin. Alternatively, the parent insulin can be an insulin analog. In a group of parent insulin analogs, the amino acid residue at position A21 is Asn. In the other group of parent insulin analogs, the amino acid residue at position A21 is Gly. A specific example from this group of analogs is Gly^A21Human insulin, Gly^A21des (B30) human insulin; and Gly^A21Arg^B31Arg^B32Human insulin.

In other groups of parent insulin analogs, the amino acid residue at position B1 has been deleted. A specific example from this group of parent insulin analogues is des (B1) human insulin. Another group of parent insulin analogs lacked the amino acid residue at position B30. A specific example from this group of parent insulin analogues is des (B30) human insulin.

Another group of parent insulin analogs lacked the amino acid residue at position B28. Is Asp. A specific example from this group of parent insulin analogues is Asp^B28Human insulin. In the other group of parent insulin analogs, the amino acid residue at position B28 is Lys and the amino acid residue at position B29 is Pro. A specific example from this group of parent insulin analogues is Lys^B28Pro^B29Human insulin.

In other groups of parent insulin analogs, the amino acid residue at position B30 is Lys and the amino acid residue at position B29 is any codeable amino acid except Cys, Met, Arg and Lys. One example is an insulin analog in which the amino acid residue at position B29 is Thr and the amino acid residue at position B30 is Lys. A specific example from this group of parent insulin analogues is Thr^B29Lys^B30Human insulin. In the other group of parent insulin analogs, the amino acid residue at position B3 is Lys and the amino acid residue at position B29 is Glu. A specific example from this group of parent insulin analogues is Lys^B3Glu^B29Human insulin.

Examples of '347 derivatives useful in the present invention are the following compounds: N^εB29-(N^α-(HOOC (CH)₂)₁₄CO) -γ-Glu) des (B30) human insulin; N^εB29-(N^α-(HOOC (CH)₂)₁₅CO) -γ-Glu) des (B30) human insulin; N^εB29-(N^α-(HOOC (CH)₂)₁₆CO) -γ-Glu) des (B30) human insulin; N^εB29-(N^α-(HOOC (CH)₂)₁₇CO) -γ-Glu) des (B30) human insulin; N^εB29-(N^α-(HOOC (CH)₂)₁₈CO) -γ-Glu) des (B30) human insulin; N^εB29-(N^α-(HOOC (CH)₂)₁₆CO) -γ-Glu-N- (γ-Glu)) des (B30) human insulin; N^εB29-(N^α-(Asp-OC (CH)₂)₁₆CO) -γ-Glu) des (B30) human insulin; N^εB29-(N^α-(Glu-OC (CH)₂)₁₄CO) -γ-Glu) des (B30) human insulin; N^εB29-(N^α-(Glu-OC (CH)₂)₁₄CO-) des (B30) human insulin; N^εB29-(N^α-(Asp-OC (CH)₂)₁₆CO-) des (B30) human insulin; N^εB29-(N^α-(HOOC (CH)₂)₁₆CO) -α-Glu-N- (β-Asp)) des (B30) human insulin; N^εB29-(N^α-(Gly-OC (CH)₂)₁₃CO) -γ-Glu) des (B30) human insulin; N^εB29-(N^α-(Sar-OC (CH)₂)₁₃CO) -γ-Glu) des (B30) human insulin; N^εB29-(N^α-(HOOC (CH)₂)₁₃CO) -γ-Glu) des (B30) human insulin; (N^εB29-(N^α-(HOOC (CH)₂)₁₃CO) -β-Asp) des (B30) human insulin; N^εB29-(N^α-(HOOC (CH)₂)₁₃CO) -α-Glu) des (B30) human insulin; N^εB29-(N^α-(HOOC (CH)₂)₁₆CO) -γ-D-Glu) des (B30) human insulin; N^εB29-(N^α-(HOOC (CH)₂)₁₄CO) -β-D-Asp) des (B30) human insulin; N^εB29-(N-HOOC (CH)₂)₁₆CO-β-D-Asp) des (B30) human insulin; N^εB29-(N-HOOC (CH)₂)₁₄CO-IDA) des (B30) human insulin; N^εB29-[N- (HOOC (CH)₂)₁₆CO) -N- (carboxyethyl) -Gly] des (B30) human insulin; N^εB29-[N- (HOOC (CH)₂)₁₄CO) -N- (carboxyethyl) -Gly] des (B30) human insulin; and N^εB29-[N- (HOOC (CH)₂)₁₄CO) -N- (carboxymethyl) -β-Ala] des (B30) human insulin.

The '347 derivative may be provided in the form of an essentially zinc-free compound or in the form of a zinc complex. If a zinc complex of the '347 derivative is provided, two Zn²⁺Ion, 3 Zn²⁺Ion or 4 Zn²+ Ions can bind to each insulin hexamer. A solution of the zinc complex of an insulin derivative will contain a mixture of such species.

Details on the preparation, formulation, pharmacological action of the '347 derivative and other related features can be found in WO 2005/012347, incorporated herein by reference.

Fast-acting insulin analog Embodiments of the methods of the invention are for more frequent administration of fast-acting naturally occurring insulin, insulin analogs or derivatives to naturally occurring insulin, insulin analogs or derivatives exhibiting a sustained action profile and / or non-insulin antidiabetic. Includes those supplemented with drug administration.

Thus, one embodiment of the invention is any suitable insulin, analog or derivative (eg, N) described above.^εB29-(N^α-(HOOC (CH)₂)₁₄CO) -γ-L-Glu) des (B30) human insulin = LysB29 (Nε-hexadecasinoyl-γ-Glu) des (B30) human insulin (Example 4) of International Publication No. 2005/012347) and It provides a combination therapy in which fast-acting insulin analogues are used, for example, in combination as a concomitant product but are also administered separately. Accordingly, all specific disclosures of this application that provide details regarding insulin useful in the inventions disclosed herein apply in combination therapies comprising the compound with fast-acting insulin analogues, subject to change. Typically, fast-acting insulin is Asp^B28Human insulin; Lys^B28Pro^B29Human insulin and Lys^B3Glu^B29Selected from the group consisting of human insulin. Concomitant agents do not show blunting. The insulin derivatives disclosed in WO 2005/012347 may be formulated with the fast-acting insulin analogs disclosed in WO 2007/074133, which is hereby incorporated by reference.

In one embodiment, the invention is N with pharmaceutically acceptable carriers and additives.^εB29-(N^α-(HOOC (CH)₂) 14CO) -γ-L-Glu) des (B30) We provide combination therapy with human insulin and AspB28 human insulin. The insulin derivatives and fast-acting insulin analogues according to the present invention are, if necessary, about 90/10%; about 80/20%, about 70/30%, about 60/40%, about 50/50%, about 40 /. It can be mixed in a ratio of 60%, about 30/60%, about 20/80% or about 10/90%.

Other combinations In one embodiment of the method of the invention, administration of a naturally occurring insulin, insulin analog or derivative exhibiting a sustained action profile is supplemented with administration of a non-insulin antidiabetic agent such as metformin.

The present invention is summarized in the following paragraphs: Claims 1. An insulin derivative for the treatment of symptoms or diseases for which insulin administration is beneficial, including administration of an effective dosage of an insulin derivative to a patient in need thereof, the insulin derivative being persistent. An insulin derivative that exhibits an action profile and the dosage is administered at intervals longer than 24 hours. 2. The insulin derivative according to paragraph 1 in which the above dosage is administered at intervals of at least 36 hours. 3. The insulin derivative according to paragraph 2 in which the above dosage is administered at intervals of at least 48 hours. 4. The insulin derivative according to paragraph 3 in which the above dosage is administered at intervals of at least 72 hours. 5. The insulin derivative according to paragraph 4, wherein the above dosage is administered at intervals of at least 96 hours. 6. The insulin derivative according to paragraph 5, wherein the above dosage is administered at intervals of at least 120 hours. 7. The insulin derivative according to paragraph 6, wherein the above dosage is administered at intervals of at least 144 hours. 8. 8. The insulin derivative according to paragraph 7, wherein the dosage is administered at intervals of at least 168 hours. 9. The insulin derivative according to any one of the preceding paragraphs, wherein the above dosage is administered at a maximum interval of 336 hours. 10. The insulin derivative according to any one of the preceding paragraphs, wherein the above dosage is administered at a maximum interval of 312 hours. 11. The insulin derivative according to any one of the preceding paragraphs, wherein the above dosage is administered at a maximum interval of 288 hours. 12. The insulin derivative according to any one of the preceding paragraphs, wherein the above dosage is administered at a maximum interval of 264 hours. 13. The insulin derivative according to any one of the preceding paragraphs, wherein the above dosage is administered at a maximum interval of 240 hours. 14. The insulin derivative according to any one of the preceding paragraphs, wherein the above dosage is administered at a maximum interval of 216 hours. 15. The insulin derivative according to any one of the preceding paragraphs, wherein the above dosage is administered at a maximum interval of 192 hours. 16. The insulin derivative according to any one of the preceding paragraphs, wherein the above dosage is administered at a maximum interval of 168 hours. 17. 17. The insulin derivative according to any one of the preceding paragraphs, wherein the dosage is administered at regular intervals. 18. The insulin derivative according to paragraph 17, wherein the above dosage is administered every other day. 19. The insulin derivative according to paragraph 17, wherein the above dosage is administered every two days. 20. The insulin derivative according to paragraph 17, wherein the above dosage is administered every three days. 21. The insulin derivative according to paragraph 17, wherein the above dosage is administered every four days. 22. The insulin derivative according to paragraph 17, wherein the above dosage is administered every five days. 23. The insulin derivative according to paragraph 17, wherein the above dosage is administered every 6 days. 24. The insulin derivative according to paragraph 17, wherein the above dosage is administered every 14 days. 25. The insulin derivative according to any one of paragraphs 1 to 16, wherein the dosage is administered on a fixed weekday. 26. The insulin derivative according to paragraph 25, wherein the dosage is administered on a fixed 3 week day. 27. The insulin derivative according to paragraph 25, wherein the dosage is administered on a fixed 2 week day. 28. The insulin derivative according to paragraph 26 or 27, wherein none of the fixed weekdays are in close proximity to each other. 29. The insulin derivative according to paragraph 27, wherein the above fixed 2 weeks are separated by only 2 and 3 other weeks. 30. Administration of naturally occurring insulin, insulin analogs or derivatives showing a long-acting profile is supplemented by more frequent administration of fast-acting naturally occurring insulin, insulin analogs or derivatives and / or administration of non-insulin antidiabetic agents. The insulin derivative according to any one of the preceding paragraphs. 31. The insulin derivative according to any one of paragraphs 1-29, wherein virtually no other naturally occurring insulin, insulin analog or derivative of naturally occurring insulin or insulin analog is administered to the patient. 32. The insulin derivative according to paragraph 31, wherein the administration of a naturally occurring insulin, insulin analog or derivative exhibiting a long-acting profile is supplemented with the administration of a non-insulin antidiabetic drug. 33. The naturally occurring insulin or a derivative of the insulin analog is administered, and the derivative is the α-amino group of the N-terminal amino acid residue of the B chain of the parent insulin or the ε-amino group of the Lys residue present in the B chain. Has a side chain attached to, which side chain has the general formula: -WXYZ [In the above formula, W is The residue is along with one of its carboxylic acid groups, along with the α-amino group of the N-terminal amino acid residue of the B chain of the parent insulin or the ε-amino group of the Lys residue present in the B chain. Α-amino acid residue having a carboxylic acid group in the side chain to form an amide group; -A chain consisting of 2, 3 or 4 α-amino acid residues linked together via an amide bond, and the chain via the amide bond is the N-terminal amino acid residue of the B chain of the parent insulin. It is linked to the α-amino group or the ε-amino group of the Lys residue present in the B chain, and the amino acid residue of W is at least one amino acid residue in which W has a carboxylic acid group in the side chain. To have, it is selected from the group of amino acid residues having a neutral side chain and amino acid residues having a carboxylic acid group in the side chain; -Covalent bond from X to the α-amino group of the N-terminal amino acid residue of the B chain of the parent insulin or the ε-amino group of the Lys residue present in the B chain Is; X is -CO-; -COCH (COOH)<u style="single">C</u>O-; -CON (CH)₂COOH) CH₂<u style="single">C</u>O-; -CON (CH)₂COOH) CH₂CON (CH₂COOH) CH₂<u style="single">C</u>O-; -CON (CH)₂CH₂COOH) CH₂CH₂<u style="single">C</u>O-; -CON (CH)₂CH₂COOH) CH₂CH₂CON (CH₂CH₂COOH) CH₂CH₂<u style="single">C</u>O-; -CONHCH (COOH) (CH₂)₄NH<u style="single">C</u>O-; -CON (CH)₂CH₂COOH) CH₂<u style="single">C</u>O-; or -CON (CH)₂COOH) CH₂CH₂<u style="single">C</u>O-and a) When W is an amino acid residue or a chain of amino acid residues, it forms an amide bond with an amino group in W through a bond from the underlined carbonyl carbon, or b) When W is a covalent bond, the α-amino group of the N-terminal amino acid residue of the B chain of the parent insulin or the ε- of the Lys residue present in the B chain via the bond from the underlined carbonyl carbon. Form an amide bond with an amino group; Y is · M is an integer in the range 6-32-(CH₂)_m-; 1, 2 or 3 -CH = CH-groups and enough -CH to provide a total number of carbon atoms in the range 10-32 in the chain₂-A divalent hydrocarbon chain containing groups; Expression-(CH₂)_vC₆H₄(CH₂)_W-(In the equation, v and w are integers such that the sum of v and w is in the range of 6 to 30, or one of them is zero). Is; and Z is -COOH; -CO-Asp; -CO-Glu; -CO-Gly; -CO-Sar; -CH (COOH)₂; -N (CH)₂COOH)₂; -SO₃H; or -PO₃H Is] What is and its Zn²⁺The insulin derivative according to any one of the preceding paragraphs, wherein Z is different from -COOH when W is a covalent bond and X is -CO-. 34. The insulin derivative according to paragraph 33, wherein the side chain-WXYZ is attached to the α-amino group of the N-terminal amino acid residue of the B chain of the parent insulin. 35. The insulin derivative according to paragraph 33, wherein the side chain-WXYZ is attached to the ε-amino group of the Lys residue present in the B chain of the parent insulin. 36. The insulin derivative according to any one of paragraphs 33 to 35, wherein W is a covalent bond. 37. The insulin derivative according to any one of paragraphs 33 to 35, wherein W is an α-amino acid residue having 4 to 10 carbon atoms. 38. The insulin derivative according to paragraph 37, wherein W is selected from the group consisting of α-Asp, β-Asp, α-Glu, γ-Glu, α-hGlu and δ-hGlu. 39. W is a chain consisting of two α-amino acid residues, one having 4 to 10 carbon atoms and a free carboxylic acid group and the other having 2 to 11 carbon atoms but no free carboxylic acid group. The insulin derivative according to any one of paragraphs 33 to 35. 40. W is α-Asp-Gly; Gly-α-Asp; β-Asp-Gly; Gly-β-Asp; α-Glu-Gly; Gly-α-Glu; γ-Glu-Gly; Gly-γ -The insulin derivative according to paragraph 39 selected from the group consisting of α-hGlu-Gly; Gly-α-hGlu; δ-hGlu-Gly; and Gly-δ-hGlu. 41. The insulin derivative according to any one of paragraphs 33 to 35, wherein W is a chain consisting of two α-amino acid residues having 4 to 10 carbon atoms independently and both having a free carboxylic acid group. .. 42. W is α-Asp-α-Asp; α-Asp-α-Glu; α-Asp-α-hGlu; α-Asp-β-Asp; α-Asp-γ-Glu; α-Asp-δ-hGlu Β-Asp-α-Asp; β-Asp-α-Glu; β-Asp-α-hGlu; β-Asp-β-Asp; β-Asp-γ-Glu; β-Asp-δ-hGlu; α -Glu-α-Asp; α-Glu-α-Glu; α-Glu-α-hGlu; α-Glu-β-Asp; α-Glu-γ-Glu; α-Glu-δ-hGlu; γ-Glu -α-Asp; γ-Glu-α-Glu; γ-Glu-α-hGlu; γ-Glu-β-Asp; γ-Glu-γ-Glu; γ-Glu-δ-hGlu; α-hGlu-α -Asp; α-hGlu-α-Glu; α-hGlu-α-hGlu; α-hGlu-β-Asp; α-hGlu-γ-Glu; α-hGlu-δ-hGlu; δ-hGlu-α-Asp Paragraph 41 selected from the group consisting of δ-hGlu-α-Glu; δ-hGlu-α-hGlu; δ-hGlu-β-Asp; δ-hGlu-γ-Glu; and δ-hGlu-δ-hGlu The insulin derivative described in. 43. The insulin derivative according to any one of paragraphs 33 to 42, wherein X is -CO- or -CH (COOH) CO-. 44. X is -CON (CH)₂COOH) CH₂<u style="single">C</u>O-; -CON (CH)₂COOH) CH₂CON (CH₂COOH) CH₂<u style="single">C</u>O-; -CON (CH)₂CH₂COOH) CH₂CH₂<u style="single">C</u>O-; -CON (CH)₂CH₂COOH) CH₂CH₂CON (CH₂CH₂COOH) CH₂CH₂<u style="single">C</u>O- -CON (CH)₂CH₂COOH) CH₂<u style="single">C</u>O-; or -CON (CH)₂COOH) CH₂CH₂<u style="single">C</u>O- The insulin derivative according to any one of paragraphs 33 to 43. 45. Y is-(CH₂)_mThe insulin derivative according to any one of paragraphs 33 to 44, wherein m is (where m is an integer in the range 6 to 32, 8 to 20, 12 to 20 or 12-16). 46. The insulin derivative according to any one of paragraphs 33-45, wherein Z is -COOH. 47. Z is -CH (COOH)₂The insulin derivative according to any one of paragraphs 33 to 45. 48. Z is -N (CH)₂COOH)₂The insulin derivative according to any one of paragraphs 33 to 45. 49. Z is -SO₃The insulin derivative according to any one of paragraphs 33 to 45, which is H. 50. Z is-PO₃The insulin derivative according to any one of paragraphs 33 to 45, which is H. 51. The insulin derivative according to any one of paragraphs 33 to 50, wherein the parent insulin has Asn or Gly at position A21. 52. The insulin derivative according to any one of paragraphs 33 to 50, wherein the parent insulin is a des (B1) analog. 53. The insulin derivative according to any one of paragraphs 33 to 50, wherein the parent insulin is a des (B30) analog. 54. The insulin derivative according to any one of paragraphs 33 to 50, wherein the parent insulin at position B29 is any codeable amino acid except Cys, Met, Arg and Lys, and the amino acid at position B30 is Lys. 55. The insulin derivative according to any one of paragraphs 33 to 50, wherein the parent insulin has Thr at the B29 position and Lys at the B30 position. 56. Parent insulin is human insulin; des (B1) human insulin; des (B30) human insulin; Gly^A21Human insulin; Gly^A21des (B30) human insulin; Asp^B28Human insulin; porcine insulin; Lys^B28Pro^B29Human insulin; Gly^A21Arg^B31Arg^B32Human insulin; and Lys^B3Glu^B29The insulin derivative according to any one of paragraphs 33 to 50 selected from the group consisting of human insulin. 57. Insulin derivative is N^εB29-(N^α-(HOOC (CH)₂)₁₄CO) -γ-Glu) des (B30) human insulin; N^εB29-(N^α-(HOOC (CH)₂)₁₅CO) -γ-Glu) des (B30) human insulin; N^εB29-(N^α-(HOOC (CH)₂)₁₆CO) -γ-Glu) des (B30) human insulin; N^εB29-(N^α-(HOOC (CH)₂)₁₇CO) -γ-Glu) des (B30) human insulin; N^εB29-(N^α-(HOOC (CH)₂)₁₈CO) -γ-Glu) des (B30) human insulin; N^εB29-(N^α-(HOOC (CH)₂)₁₆CO) -γ-Glu-N- (γ-Glu)) des (B30) Human insulin; N^εB29-(N^α-(Asp-OC (CH)₂)₁₆CO) -γ-Glu) des (B30) human insulin; N^εB29-(N^α-(Glu-OC (CH)₂)₁₄CO) -γ-Glu) des (B30) human insulin; N^εB29-(N^α-(Glu-OC (CH)₂)₁₄CO-) des (B30) human insulin; N^εB29-(N^α-(Asp-OC (CH)₂)₁₆CO-) des (B30) human insulin; N^εB29-(N^α-(HOOC (CH)₂)₁₆CO) -α-Glu-N- (β-Asp)) des (B30) Human insulin; N^εB29-(N^α-(Gly-OC (CH)₂)₁₃CO) -γ-Glu) des (B30) human insulin; N^εB29-(N^α-(Sar-OC (CH)₂)₁₃CO) -γ-Glu) des (B30) human insulin; N^εB29-(N^α-(HOOC (CH)₂)₁₃CO) -γ-Glu) des (B30) Human insulin; (N^εB29-(N^α-(HOOC (CH)₂)₁₃CO) -β-Asp) des (B30) human insulin; N^εB29-(N^α-(HOOC (CH)₂)₁₃CO) -α-Glu) des (B30) human insulin; N^εB29-(N^α-(HOOC (CH)₂)₁₆CO) -γ-D-Glu) des (B30) human insulin; N^εB29-(N^α-(HOOC (CH)₂)₁₄CO) -β-D-Asp) des (B30) human insulin; N^εB29-(N^α-(HOOC (CH)₂)₁₄CO) -β-D-Asp) des (B30) human insulin; N^εB29-(N-HOOC (CH)₂)₁₆CO-β-D-Asp) des (B30) human insulin; N^εB29-(N-HOOC (CH)₂)₁₄CO-IDA) des (B30) human insulin; N^εB29-[N- (HOOC (CH)₂)₁₆CO) -N- (carboxyethyl) -Gly] des (B30) human insulin; N^εB29-[N- (HOOC (CH)₂)₁₄CO) -N- (carboxyethyl) -Gly] des (B30) human insulin; and N^εB29-[N- (HOOC (CH)₂)₁₄The insulin derivative according to paragraph 33 selected from the group consisting of CO) -N- (carboxymethyl) -β-Ala] des (B30) human insulin. 58. Insulin derivative is N^εB29-(N^α-(HOOC (CH)₂)₁₄CO) -γ-Glu) des (B30) The insulin derivative according to paragraph 57, which is human insulin. 59. Insulin derivative is N^εB29-(N^α-(HOOC (CH)₂)₁₅CO) -γ-Glu) des (B30) The insulin derivative according to paragraph 57, which is human insulin. 60. Insulin derivative is N^εB29-(N^α-(HOOC (CH)₂)₁₆CO) -γ-Glu) des (B30) The insulin derivative according to paragraph 57, which is human insulin. 61. Insulin derivative is N^εB29-(N^α-(HOOC (CH)₂)₁₇CO) -γ-Glu) des (B30) The insulin derivative according to paragraph 57, which is human insulin. 62. Insulin derivative is N^εB29-(N^α-(HOOC (CH)₂)₁₈CO) -γ-Glu) des (B30) The insulin derivative according to paragraph 57, which is human insulin. 63. Insulin derivative is N^εB29-(N^α-(HOOC (CH)₂)₁₆CO) -γ-Glu-N- (γ-Glu)) des (B30) The insulin derivative according to paragraph 57, which is human insulin. 64. Insulin derivative is N^εB29-(N^α-(Asp-OC (CH)₂)₁₆CO) -γ-Glu) des (B30) The insulin derivative according to paragraph 57, which is human insulin. 65. Insulin derivative is N^εB29-(N^α-(Glu-OC (CH)₂)₁₄CO) -γ-Glu) des (B30) The insulin derivative according to paragraph 57, which is human insulin. 66. Insulin derivative is N^εB29-(N^α-(Glu-OC (CH)₂)₁₄CO-) des (B30) The insulin derivative according to paragraph 57, which is human insulin. 67. Insulin derivative is N^εB29-(N^α-(Asp-OC (CH)₂)₁₆CO-) des (B30) The insulin derivative according to paragraph 57, which is human insulin. 68. Insulin derivative is N^εB29-(N^α-(HOOC (CH)₂)₁₆CO) -α-Glu-N- (β-Asp)) des (B30) The insulin derivative according to paragraph 57, which is human insulin. 69. Insulin derivative is N^εB29-(N^α-(Gly-OC (CH)₂)₁₃CO) -γ-Glu) des (B30) The insulin derivative according to paragraph 57, which is human insulin. 70. Insulin derivative is N^εB29-(N^α-(Sar-OC (CH)₂)₁₃CO) -γ-Glu) des (B30) The insulin derivative according to paragraph 57, which is human insulin. 71. Insulin derivative is N^εB29-(N^α-(HOOC (CH)₂)₁₃CO) -γ-Glu) des (B30) The insulin derivative according to paragraph 57, which is human insulin. 72. Insulin derivative (N^εB29-(N^α-(HOOC (CH)₂)₁₃CO) -β-Asp) des (B30) The insulin derivative according to paragraph 57, which is human insulin. 73. Insulin derivative is N^εB29-(N^α-(HOOC (CH)₂)₁₃CO) -α-Glu) des (B30) The insulin derivative according to paragraph 57, which is human insulin. 74. Insulin derivative is N^εB29-(N^α-(HOOC (CH)₂)₁₆CO) -γ-D-Glu) des (B30) The insulin derivative according to paragraph 57, which is human insulin. 75. Insulin derivative is N^εB29-(N^α-(HOOC (CH)₂)₁₄CO) -β-D-Asp) des (B30) The insulin derivative according to paragraph 57, which is human insulin. 76. N^εB29-(N^α-(HOOC (CH)₂)₁₄CO) -β-D-Asp) des (B30) human insulin. 77. Insulin derivative is N^εB29-(N-HOOC (CH)₂)₁₆CO-β-D-Asp) des (B30) The insulin derivative according to paragraph 57, which is human insulin. 78. Insulin derivative is N^εB29-(N-HOOC (CH)₂)₁₄CO-IDA) des (B30) The insulin derivative according to paragraph 57, which is human insulin. 79. Insulin derivative is N^εB29-[N- (HOOC (CH)₂)₁₆CO) -N- (carboxyethyl) -Gly] des (B30) The insulin derivative according to paragraph 57, which is human insulin. 80. Insulin derivative is N^εB29-[N- (HOOC (CH)₂)₁₄CO) -N- (carboxyethyl) -Gly] des (B30) The insulin derivative according to paragraph 57, which is human insulin. 81. Insulin derivative is N^εB29-[N- (HOOC (CH)₂)₁₄CO) -N- (carboxymethyl) -β-Ala] des (B30) The insulin derivative according to paragraph 57, which is human insulin. 82. The insulin derivative according to any one of paragraphs 33-57, wherein the insulin derivative is in the form of a zinc complex and each insulin hexamer binds to two zinc ions, three zinc ions or four zinc ions. 83. From other symptoms characterized by diabetes mellitus or hyperglycemia, prediabetes, impaired glucose tolerance, metabolic syndrome, obesity, cahexy, in vivo β-cell depletion / death, excess appetite, and inflammation. The insulin derivative according to any one of the preceding paragraphs selected from the group. 84. The insulin derivative according to paragraph 83, wherein the diabetes mellitus is type 1 or type 2 diabetes. 85. The insulin derivative according to paragraph 83, wherein diabetes mellitus is type 2 diabetes in which oral antidiabetic treatment fails. 86. The insulin derivative according to any one of the preceding paragraphs, wherein a naturally occurring insulin, analog or derivative exhibiting a sustained action profile is administered by injection. 87. The insulin derivative according to any one of the preceding paragraphs, wherein the insulin derivative is formulated with a pharmaceutically acceptable carrier and / or vehicle and / or diluent and / or excipient. 88. Pharmaceuticals for the treatment of other symptoms characterized by diabetes mellitus or hyperglycemia, prediabetes, impaired glucose tolerance, metabolic syndrome, obesity, cahexy, in vivo β-cell depletion / death, excess appetite, and inflammation Use of an insulin derivative in the preparation of a composition, wherein the insulin derivative is as described in any one of paragraphs 1-87.

Preparation of insulin, insulin analogs or derivatives thereof A pharmaceutical composition comprising a naturally occurring insulin, an insulin analog, or a naturally occurring derivative of insulin or an insulin analog is referred to herein as an "insulin composition". To carry out the present invention, the insulin composition can be administered parenterally to patients in need of such treatment. Parenteral administration can be performed by subcutaneous, intramuscular or intravenous injection with a syringe, and in some cases a pen-like syringe. Alternatively, parenteral administration can be performed by an infusion pump. A further option is to administer the insulin composition nasally or pulmonary, preferably in a composition, powder or liquid specifically designed for that purpose.

Injectable insulin compositions can be prepared using common techniques of the pharmaceutical industry, including dissolving and mixing the ingredients as needed to obtain the desired final product. Thus, in one procedure, the natural insulin, analog or derivative is dissolved in a slightly smaller amount of water than the final volume of the composition prepared. If necessary, isotonic agents, preservatives and buffers are added, and if necessary, an acid such as hydrochloric acid or a required base such as sodium hydroxide water is used to adjust the pH value of the solution. Finally, the volume of the solution is adjusted with water to obtain the desired concentration of components.

Buffers are typically sodium acetate, sodium carbonate, citrate, glycylglycine, histidine, glycine, lysine, arginine, sodium dihydrogen phosphate, disodium hydrogen phosphate, sodium phosphate, and tris (hydroxy). It is selected from the group consisting of methyl) aminomethane, bicin, tricin, malic acid, succinate, maleic acid, fumaric acid, tartaric acid, aspartic acid or mixtures thereof. Each one of these particular buffers constitutes a useful alternative in embodiments of the present invention.

In a further embodiment of the invention, the formulation is phenol, o-cresol, m-cresol, p-cresol, methyl p-hydroxybenzoate, propyl p-hydroxybenzoate, 2-phenoxyethanol, butyl p-hydroxybenzoate. , 2-Phenylethanol, benzyl alcohol, chlorobutanol, and thiomerosal, bronopol, benzoic acid, imidourea, chlorohexidine, sodium dehydroacetate, chlorocresol, ethyl p-hydroxybenzoate, benzethonium chloride, chlorphenesine ) (3p-Chlorophenoxypropane-1,2-diol) or a mixture thereof further contains a pharmaceutically acceptable preservative that can be selected from the group. In a further embodiment of the invention, the preservative is present in a concentration of 0.1 mg / ml to 20 mg / ml. In a further embodiment of the invention, the preservative is present in a concentration of 0.1 mg / ml to 5 mg / ml. In a further embodiment of the invention, the preservative is present at a concentration of about 5 mg / ml to 10 mg / ml. In a further embodiment of the invention, the preservative is present at a concentration of 10 mg / ml to 20 mg / ml. Each one of these particular preservatives constitutes another embodiment of the invention. The use of preservatives in pharmaceutical compositions is well known to those of skill in the art. For convenience, see Remington: The Science and Practice of Pharmacy, 19th Edition, 1995.

3-Butandiol) Further contains an isotonic agent that can be selected from the group consisting of polyethylene glycol (eg, PEG400), or mixtures thereof. Any sugar, such as monosaccharides, disaccharides or polysaccharides, or water-soluble glucans, such as fructose, glucose, mannose, sorbose, xylose, maltose, lactose, sucrose, trehalose, dextran, purulan, dextrin, cyclodextrin, soluble starch. , Hydroxyethyl starch and carboxymethyl cellulose-Na can also be used. In one embodiment, the sugar additive is sucrose. Sugar alcohols are defined as C4-C8 hydrocarbons with at least one -OH group and include, for example, mannitol, sorbitol, inositol, galactitol, zulcitol, xylitol, and arabitol. In one embodiment, the sugar alcohol additive is mannitol. The sugars or sugar alcohols mentioned above can be used individually or in combination. As long as the sugar or sugar alcohol is soluble in the liquid preparation and does not adversely affect the stabilizing effect achieved using the methods of the invention, there is no fixed limit on the amount used. In one embodiment, the concentration of sugar or sugar alcohol is from about 1 mg / ml to about 150 mg / ml. In a further embodiment of the invention, the tonicity agent is present at a concentration of 1 mg / ml to 50 mg / ml. In a further embodiment of the invention, the tonic is present at a concentration of 1 mg / ml to 7 mg / ml. In a further embodiment of the invention, the tonic is present at a concentration of 8 mg / ml to 24 mg / ml. In a further embodiment of the invention, the tonic is present at a concentration of 25 mg / ml to 50 mg / ml. Each one of these particular isotonic agents constitutes another embodiment of the invention. The use of isotonic agents in pharmaceutical compositions is well known to those of skill in the art. For convenience, see Remington: The Science and Practice of Pharmacy, 19th Edition, 1995.

Suitable isotonic agents are sodium chloride, mannitol, dimethylsulfone and glycerol, and typical preservatives are phenol, m-cresol, methyl p-hydroxybenzoate and benzyl alcohol. Examples of suitable buffers are sodium acetate, glycylglycine, HEPES (4- (2-hydroxyethyl) -1-piperazine ethanesulfonic acid), TRIS (2-amino-2-hydroxymethyl-1,3-propanediol). ) And sodium phosphate.

Compositions for nasal administration can be prepared, for example, as described in European Patent No. 272097 (Novo Nordisk A / S).

Insulin-containing compositions can be used to treat insulin-sensitive conditions. Thus, they can be used to treat type 1 diabetes, type 2 diabetes and hyperglycemia, which is often found in severely ill humans and those who have undergone major surgery. The optimal dose level for any patient is the efficacy of the particular insulin, analog or derivative used, age, weight, physical activity, various factors including the patient's diet, combination with other drugs. It will depend on the likelihood and the severity of the condition being treated. It is recommended that the dosage regimen be determined by one of ordinary skill in the art for each individual patient, as well as known insulin compositions, taking into account this teaching of dosing intervals.

For convenience, the insulin composition can be used in combination with other types of insulin, such as insulin analogues, which exhibit faster onset of action. Examples of such insulin analogues are described in European patent applications with publication numbers EP214826 (Novo Nordisk A / S), EP375437 (Novo Nordisk A / S) and EP383472 (Eli Lilly), for example.

The present invention will be further described by the following examples, which should not be construed as limiting the scope of protection.

Definition As used herein, "insulin analog" is by deleting and / or substituting at least one amino acid residue that occurs in natural insulin and / or by adding at least one amino acid residue. Means a polypeptide having a molecular structure that can be formally derived from the structure of naturally occurring insulin, such as human insulin. The added and / or substituted amino acid residues can be either encoded amino acid residues or other naturally occurring amino acid residues or purely synthetic amino acid residues. Insulin analogs can be such that the 28th position of the B chain can be modified from a native Pro residue to one of Asp, Lys or Ile. In another embodiment, Lys at position B29 is modified to Pro. In one embodiment, B30 can be Lys, in which case B29 can be any coding amino acid other than Cys, Met, Arg and Lys.

Asn at the A21 position is modified to Ala, Gln, Glu, Gly, His, Ile, Leu, Met, Ser, Thr, Trp, Tyr or Val, especially Gly, Ala, Ser, or Thr, preferably Gly. sell. Furthermore, Asn at the B3 position can be modified to Lys or Asp. Further examples of insulin analogs are des (B30) human insulin; des (B30) human insulin analog; insulin analog lacking PheB1; insulin with A and / or B chains having N-terminal elongation. Analogs, and insulin analogs in which the A and / or B chains have C-terminal extensions. Therefore, 1 or 2 Args may be added to the B1 position.

In aspects of the invention, up to 17 amino acids are modified. In aspects of the invention, up to 15 amino acids are modified. In aspects of the invention, up to 10 amino acids are modified. In aspects of the invention, up to 8 amino acids are modified. In aspects of the invention, up to 7 amino acids are modified. In aspects of the invention, up to 6 amino acids are modified. In aspects of the invention, up to 5 amino acids are modified. In aspects of the invention, up to 4 amino acids are modified. In aspects of the invention, up to 3 amino acids are modified. In aspects of the invention, up to 2 amino acids are modified. In aspects of the invention, one amino acid is modified.

The "insulin derivative" used herein is, for example, by introducing a side chain into one or more insulin skeletons, or by oxidizing or reducing a group of amino acid residues in insulin, or by esterifying a free carboxylic acid group. Means a naturally occurring insulin or insulin analog that is chemically modified by conversion to a group or by acylating a free amino or hydroxy group.

DesB30 insulin and desB30 human insulin mean natural insulin lacking a B30 amino acid residue or an analog thereof. Similarly, "desB29desB30 insulin" or "desB29desB30 human insulin" means natural insulin or an analog thereof lacking B29 and B30 amino acid residues.

B1, A1, etc. mean the amino acid residue at the 1-position (counting from the N-terminal) of the insulin B chain and the amino acid residue at the 1-position (counting from the N-terminal) of the insulin A chain, respectively. .. The amino acid residue at a particular position can also be represented, for example, as PheB1, which means that the amino acid residue at position B1 is a phenylalanine residue.

As used herein, "insulin" means human insulin, porcine insulin or bovine insulin that has a disulfide bridge between CysA7 and CysB7, between CysA20 and CysB19, and an internal disulfide bridge between CysA6 and CysA11. To do. "Parent insulin" means naturally occurring insulin, such as human insulin or porcine insulin. Alternatively, the parent insulin can be an insulin analog.

The term "no branding" as used herein refers to the case where both fast-acting insulin and acylated insulin are administered in separate formulations when formulated into one formulation. It means having an action profile that is the same as or substantially the same as the action profile.

The expression "encoding amino acid" or "encoding amino acid residue" is used to indicate an amino acid or amino acid residue that can be encoded by a triplet of nucleotides ("codon"). hGlu is homoglutamic acid. α-Asp is -HNCH (CO-) CH₂It is an L type of COOH. β-Asp is -HNCH (COOH) CH₂It is an L type of CO-. α-Glu is -HNCH (CO-) CH₂CH₂It is an L type of COOH. γ-Glu is -HNCH (COOH) CH₂CH₂It is an L type of CO-. α-hGlu is -HNCH (CO-) CH₂CH₂CH₂It is an L type of COOH. δ-h Glu is -HNCH (COOH) CH₂CH₂CH₂It is an L type of CO-. β-Ala is -NH-CH₂-CH₂-COOH. Sar is sarcosine (N-methylglycine).

The expression "amino acid residue having a carboxylic acid group in the side chain" means an amino acid residue such as Asp, Glu and hGlu. Amino acids can be either L-type or D-type. If nothing is specified, the amino acid residue is understood to be of type L. The expression "amino acid residues with neutral side chains" means amino acid residues such as Gly, Ala, Val, Leu, Ile, Phe, Pro, Ser, Thr, Cys, Met, Tyr, Asn and Gln. ..

When the insulin derivative according to the present invention is described as "soluble at a physiological pH value", it can be used to prepare an injectable insulin composition in which the insulin derivative is sufficiently dissolved at a physiological pH value. Means. Such preferred solubility is due to either the unique properties of the insulin derivative alone, or the result of a preferred interaction of the insulin derivative with one or more components contained in the vehicle.

The following abbreviations were used in the specification and examples: IDA: Iminodiacetic acid Sar: Sarcosine (N-methyl-glycine) Su: succinimidyl = 2,5-dioxo-pyrrolidin-1-yl

The present invention is further summarized in the following paragraphs: 1. Treat symptoms or disorders for which insulin administration is beneficial, including the administration of effective dosages of naturally occurring insulin, insulin analogs, naturally occurring insulin or derivatives of insulin analogs to patients in need thereof. A method in which the naturally occurring insulin, insulin analog, or derivative exhibits a sustained action profile and the dosage is administered at intervals longer than 24 hours. 2. The method of claim 1, wherein the dosage is administered at intervals of at least 36 hours. 3. The method of claim 2, wherein the dosage is administered at intervals of at least 48 hours. 4. The method of claim 3, wherein the dosage is administered at intervals of at least 72 hours. 5. The method of claim 4, wherein the dosage is administered at intervals of at least 96 hours. 6. The method of claim 5, wherein the dosage is administered at intervals of at least 120 hours. 7. The method of claim 6, wherein the dosage is administered at intervals of at least 144 hours. 8. The method of claim 7, wherein the dosage is administered at intervals of at least 168 hours. 9. The method according to any one of the preceding claims, wherein the dosage is administered at a maximum interval of 336 hours. 10. The method according to any one of the preceding claims, wherein the above dosage is administered at a maximum interval of 312 hours. 11. The method according to any one of the preceding claims, wherein the above dosage is administered at a maximum interval of 288 hours. 12. The method according to any one of the preceding claims, wherein the above dosage is administered at a maximum interval of 264 hours. 13. The method according to any one of the preceding claims, wherein the above dosage is administered at a maximum interval of 240 hours. 14. The method according to any one of the preceding claims, wherein the above dosage is administered at a maximum interval of 216 hours. 15. The method according to any one of the preceding claims, wherein the above dosage is administered at a maximum interval of 192 hours. 16. The method according to any one of the preceding claims, wherein the above dosage is administered at a maximum interval of 168 hours. 17. The method according to any one of the preceding claims, wherein the above dosage is administered at regular intervals. 18. The method of claim 17, wherein the dosage is administered every other day. 19. The method of claim 17, wherein the dosage is administered every two days. 20. The method of claim 17, wherein the dosage is administered every three days. 21. The method of claim 17, wherein the dosage is administered every four days. 22. The method of claim 17, wherein the dosage is administered every five days. 23. The method of claim 17, wherein the dosage is administered every 6 days. 24. The method of claim 17, wherein the dosage is administered every 14 days. 25. The method of any one of claims 1-16, wherein the dosage is administered on a fixed weekday. 26. The method of claim 25, wherein the dosage is administered on a fixed 3 week day. 27. The method of claim 25, wherein the dosage is administered on a fixed 2 week day. 28. The method of claim 26 or 27, wherein none of the above fixed weekdays are in close proximity to each other. 29. The method of claim 27, wherein the fixed two weekdays are separated by only two and three other weekdays. 30. Administration of naturally occurring insulin, insulin analogs or derivatives showing a long-acting profile is supplemented by more frequent administration of fast-acting naturally occurring insulin, insulin analogs or derivatives and / or administration of non-insulin antidiabetic agents. The method according to any one of the above claims. 31. The method of any one of claims 1-29, wherein virtually no other naturally occurring insulin, insulin analog or derivative of naturally occurring insulin or insulin analog is administered to the patient. 32. The method of claim 31, wherein the administration of a naturally occurring insulin, insulin analog or derivative exhibiting a sustained action profile is supplemented with administration of a non-insulin antidiabetic drug. 33. The naturally occurring insulin or a derivative of the insulin analog is administered, and the derivative is the α-amino group of the N-terminal amino acid residue of the B chain of the parent insulin or the ε-amino group of the Lys residue present in the B chain. Has a side chain attached to, which side chain has the general formula: -WXYZ [In the above formula, W is The residue is along with one of its carboxylic acid groups, along with the α-amino group of the N-terminal amino acid residue of the B chain of the parent insulin or the ε-amino group of the Lys residue present in the B chain. Α-amino acid residue having a carboxylic acid group in the side chain to form an amide group; -A chain consisting of 2, 3 or 4 α-amino acid residues linked together via an amide bond, and the chain via the amide bond is the N-terminal amino acid residue of the B chain of the parent insulin. It is linked to the α-amino group or the ε-amino group of the Lys residue present in the B chain, and the amino acid residue of W is at least one amino acid residue in which W has a carboxylic acid group in the side chain. To have, it is selected from the group of amino acid residues having a neutral side chain and amino acid residues having a carboxylic acid group in the side chain; -Covalent bond from X to the α-amino group of the N-terminal amino acid residue of the B chain of the parent insulin or the ε-amino group of the Lys residue present in the B chain Is; X is -CO-; -CH (COOH)<u style="single">C</u>O-; -N (CH)₂COOH) CH₂<u style="single">C</u>O-; -N (CH)₂COOH) CH₂CON (CH₂COOH) CH₂<u style="single">C</u>O-; -N (CH)₂CH₂COOH) CH₂CH₂<u style="single">C</u>O-; -N (CH)₂CH₂COOH) CH₂CH₂CON (CH₂CH₂COOH) CH₂CH₂<u style="single">C</u>O-; -NHCH (COOH) (CH₂)₄NH<u style="single">C</u>O-; -N (CH)₂CH₂COOH) CH₂<u style="single">C</u>O-; or -N (CH)₂COOH) CH₂CH₂<u style="single">C</u>O-and a) When W is an amino acid residue or a chain of amino acid residues, it forms an amide bond with an amino group in W through a bond from the underlined carbonyl carbon, or b) When W is a covalent bond, the α-amino group of the N-terminal amino acid residue of the B chain of the parent insulin or the ε- of the Lys residue present in the B chain via the bond from the underlined carbonyl carbon. Form an amide bond with an amino group; Y is · M is an integer in the range 6-32-(CH₂)_m-; 1, 2 or 3 -CH = CH-groups and enough -CH to provide a total number of carbon atoms in the range 10-32 in the chain₂-A divalent hydrocarbon chain containing groups; Expression-(CH₂)_vC₆H₄(CH₂)_W-(In the equation, v and w are integers such that the sum of v and w is in the range of 6 to 30, or one of them is zero). Is; and Z is -COOH; -CO-Asp; -CO-Glu; -CO-Gly; -CO-Sar; -CH (COOH)₂; -N (CH)₂COOH)₂; -SO₃H; or -PO₃H Is] What is and its Zn²⁺The method according to any one of the preceding claims, wherein the complex is a complex, where W is a covalent bond and X is -CO-, then Z is different from -COOH. 34. The method of claim 33, wherein the side chain-WXYZ is attached to the α-amino group of the N-terminal amino acid residue of the B chain of the parent insulin. 35. The method of claim 33, wherein the side chain-WXYZ is attached to the ε-amino group of the Lys residue present in the B chain of the parent insulin. 36. The method of any one of claims 33-35, wherein W is a covalent bond. 37. The method according to any one of claims 33 to 35, wherein W is an α-amino acid residue having 4 to 10 carbon atoms. 38. The method of claim 37, wherein W is selected from the group consisting of α-Asp, β-Asp, α-Glu, γ-Glu, α-hGlu and δ-hGlu. 39. W is a chain consisting of two α-amino acid residues, one having 4 to 10 carbon atoms and a free carboxylic acid group and the other having 2 to 11 carbon atoms but no free carboxylic acid group. The method according to any one of claims 33 to 35. 40. W is α-Asp-Gly; Gly-α-Asp; β-Asp-Gly; Gly-β-Asp; α-Glu-Gly; Gly-α-Glu; γ-Glu-Gly; Gly-γ-Glu 39. The method of claim 39 selected from the group consisting of α-hGlu-Gly; Gly-α-hGlu; δ-hGlu-Gly; and Gly-δ-hGlu. 41. The claim according to any one of claims 33 to 35, wherein W is a chain consisting of two α-amino acid residues having 4 to 10 carbon atoms independently and both having a free carboxylic acid group. Method. 42. W is α-Asp-α-Asp; α-Asp-α-Glu; α-Asp-α-hGlu; α-Asp-β-Asp; α-Asp-γ-Glu; α-Asp-δ-hGlu Β-Asp-α-Asp; β-Asp-α-Glu; β-Asp-α-hGlu; β-Asp-β-Asp; β-Asp-γ-Glu; β-Asp-δ-hGlu; α -Glu-α-Asp; α-Glu-α-Glu; α-Glu-α-hGlu; α-Glu-β-Asp; α-Glu-γ-Glu; α-Glu-δ-hGlu; γ-Glu -α-Asp; γ-Glu-α-Glu; γ-Glu-α-hGlu; γ-Glu-β-Asp; γ-Glu-γ-Glu; γ-Glu-δ-hGlu; α-hGlu-α -Asp; α-hGlu-α-Glu; α-hGlu-α-hGlu; α-hGlu-β-Asp; α-hGlu-γ-Glu; α-hGlu-δ-hGlu; δ-hGlu-α-Asp A claim selected from the group consisting of δ-hGlu-α-Glu; δ-hGlu-α-hGlu; δ-hGlu-β-Asp; δ-hGlu-γ-Glu; and δ-hGlu-δ-hGlu. 41. 43. The method according to any one of claims 33 to 42, wherein X is -CO- or -CH (COOH) CO-. 44. X is -N (CH)₂COOH) CH₂<u style="single">C</u>O-; -N (CH)₂COOH) CH₂CON (CH₂COOH) CH₂<u style="single">C</u>O-; -N (CH)₂CH₂COOH) CH₂CH₂<u style="single">C</u>O-; -N (CH)₂CH₂COOH) CH₂CH₂CON (CH₂CH₂COOH) CH₂CH₂<u style="single">C</u>O- -N (CH)₂CH₂COOH) CH₂<u style="single">C</u>O-; or -N (CH)₂COOH) CH₂CH₂<u style="single">C</u>O- The method according to any one of claims 33 to 43. 45. Y is-(CH₂)_m-The method of any one of claims 33 to 44, wherein m is an integer in the range 6 to 32, 8 to 20, 12 to 20 or 12-16). 46. The method of any one of claims 33-45, wherein Z is -COOH. 47. Z is -CH (COOH)₂The method according to any one of claims 33 to 45. 48. Z is -N (CH)₂COOH)₂The method according to any one of claims 33 to 45. 49. Z is -SO₃The method according to any one of claims 33 to 45, which is H. 50. Z is-PO₃The method according to any one of claims 33 to 45, which is H. 51. The method according to any one of claims 33 to 50, wherein the parent insulin has Asn or Gly at the A21 position. 52. The method of any one of claims 33-50, wherein the parent insulin is a des (B1) analog. 53. The method of any one of claims 33-50, wherein the parent insulin is a des (B30) analog. 54. The method according to any one of claims 33 to 50, wherein the B29 position of the parent insulin is any codeable amino acid except Cys, Met, Arg and Lys, and the amino acid at the B30 position is Lys. 55. The method according to any one of claims 33 to 50, wherein the parent insulin has Thr at the B29 position and Lys at the B30 position. 56. Parent insulin is human insulin; des (B1) human insulin; des (B30) human insulin; Gly^A21Human insulin; Gly^A21des (B30) human insulin; Asp^B28Human insulin; porcine insulin; Lys^B28Pro^B29Human insulin; Gly^A21Arg^B31Arg^B32Human insulin; and Lys^B3Glu^B29The method according to any one of claims 33 to 50, which is selected from the group consisting of human insulin. 57. Insulin derivative is N^εB29-(N^α-(HOOC (CH)₂)₁₄CO) -γ-Glu) des (B30) human insulin; N^εB29-(N^α-(HOOC (CH)₂)₁₅CO) -γ-Glu) des (B30) human insulin; N^εB29-(N^α-(HOOC (CH)₂)₁₆CO) -γ-Glu) des (B30) human insulin; N^εB29-(N^α-(HOOC (CH)₂)₁₇CO) -γ-Glu) des (B30) human insulin; N^εB29-(N^α-(HOOC (CH)₂)₁₈CO) -γ-Glu) des (B30) human insulin; N^εB29-(N^α-(HOOC (CH)₂)₁₆CO) -γ-Glu-N- (γ-Glu)) des (B30) Human insulin; N^εB29-(N^α-(Asp-OC (CH)₂)₁₆CO) -γ-Glu) des (B30) human insulin; N^εB29-(N^α-(Glu-OC (CH)₂)₁₄CO) -γ-Glu) des (B30) human insulin; N^εB29-(N^α-(Glu-OC (CH)₂)₁₄CO-) des (B30) human insulin; N^εB29-(N^α-(Asp-OC (CH)₂)₁₆CO-) des (B30) human insulin; N^εB29-(N^α-(HOOC (CH)₂)₁₆CO) -α-Glu-N- (β-Asp)) des (B30) Human insulin; N^εB29-(N^α-(Gly-OC (CH)₂)₁₃CO) -γ-Glu) des (B30) human insulin; N^εB29-(N^α-(Sar-OC (CH)₂)₁₃CO) -γ-Glu) des (B30) human insulin; N^εB29-(N^α-(HOOC (CH)₂)₁₃CO) -γ-Glu) des (B30) Human insulin; (N^εB29-(N^α-(HOOC (CH)₂)₁₃CO) -β-Asp) des (B30) human insulin; N^εB29-(N^α-(HOOC (CH)₂)₁₃CO) -α-Glu) des (B30) human insulin; N^εB29-(N^α-(HOOC (CH)₂)₁₆CO) -γ-D-Glu) des (B30) human insulin; N^εB29-(N^α-(HOOC (CH)₂)₁₄CO) -β-D-Asp) des (B30) human insulin; N^εB29-(N^α-(HOOC (CH)₂)₁₄CO) -β-D-Asp) des (B30) human insulin; N^εB29-(N-HOOC (CH)₂)₁₆CO-β-D-Asp) des (B30) human insulin; N^εB29-(N-HOOC (CH)₂)₁₄CO-IDA) des (B30) human insulin; N^εB29-[N- (HOOC (CH)₂)₁₆CO) -N- (carboxyethyl) -Gly] des (B30) human insulin; N^εB29-[N- (HOOC (CH)₂)₁₄CO) -N- (carboxyethyl) -Gly] des (B30) human insulin; and N^εB29-[N- (HOOC (CH)₂)₁₄33. The method of claim 33, which is selected from the group consisting of CO) -N- (carboxymethyl) -β-Ala] des (B30) human insulin. 58. Insulin derivative is N^εB29-(N^α-(HOOC (CH)₂)₁₄58. The method of claim 57, which is CO) -γ-Glu) des (B30) human insulin. 59. Insulin derivative is N^εB29-(N^α-(HOOC (CH)₂)₁₅58. The method of claim 57, which is CO) -γ-Glu) des (B30) human insulin. 60. Insulin derivative is N^εB29-(N^α-(HOOC (CH)₂)₁₆58. The method of claim 57, which is CO) -γ-Glu) des (B30) human insulin. 61. Insulin derivative is N^εB29-(N^α-(HOOC (CH)₂)₁₇58. The method of claim 57, which is CO) -γ-Glu) des (B30) human insulin. 62. Insulin derivative is N^εB29-(N^α-(HOOC (CH)₂)₁₈58. The method of claim 57, which is CO) -γ-Glu) des (B30) human insulin. 63. Insulin derivative is N^εB29-(N^α-(HOOC (CH)₂)₁₆58. The method of claim 57, which is CO) -γ-Glu-N- (γ-Glu)) des (B30) human insulin. 64. Insulin derivative is N^εB29-(N^α-(Asp-OC (CH)₂)₁₆58. The method of claim 57, which is CO) -γ-Glu) des (B30) human insulin. 65. Insulin derivative is N^εB29-(N^α-(Glu-OC (CH)₂)₁₄58. The method of claim 57, which is CO) -γ-Glu) des (B30) human insulin. 66. Insulin derivative is N^εB29-(N^α-(Glu-OC (CH)₂)₁₄58. The method of claim 57, which is CO-) des (B30) human insulin. 67. Insulin derivative is N^εB29-(N^α-(Asp-OC (CH)₂)₁₆58. The method of claim 57, which is CO-) des (B30) human insulin. 68. Insulin derivative is N^εB29-(N^α-(HOOC (CH)₂)₁₆58. The method of claim 57, which is CO) -α-Glu-N- (β-Asp)) des (B30) human insulin. 69. Insulin derivative is N^εB29-(N^α-(Gly-OC (CH)₂)₁₃58. The method of claim 57, which is CO) -γ-Glu) des (B30) human insulin. 70. Insulin derivative is N^εB29-(N^α-(Sar-OC (CH)₂)₁₃58. The method of claim 57, which is CO) -γ-Glu) des (B30) human insulin. 71. Insulin derivative is N^εB29-(N^α-(HOOC (CH)₂)₁₃58. The method of claim 57, which is CO) -γ-Glu) des (B30) human insulin. 72. Insulin derivative (N^εB29-(N^α-(HOOC (CH)₂)₁₃58. The method of claim 57, which is CO) -β-Asp) des (B30) human insulin. 73. Insulin derivative is N^εB29-(N^α-(HOOC (CH)₂)₁₃58. The method of claim 57, which is CO) -α-Glu) des (B30) human insulin. 74. Insulin derivative is N^εB29-(N^α-(HOOC (CH)₂)₁₆58. The method of claim 57, which is CO) -γ-D-Glu) des (B30) human insulin. 75. Insulin derivative is N^εB29-(N^α-(HOOC (CH)₂)₁₄58. The method of claim 57, which is CO) -β-D-Asp) des (B30) human insulin. 76. N^εB29-(N^α-(HOOC (CH)₂)₁₄CO) -β-D-Asp) des (B30) human insulin. 77. Insulin derivative is N^εB29-(N-HOOC (CH)₂)₁₆58. The method of claim 57, which is CO-β-D-Asp) des (B30) human insulin. 78. Insulin derivative is N^εB29-(N-HOOC (CH)₂)₁₄The method of claim 57, which is CO-IDA) des (B30) human insulin. 79. Insulin derivative is N^εB29-[N- (HOOC (CH)₂)₁₆58. The method of claim 57, which is CO) -N- (carboxyethyl) -Gly] des (B30) human insulin. 80. Insulin derivative is N^εB29-[N- (HOOC (CH)₂)₁₄58. The method of claim 57, which is CO) -N- (carboxyethyl) -Gly] des (B30) human insulin. 81. Insulin derivative is N^εB29-[N- (HOOC (CH)₂)₁₄58. The method of claim 57, which is CO) -N- (carboxymethyl) -β-Ala] des (B30) human insulin. 82. The method of any one of claims 33-57, wherein the insulin derivative is in the form of a zinc complex and each insulin hexamer binds to two zinc ions, three zinc ions or four zinc ions. 83. From other symptoms characterized by diabetes mellitus or hyperglycemia, prediabetes, impaired glucose tolerance, metabolic syndrome, obesity, cahexy, in vivo β-cell depletion / death, excess appetite, and inflammation. The method according to any one of the preceding claims selected from the group. 84. The method of claim 83, wherein the diabetes mellitus is type 1 or type 2 diabetes. 85. The method of claim 83, wherein the diabetes mellitus is type 2 diabetes in which oral antidiabetic drug treatment fails. 86. The method of any one of the preceding claims, wherein a naturally occurring insulin, analog or derivative exhibiting a sustained action profile is administered by intramuscular injection. 87. The preceding claim, wherein a naturally occurring insulin, insulin analog or derivative is formulated with a pharmaceutically acceptable carrier and / or vehicle and / or diluent and / or excipient. Method. 88. A naturally occurring insulin, insulin analog, or derivative of a naturally occurring insulin or insulin analog used in the method according to any one of the preceding claims. 89. Pharmaceuticals for the treatment of other symptoms characterized by diabetes mellitus or hyperglycemia, pre-diabetes, glucose intolerance, metabolic syndrome, obesity, cahexy, in vivo β-cell depletion / death, excess appetite, and inflammation Use of a naturally occurring insulin, insulin analog, or derivative of a naturally occurring insulin or insulin analog in the preparation of a composition, wherein the treatment is as described in any one of claims 1-87.

The duration of action must be long enough in most patients who use insulin to show the possibility of using insulin less than once daily. Indicators of duration of action in clinical use can be obtained in the normoglycemic clamp test under single-dose experimental conditions (L. Heinemann and JH Anderson-Jr. Measurement of insulin absorption and insulin action. Diabetes Technol Ther 6 (5)). : 698-718, 2004), see Example 1).

In order to study the clinical effects of insulin preparations, clinical trials must be conducted under conditions that represent the mode of use of the present invention. Clinical trials studying compounds for the treatment of diabetes for approval and registration must comply with guidelines provided by local authorities (European guidelines are an example: Note for Guidance on Clinical Investigations). of Medicinal Products in the Treatment of diabetes Mellitus, EMEA, London, 2002).

As an example of an insulin analog with a sufficiently long duration of action, N^εB29-(N^α-(HOOC (CH)₂)₁₄CO) -γ-L-Glu) des (B30) Lys B29 (Nε-hexadecane oil-γ-Glu) des (B30) human insulin corresponding to human insulin (Example 4 of International Publication No. 2005/012347; "LysB29 (Nε-hexadecane oil-γ-Glu) des (B30) human insulin") was studied for its clinical effect after less frequent injections daily.

Example 1 LysB29 (Nε-hexadecane oil-γ-Glu) des (B30) Study of activity profile and duration of action of human insulin<u style="single">Method</u> Randomized to compare the activity profiles of LysB29 (Nε-hexadecane oil-γ-Glu) des (B30) human insulin and insulin glargine (IGlar) in patients with type 1 and type 2 diabetes, respectively. The study was conducted as a single-center, crossover clinical trial for 6 periods of critical blindness. 10.4 nmol / kg LysB29 (Nε-hexadecane oil-γ-Glu) des (B30) human insulin and 7.2 nmol / kg IGlar in patients with type 1 diabetes, or 14.0 nmol / kg in patients with type 2 diabetes Patients were randomized to different rows of single subcutaneous (sc) doses of Lys B29 (Nε-hexadecane oil-γ-Glu) des (B30) human insulin and 9.6 nmol / kg IGlar.

With each medication, glucose and human soluble insulin were given to visiting patients to maintain stable blood glucose levels at 90 mg / dL (5.0 mmol / L) levels for 4-6 hours prior to study drug administration. Received a controlled intravenous infusion of (Actrapid®). That is, the normal blood glucose clamp test was started with a target blood glucose level of 90 mg / dL (5.0 mmol / L). The normoglycemia clamp test was accelerated during the last 30 minutes when blood glucose levels increased above 160 mg / dL (8.9 mmol / L) without glucose infusion, but was terminated 24 hours after dosing.

Patients fasted for a period of 24 to 30 hours after administration of the study drug. During the last 6 hours, if blood glucose dropped to near or below 70 mg / dL (3.9 mmol / L), the patient received one or more oral doses of 10 g of carbohydrates. Serum Lys B29 (Nε-hexadecane oil-γ-Glu) des (B30) human insulin / plasma IGlar and blood samples for blood glucose measurement were taken before and up to 96 hours after dosing. A standard safety assessment was performed.

<u style="single">Number of patients</u> Twenty patients with type 1 diabetes and 18 patients with type 2 diabetes completed the trial.

<u style="single">Diagnostic and key criteria for incorporation</u> Glycosylated blood pigment (HbA) at age 18-69 years (incorporation)_1c) 10%, men with type 1 or type 2 diabetes (12 months), usually treated with insulin (1.2 U / kg / day). Patients with type 1 diabetes are treated with insulin 12 months, 18-27 kg / m²Must have a (incorporated) body mass index (BMI) and &lt;0.3 nmol / L fasting C-peptide. Patients with type 2 diabetes are treated with insulin 3 months and 22-35 kg / m²Must have (incorporation) BMI and &lt;1.0 nmol / L fasting C-peptide.

<u style="single">Test agent, dose and administration mode</u> Lys B29 (Nε-hexadecandioil-γ-Glu) des (B30) human insulin, 1200 nmol / mL, single dose (10.4 nmol / kg for patients with type 1 diabetes and 14.0 nmol / kg for patients with type 2 diabetes), Put 6Zn2 + / 6 LysB29 (Nε-hexadecane oil-γ-Glu) des (B30) human insulin in a 1.5mL cartridge and use the attached needle (29G ×) using a Becton-Dickinson Microfine TM syringe (1000μL). It was injected subcutaneously into the thigh at 12.7 mm).

<u style="single">Treatment period</u> A single single dose of LysB29 (Nε-hexadecane oil-γ-Glu) des (B30) human insulin and IGlar was administered at intervals of 7-2 days at two different times.

<u style="single">Reference treatment method, dose and administration mode</u> Single doses (7.2 nmol / kg for patients with type 1 diabetes and 9.6 nmol / kg for patients with type 2 diabetes) IGlar (Lantus®), 100 IU / mL, 600 nmol / mL in 3.0 mL cartridges , Becton-Dickinson Microfine TM syringe (1000 μL) was used and the attached needle (29 G × 12.7 mm) was used for subcutaneous injection into the thigh.

<u style="single">Evaluation Criteria-Efficacy</u>Pharmacodynamics: --Glucose infusion rate (GIR) during the euglycemic clamp test 24 hours after administration of the study drug. --Blood sugar concentration. --Number of oral carbohydrate doses given 24 to 30 hours after dosing to avoid hypoglycemia. Pharmacokinetics: --LysB29 (Nε-hexadecane oil-γ-Glu) des (B30) human insulin or serum LysB29 (Nε-hexadecane oil-γ-Glu) des (B30) human insulin 96 hours after a single dose of IGlar / Plasma IGlar concentration

<u style="single">Key endpoints:</u>--AUCGIR (0-24 hours), that is, the density of the GIR curve from 0 to 24 hours-Area under the time curve (AUC)

<u style="single">Key secondary endpoints:</u>--Oral Carbohydrate Administration: Number of oral carbohydrate administrations given 24 to 30 hours after dosing to avoid hypoglycemia --Pharmacokinetics (tmax (time to maximum concentration), terminal half-life)

<u style="single">Population statistics of clinical trial population</u> Twenty male patients with type 1 diabetes and 20 male patients with type 2 diabetes averaged 37 and 56 years, with average weights of 74 kg and 93 kg, and average HbA1c of 7.9% and 7.7%, respectively. He had an average diabetic duration of 21 and 14 years.

<u style="single">Key results</u>--AUC GIR (0-24 hours) of LysB29 (Nε-hexadecane oil-γ-Glu) des (B30) human insulin exerts total insulin action, as significant levels of GIR were still present at the end of the clamp test. I didn't capture it. GIR levels at 24 hours were approximately 3.5 and 2.5 mg / kg / min for both type 1 and type 2, respectively. --Average GIRmax is higher for IGlar than for LysB29 (Nε-hexadecane oil-γ-Glu) des (B30) human insulin (4.1 and 3.1 mg / kg / min) in both types 1 and 2. It was high (5.6 and 4.2 mg / kg / min). --The mean GIR time to GIRmax was not clearly different between the type 1 and type 2 populations and was higher than for IGlar (11 to 13 hours) LysB29 (Nε-hexadecane oil-γ-Glu) des ( B30) Longer than human insulin (13 to 20 hours). --- The average number of oral carbohydrate doses required to maintain blood glucose above 70 mg / dL (3.9 mmol / L) during the first 6 hours after the normoglycemic clamp test was IGlar (6.8) for types 1 and 2, respectively. And 4.2) appeared to be higher for Lys B29 (Nε-hexadecane oil-γ-Glu) des (B30) human insulin (7.6 and 8.3). --Average t_maxWas significantly longer for LysB29 (Nε-hexadecane oil-γ-Glu) des (B30) human insulin (19-26 hours) than for IGlar (11-13 hours). --The average terminal half-life is 18 to 19 hours for LysB29 (Nε-hexadecane oil-γ-Glu) des (B30) human insulin and 13 to 25 hours for IGlar, patients with type 1 diabetes. There was no difference between LysB29 (Nε-hexadecane oil-γ-Glu) des (B30) human insulin and IGlar in patients with type 2 diabetes.

<u style="single">Key safety results</u> In general, single doses of LysB29 (Nε-hexadecane oil-γ-Glu) des (B30) human insulin and IGlar, respectively, were well tolerated in patients with type 1 and type 2 diabetes.

<u style="single">Key conclusions</u> LysB29 (Nε-hexadecane oil-γ-Glu) des (B30) human insulin has GIR profile characteristics (slow and low GIRmax and substantial activity present at the end of the clamp test) and 24-hour normoglycemia compared to IGlar. A more delayed action profile and a longer duration, supported by the number of carbohydrate doses required to maintain blood glucose above 70 mg / dL (3.9 mmol / L) in the first 6 hours after the end of the clamp study. It seemed to have an effect. Conclusions based on activity data (pharmacodynamics) are supported by pharmacokinetic data.

Example 2 Study of clinical effects of LysB29 (Nε-hexadecane oil-γ-Glu) des (B30) human insulin administered on Monday, Wednesday and Friday

<u style="single">Key methodological elements and results</u> LysB29 (Nε-) for the treatment of type 2 diabetic patients who have failed oral antidiabetic drug (OAD) treatment, all in combination with metformin, three times a week (Monday, Wednesday, Friday) Hexadecane oil-γ-Glu) des (B30) A clinical trial was designed to evaluate the feasibility, efficacy, safety and tolerability of human insulin. LysB29 (Nε-hexadecane oil-γ-Glu) des (B30) human insulin (900 nmol / L concentration) was studied. LysB29 (Nε-hexadecane oil-γ-Glu) des (B30) Due to the long duration of action (&gt; 24 hours) of human insulin, it was assumed that the combination with metformin could adequately control patients with three weekly injections. ..

<u style="single">Main purpose</u> LysB29 (Nε-hexadecane oil-γ-Glu) des (B30) three times a week (Monday, Wednesday, Friday) in combination with metformin in patients with type 2 diabetes who have failed insulin treatment and who have failed OAD treatment. To assess glucose control over HbA1c after 16 weeks of treatment with human insulin or with insulin glargine once daily.

<u style="single">Materials and methods</u> The trial was conducted in patients who had previously been treated with one or two oral antidiabetic agents: metformin, SU (or other insulin-promoting substances such as repaglinide, nateglinide), and α-glucosidase inhibitors. .. At the beginning of the induction period, all patients discontinued their current diabetes treatment and took a one-week maintenance period after starting a two-week dose increase in metformin. Randomized, patients were given metformin three times weekly with basal insulin LysB29 (Nε-hexadecane oil-γ-Glu) des (B30) human insulin or with insulin glargine once daily.

Average age 54 years, average diabetes period 6.9 years, 29.5 kg / m²Average BMI, 10.2 mmol / L average FPG, and 8.7% average HbA_1cLysB29 (Nε-hexadecandioil-γ-Glu) des (B30) human insulin (Nε-hexadecandioil-γ-Glu) des (B30) once daily for a 16-week treatment period in all 124 patients with type 2 diabetes, both in combination with metformin. 900 nmol / mL) (62 patients) or insulin glargine (62 patients) once daily.

<u style="single">Results of efficacy</u>HbA_1c Treatment group average HbA from baseline to end of treatment_1cThe changes were similar (Tables 1 and 2).<img file="JP4959005B2_D0001.tif" /><img file="JP4959005B2_D0002.tif" />

<u style="single">Hypoglycemia</u> For both treatment arms, more than 50% of patients did not report the development of hypoglycemic symptoms. See Table 3. Only one major hypoglycemic event was reported during the trial.

<img file="JP4959005B2_D0003.tif" />

<u style="single">Insulin dose</u><img file="JP4959005B2_D0004.tif" />

<u style="single">Conclusion</u> LysB29 (Nε-hexadecane oil-γ-Glu) des (B30) human insulin three times a week (Monday, Wednesday, Friday) in combination with metformin in patients with type 2 diabetes who have failed insulin treatment with OAD treatment The results of 16-week treatment with metformin achieved glycemic control comparable to that observed for insulin glargine given once daily in combination with metformin.

Example 3 Steady state clamp-LysB29 (Nε-hexadecane oil-γ-Glu) des (B30) Study of activity profile and duration of action of human insulin.<u style="single">Method</u> Randomized, double-blind, single-center, 2-period study to compare the activity profiles of LysB29 (Nε-hexadecane oil-γ-Glu) des (B30) human insulin and insulin glargine (IGlar) in patients with type 1 diabetes The study was conducted as a crossover clinical trial. Patients were randomized to different rows of daily doses of Lys B29 (Nε-hexadecane oil-γ-Glu) des (B30) human insulin and subcutaneous (sc) multiple doses of IGlar. The doses were 0.57 U / kg or 0.85 U / kg LysB29 (Nε-hexadecane oil-γ-Glu) des (B30) human insulin, and 0.4 U / kg or 0.6 U / kg IGlar. Patients were treated for 8 days for each dosing period. There was a 10-20 day washout period between the two dosing periods.

On the last day of each dosing period, patients were given glucose and human solubility to maintain stable blood glucose levels at 100 mg / dL (5.5 mmol / L) levels for 8-4 hours prior to study drug administration. He received a controlled intravenous infusion of type insulin (Actrapid®). That is, the normal blood glucose clamp test was started with a target blood glucose level of 100 mg / dL (5.5 mmol / L). The normoglycemia clamp test was accelerated during the last 30 minutes when blood glucose levels increased above 200 mg / dL (11.1 mmol / L) without glucose infusion, but was terminated 42 hours after dosing. Serum Lys B29 (Nε-hexadecane oil-γ-Glu) des (B30) human insulin / plasma IGlar and blood samples for blood glucose measurement were taken before and up to 146 hours after dosing. A standard safety assessment was performed.

<u style="single">Number of patients</u> Twenty-one patients completed the trial.

<u style="single">Diagnostic and key criteria for incorporation</u> Glycosylated blood pigment (HbA) at age 18-69 years (incorporation)_1c) 10%, male or female patients with type 1 diabetes (12 months), usually treated with insulin (1.2 U / kg / day). Patients are treated with insulin 12 months, 18-28 kg / m²Must have a (incorporated) body mass index (BMI) and &lt;0.3 nmol / L fasting C-peptide.

<u style="single">Test agent, dose and administration mode</u> Multiple doses of 0.57 U / kg or 0.85 U / kg LysB29 (Nε-hexadecane oil-γ-Glu) des (B30) human insulin, 600 nmol / ml, LysB29 (Nε-hexadecane oil-γ-Glu) des ( B30) Human insulin was placed in a 3 ml FlexPen® (100 DU / ml) cartridge and a NovoFine® 30 G, 8 mm needle was used.

<u style="single">Treatment period</u> Multiple doses of LysB29 (Nε-hexadecane oil-γ-Glu) des (B30) human insulin and IGlar, followed by 8 days (possibly +1-5 days) at intervals of 10-20 days, two different It was administered using the dosing period.

<u style="single">Reference treatment method, dose and administration mode</u> Multiple doses (0.4 U / lg or 0.6 U / kg) of IGlar (Lantus®), 100 IU / mL, 600 nmol / mL were placed in a 3.0 mL 3 mL Optiset® cartridge and PenFine® 31 G. , 8 mm was used for subcutaneous injection into the thigh.

<u style="single">Evaluation Criteria-Efficacy</u>Pharmacodynamics: --Glucose infusion rate (GIR) during the 42-hour normoglycemia clamp test between the 8th and last dosing day. --Blood sugar concentration. Pharmacokinetics: --LysB29 (Nε-hexadecane oil-γ-Glu) des (B30) human insulin or plasma LysB29 (Nε-hexadecane oil-γ-Glu) des (B30) human insulin 144 hours after a single dose of IGlar / Plasma IGlar concentration

<u style="single">Key endpoints:</u>--AUCGIR (0-24 hours), that is, the density of the GIR curve from 0 to 24 hours-Area under the time curve (AUC)

<u style="single">Key secondary endpoints:</u>--Blood glucose level during the normal blood glucose level clamp period --Pharmacokinetics (tmax, terminal half-life)

<u style="single">Population statistics of clinical trial population</u> Thirty-five male and seven female patients with type 1 diabetes each had an average age of 40 years, an average weight of 75 kg, an average HbA1c of 7.8%, and they had an average duration of diabetes of 21 years.

<u style="single">Key results</u>AUC GIR (0-24 hours) of LysB29 (Nε-hexadecane oil-γ-Glu) des (B30) human insulin has total insulin action, as significant levels of GIR were still present at 24 hours. Did not capture. GIR levels at 24 hours were approximately 2.0 and 3.0 mg / kg / min after low and high doses, respectively. Correspondence values for insulin glargine were approximately 0.8 and 1.8 mg / kg / min. --Average GIRmax for IGlar after the highest dose than for LysB29 (Nε-hexadecane oil-γ-Glu) des (B30) human insulin (4.68 and 4.02 mg / kg / min, respectively) It was high (5.6 and 4.2 mg / kg / min), but GIRmax was equal (3.07 mg / kg / min) after the low dose. --- Average GIR time to GIRmax is LysB29 (Nε-hexadecane oil-γ-Glu) des (B30) human insulin (lower) than for IGlar (5.0 hours and 4.1 hours for low and high doses, respectively) It was longer for 13.2 hours and 6.1 hours) for dose and high dose, respectively. --The mean trough vs. peak range was lower for LysB29 (Nε-hexadecane oil-γ-Glu) des (B30) human insulin than after insulin glargine. Values were 1.0 and 0.7 mg / kg / min, respectively, after low and high doses. For insulin glargine, the corresponding values were 1.6 and 1.1 mg / kg / min. --- The mean time to loss of glucose control was longer for LysB29 (Nε-hexadecane oil-γ-Glu) des (B30) human insulin than for glargine at both dose levels. It occurs approximately 40 hours after low LysB29 (Nε-hexadecane oil-γ-Glu) des (B30) human insulin dose and is high LysB29 (Nε-hexadecane oil-γ-Glu) des (B30) human. No significant loss of glucose control (defined as increased glycemic activity above 10 mg / dl) was observed at 42 hours after insulin dose. After insulin glargine administration, loss of glucose control occurred approximately 24 and 26 hours after low and high doses, respectively. --- The average time to maximum concentration (Cmax) was shorter for insulin glargine than for LysB29 (Nε-hexadecane oil-γ-Glu) des (B30) human insulin. After medium and high doses, respectively, for insulin glargine, the values were 7.2 and 6.4 hours, and for LysB29 (Nε-hexadecane oil-γ-Glu) des (B30) human insulin, the values were 9.2 and 10.1 hours. --Average terminal half-life is 25.2 hours (95% CI 23 to 28 hours) for LysB29 (Nε-hexadecane oil-γ-Glu) des (B30) human insulin and 13.9 hours (95%) for IGlar. It was CI 13 to 15).

<u style="single">Key safety results</u> In general, multiple doses of LysB29 (Nε-hexadecane oil-γ-Glu) des (B30) human insulin and IGlar were well tolerated in patients with type 1 diabetes, respectively.

<u style="single">Key conclusions</u> LysB29 (Nε-hexadecane oil-γ-Glu) des (B30) human insulin has a flatter and more lasting effect compared to IGlar, as evidenced by the GIR profile properties shown in Figure 1. It appeared to have a profile and a longer duration of action. The figure shows that LysB29 (Nε-hexadecane oil-γ-Glu) des (B30) human insulin has a lower GIRmax at comparable doses and a longer time to GIRmax at both dose levels, less. It shows that it has a trough vs. peak range. The duration of action of LysB29 (Nε-hexadecane oil-γ-Glu) des (B30) human insulin under current circumstances is approximately 40 hours or more, as seen in FIG. 2, which is LysB29. (Nε-Hexadecane oil-γ-Glu) des (B30) Shows that human insulin has the ability to control blood glucose over a longer period of time. Conclusions based on activity data (pharmacodynamics) are supported by pharmacokinetic data (time to longer Cmax and longer terminal half-life).

Example 4 Study of clinical effect of LysB29 (Nε-hexadecane oil-γ-Glu) des (B30) human insulin administered three times a week. The incidence of hypoglycemia and the incidence of hypoglycemia in two different treatment regimens (once daily and three times weekly) for LysB29 (Nε-hexadecandioil-γ-Glu) des (B30) human insulin 200 U / ml in patients with type 1 diabetes. A clinical trial evaluating glycemia variability.

<u style="single">Key methodological elements and results</u> A clinical trial to evaluate the feasibility, efficacy, safety and tolerability of LysB29 (Nε-hexadecane oil-γ-Glu) des (B30) human insulin for the treatment of patients with type 1 diabetes three times a week Designed. The trial was a single-center, double-blind, crossover trial with two in-hospital treatment periods, each consisting of 9 days. Lys B29 (Nε-hexadecane oil-γ-Glu) des (B30) human insulin (1200 nmol / L concentration = 200 U / ml)) was investigated. Due to the long duration of action (&gt; 24 hours) of LysB29 (Nε-hexadecane oil-γ-Glu) des (B30) human insulin, it was hypothesized that patients could be well controlled with three weekly injections.

<u style="single">Main purpose</u>To evaluate the applicability of LysB29 (Nε-hexadecane oil-γ-Glu) des (B30) human insulin three times a week in terms of glycemic volatility in patients with type 1 diabetes. This is done by comparing the number of hypoglycemic interventions during weekly treatment with LysB29 (Nε-hexadecane oil-γ-Glu) des (B30) human insulin once daily and three times weekly. ..

<u style="single">Materials and methods</u> The trial was conducted in insulin-treated patients with type 1 diabetes (pre-trial&gt; 12 months) 12 months after diagnosis. Patients were randomized to one of two possible treatment lines in which LysB29 (Nε-hexadecane oil-γ-Glu) des (B30) human insulin was injected three times weekly and once daily. The two in-hospital treatment periods were separated by a 5-9 day washout period. The daily dose of LysB29 (Nε-hexadecane oil-γ-Glu) des (B30) human insulin was determined by the individual dose used at the time of entry into the trial and fixed during the trial. When using LysB29 (Nε-hexadecane oil-γ-Glu) des (B30) human insulin three times a week, the dose per injection is one-third of the weekly dose obtained during the daily use. there were. Lys B29 (Nε-hexadecane oil-γ-Glu) des (B30) Treatment with human insulin was supplemented with insulin aspart (Novorapid®) for dietary insulin coverage.

Participant plasma glucose levels were regularly measured by a self-monitoring procedure. If hypoglycemia was detected (plasma glucose 71 mg / dl), investigators intervened with carbohydrate intake until plasma glucose was stabilized above 71 mg / dl again. The clinical trial flow is shown in Figure 3. Average age 43 years, average diabetes period 18 years, 26 kg / m²Average BMI, and 8.3% average HbA_1cA total of 18 male patients were randomized to each treatment line (1: 1).

<u style="single">Key results</u>Hypoglycemic event<img file="JP4959005B2_D0005.tif" />

<u style="single">Plasma glucose</u> Fasting plasma glucose was similar after treatment three times weekly and once daily, at 8.05 and 7.33 mM, respectively.

<u style="single">Insulin dose</u> The total daily bolus insulin dose was similar after treatment three times weekly and once daily, at 27.4 and 26.3 U, respectively. The daily total bolus dose during the three weekly treatments was higher than the daily period, at 41.8 and 30.3%, respectively.

<u style="single">Conclusion</u> In patients with type 1 diabetes, 7-day fixed-dose treatment with basal insulin LysB29 (Nε-hexadecandioil-γ-Glu) des (B30) human insulin three times weekly is planned to be a fixed-dose injection once daily. There was no significant difference in the total number of hypoglycemic events when compared to. Fasting plasma glucose and dietary insulin doses (bolus doses) were similar during the two treatment periods, but large fluctuations of 11.5% in the total daily bolus dose were observed during the treatment period three times a week. This high variation is likely caused by the need for compensatory insulin due to the difference in basal insulin coverage between the two treatment regimens. Overall, this trial shows that the use of LysB29 (Nε-hexadecane oil-γ-Glu) des (B30) human insulin three times weekly can be performed in patients with type 1 diabetes.

All documents cited herein, including publications, patent applications and patents, are sourced in their entirety, as if each document was individually and specifically incorporated by source. The entire content is explicitly incorporated herein by reference (the maximum range permitted by law). All titles and subtitles are used herein for convenience and should by no means be construed as limiting the invention. The use of any and all examples, or exemplary languages (eg, "etc.") provided herein is merely intended to further articulate the present invention and unless otherwise stated in the invention. It does not limit the scope of the invention. It should not be construed that any phrase in the specification does not indicate that an element not described in the claims is essential for the practice of the present invention. The citations and references of patent documents herein are for convenience only and do not reflect views on the validity, patentability, and / or exercise of such patent documents. The present invention, where permitted by applicable law, includes all modifications and equivalents of the subject matter set forth in the claims attached herein.