KR20160073383A - Pharmaceutical composition - Google Patents

Abstract

The present invention includes readily dissociable molecular aggregates formed by combining insulin, insulin analogs, derivatives or metabolites having an isoelectric point of 5.8 to 8.5 with one or more insulin, insulin analogs, derivatives or metabolites having an isoelectric point of 4.0 to 5.7 ≪ / RTI >

Description

[0001] PHARMACEUTICAL COMPOSITION [0002]

Invention field

The present invention is also directed to a pharmaceutical composition comprising an insulin analogue, derivative or metabolite having an isoelectric point between 4.0 and 5.7, optionally in combination with one or more excipients, and an insulin analogue, derivative or metabolite having an isoelectric point between 5.8 and 8.5, , And a readily dissociable molecular aggregate, wherein the molecular aggregate has an average particle size of about 5 [mu] m to about 20 [mu] m. The present invention also provides processes for the preparation of biphasic preparations and uses thereof in the treatment of diabetic disorders.

BACKGROUND OF THE INVENTION

Glucose is a monosaccharide that is used by all cells of the body to produce energy and support life. Humans always need a minimum level of glucose in their blood to survive. The primary way in which the body produces blood glucose is through the digestion of food. When humans do not get enough glucose from food digestion, glucose is produced from the tissue reservoir and released by the liver. Glucose levels in the body are preferentially regulated by insulin. Insulin is a peptide hormone secreted naturally by the pancreas. Insulin helps glucose enter the body's cells and provide an essential source of energy.

Diabetes is a disease characterized by abnormally high levels of blood glucose and insufficient levels of insulin. Diabetes is a common term for disorders in humans with excessive urinary excretion as diabetes mellitus and diabetes insipidus. Diabetes mellitus (DM) is a major chronic disease found in humans with many consequences. Some complications from long-term diabetes are blindness, kidney failure, and limb amputation. Insulin-dependent diabetes mellitus (IDDM) accounts for 10 to 15% of all cases of diabetes mellitus.

Insulin injections are prescribed to patients suffering from diabetes. Insulin is a natural hormone that regulates glucose levels in the blood. In healthy humans, insulin is released into the blood by the pancreas as the blood glucose concentration increases. Blood glucose levels are increased after meals and the elevated levels are rapidly abolished by the corresponding increase in insulin secretion. Insulin plays a major role in converting excess blood glucose to glycogen and storing it in the liver.

Since the introduction of insulin in the 1920s, progress has been made to improve the treatment of diabetes mellitus. To help avoid extreme blood glucose levels, people with diabetes often live multiple injections and thus receive insulin along with each meal.

Insulin is a polypeptide of 51 amino acids, divided into two amino acid chains: the A chain with 21 amino acids and the B chain with 30 amino acids. The chains are connected to each other by two disulfide bridges. Insulin preparations have been used for diabetes therapy for many years.

Traditionally, short-acting regular insulin preparations or their interim insulin protamine formulations have been used to treat patients with diabetes mellitus. Over time, new insulin analogs and derivatives have been developed. Insulin analogues and derivatives differ from human insulin at one or more amino acid positions and / or amino acid chain length.

Numerous insulin, insulin analogs and derivatives are commercially available. Commonly used types of insulin, insulin analogs or insulin derivatives are classified as follows:

Rapid-acting insulin analogs ( bolus ): for example, insulin aspirate (Novolog ^® ); Insulin lispro (Humalog ^® ), insulin glucurin (Aprida ^® ), fast acting human insulin (Viaject ^® ). These analogs start to act within 5 to 15 minutes of administration and are active for 3 to 4 hours.

Short-acting insulin (Russ Ball): For ^(® Humulin ^® or Novolin) For Regular insulin. Regular insulin starts to work within 30 minutes after administration and duration of action lasts about 5 to 8 hours.

Intermediate-acting insulins: eg insulin insulin, aspartate protamine, lispro protamine. The action starts within 1 to 3 hours after administration. The duration of its action varies from 16 hours to 24 hours.

Persistent-acting insulin (basal): for example, insulin glargine and insulin detemir. Both of these analogs start to work within 1-2 hours and their duration of action varies from about 12 hours to about 24 hours.

Mixed insulin: a mixture of NPH and regular insulin, for example. There are many variations with different ratios of mixed insulin. The onset of action of these mixed preparations is about 30 minutes. Mixed insulin contains the same type of insulin. Two different types of insulins can not be mixed, i. E. Insulin lispro can not be mixed with insulin dimer, insulin aspirate or insulin glargine. Mixed formulations of insulin lispro may include only two forms of insulin lispro: insulin lispro regular and insulin lispro protamine.

Insulin analogues with accelerated onset of action are described in EP0214826, EP0375437 and EP0678522. EP0124826 relates, inter alia, to the substitution of B27 and B28. EP0678522 discloses, at position B29, an insulin analog having various amino acids, preferably proline, but not glutamic acid.

EP0375437 includes an insulin analog having lysine or arginine at B28, which may optionally be further modified at B3 and / or A21. EP0419504 discloses an insulin analogue that is protected from chemical modification, wherein the asparagine at B3 and at least one additional amino acid at position A5, A15, A18 or A21 is modified. WO 92/00321 discloses insulin analogues in which at least one amino acid in positions B1-B6 is replaced by lysine or arginine. According to WO 92/00321, this type of insulin has an extended action.

Ideally, the exogenous insulin is administered at the time and dose to obtain the plasma profile, which mimics the plasma profile of normal endogenous insulin. Commercially available insulin preparations of insulin for insulin replacement have a different origin and composition of insulin (e.g., bovine, porcine, human insulin, or other mammalian or animal insulin), and thus the profile of action The duration of action) may be affected. Plasma profiles of endogenous insulin can be obtained by a combination of various insulin preparations. The manufacture of naturally occurring insulins and the production of insulin derivatives or insulin analogs that exhibit altered kinetics have been on the market for some time. Generally, basal insulin is provided with bolus insulin to mimic the normal endogenous plasma profile of insulin and to provide better control of postprandial levels.

There are two types of basal insulin available on the market - insulin glargine and insulin ditermine. Insulin Gly (A21) -Arg (B31) -Arg (B32) -human insulin, basal insulin has an extended period of action. It is injected once daily and is distinguished by its reduced serum profile and its associated nocturnal hypoglycemia risk compared to other sustained-acting insulins (Schubert-Zsilavecz et al., 2: 125-130 (2001)).

It is marketed by Sanofi Aventis under the trade name Lantus. Lantus is injected as an acidic clear solution and is stable hexamer adduct, sinking due to its solution properties in the physiological pH range of subcutaneous tissue. Two formulations of Lantus are available in the market:

3ml cartridge composition

● 10ml vial composition

The 3 ml cartridge composition comprises 100 IU (3.6378 mg) insulin glargine, zinc, m-cresol, glycerol, and water for injection. The pH of the composition is adjusted to pH 4.0. The 10 ml vial composition comprises 100 IU insulin glargine, zinc, m-cresol, glycerol, and distilled water for injection. The pH of the composition is adjusted to pH 4.0 by addition of hydrochloric acid and an aqueous solution of sodium hydroxide.

Fast acting insulin includes insulin lispro, insulin aspartate and insulin glucurin. Fast acting insulin begins to work very quickly, that is, within 30 minutes of administration. Therefore, they are used to efficiently control postprandial levels. These analogs are used to treat type 1 (insulin-dependent) diabetes and type 2 (non-insulin-dependent) diabetes. Insulin aspartate is primarily provided with another persistent-acting insulin.

Commercially available compositions of NovoLog < RTI ID = 0.0 > Insulin aspartate, glycerin, phenol, metacresol, zinc, disodium hydrogen phosphate dihydrate, sodium chloride and distilled water for injection. The pH of the composition is adjusted to pH 7.2 to 7.6.

Commercially available compositions of Humalog® include 100 IU insulin lispro, glycerin, dibasic sodium phosphate, metacresol, zinc oxide, phenol, and distilled water for injection. The pH of the composition is adjusted at pH 7.0-8.0.

Commercially available compositions of Aprida (R) include 100 IU of insulin glucurin, metacresol, tromethamine, sodium chloride, polysorbate 20, and distilled water for injection. The pH of the composition is adjusted to pH 7.3.

Novo Nordisk prepared a soluble co-formulation of sustained basal insulin, insulin degludec and fast acting insulin analog, insulin aspirate (B28Asp human insulin). Ryzodeg is the first complete dissolution ready to use insulin products for subcutaneous (sc) injection.

Basal-bolus insulin therapy, provided as multiple daily injections or as an insulin pump, is the mainstay of diabetes therapy to achieve optimal blood glucose control in type 1 diabetes. Attempts have been made to mix different types of insulin in one shot to reduce the number of injections to be administered to a patient per day. A number of warnings have been raised about the intermixing of sustained- and fast-acting insulin by transfusions of fast acting insulin and basal insulin (insulin glargine, Lantus; sanofi-aventis; Sanofi- aventis, available from http://www.lantus.com/hcp/closing.aspx; origin of insulin ditermine rDNA, product name Levemir drug description; Novo Nordisk, Bagsvaerd, Denmark).

Despite the warning from the manufacturer of insulin preparations, some patients and pediatricians blended basal insulin and bolus insulin in one syringe just before the injection. The reason for this warning is that when insulin at different isoelectric points (pI) is mixed in the syringe, it causes uncontrolled sedimentation and it is difficult to predict the time and exact capacity of the sedimented mixture.

Known fast acting insulin analogs and unmodified insulins have a pI of 5-5.5 and thus the formulations containing them in solution form are within the baseline range of 7.0 to 8.0 while the pI of insulin glargine is 6.5 and therefore the formulation of Lantus Is within the acid range, i.e., pH 3.8-4.2. Glazin can not be mixed with any other kind of insulin, such as short acting or rapid acting insulin, because the pI of glazine is different from other insulin analogs or derivatives. No prior art discloses stable formulations comprising combinations of insulin with different isoelectric points, including readily dissociable molecular aggregates of limited particle size.

There are a number of prior art disclosing the combination / mixing of a pharmaceutical composition comprising a combination and a fast acting insulin analog and basal insulin.

Kaplan W et al. (2004) The effect of mixing short-acting insulin analogs with glazine on glucose regulation. The authors concluded that mixing Lisp or aspirant insulin and glazine in the same syringe and dividing the glazine dose or dosing the dose twice daily does not affect the short-term blood glucose profile. (Diabetes Care 2004 Nov; 27 (11): 2739-40)

Fiallo-Scharer R et al. (2006) demonstrated that there was no significant difference in glycemic control between children with insulin glargine and fast acting cis-syn analogs in the same syringe compared to children receiving separate injections. (J Pediatr 2006 Apr; 148 (4): 481-4.)

Hassan K et al. (2008) discloses that glucose control to insulin glargine mixed with fast-acting insulin analogs, which is twice daily, appears to be significantly more effective than standard therapy in newly diagnosed type 1 diabetes. Moreover, by allowing the patient to mix the rapid-acting insulin analog and glazine, it reduces pain and the burden of injection in children with diabetes. (Pediatrics 2008; 121: e466-e472.)

Evans et al. (2011), it is not appropriate to mix either insulin glargine or insulin ditermir with other insulin analogues, since it is because these mixtures substantially alter their pharmacokinetic properties.

Nicolacci, (2011) Antonio et al. Disclose the optimization of basal insulin glargine using one bolus injection of insulin glulisine provided separately (Diabetes Care (2011), 34 (12), 2524-2526)

Al Shamsi A. M et. al. (2008) found that glucose control to insulin glargine (IG) mixed with fast-acting insulin analogs twice daily is significantly more effective than standard therapy in newly diagnosed type 1 diabetes do. (Pediatrics. 2008 Sep; 122 (3): 675-6; author reply 676)

Cengiz E et. al. (2010) reported that mixing insulin glazin with insulin lispro significantly reduced the initial pharmacodynamic peak of lispro and the glucose uptake rate (GIR) curve change, which may cause difficulty in controlling the meal-related glucose excursion To the right. ≪ RTI ID = 0.0 > (Diabetes Care 2010; 33: 1009-1012.)

Lucchesi Mb et al. (2012) reported that mixing insulin glycine and insulin lispro directly prior to subcutaneous injection reduced serum peak concentrations in insulin lisp without affecting blood glucose profiles after 12 weeks in this group with type 1 diabetes mellitus do. (Dib SA.2012 Nov; 13 (7): 519-24. Doi: 10.1111 / j.1399-5448.2012.00867)

Thanh M. N. et. al. (2010) compared insulin insulin and insulin aspirate as twice-daily injections in children with type 1 diabetes, compared with insulin aspirate, which is given twice daily, insulin dimyrmide is equivalent to blood glucose ≪ / RTI > (Diabetes Care 2010 August; 33 (8): 1750-1752.)

Cengiz E et. al. (2012) discloses that mixing insulin ditamir with insulin aspart significantly lowers the initial pharmacodynamic action of insulin aspartate and prolongs its time-action profile compared to separate injections of these analogues. (Diabetes Care. 2012 Apr; 35 (4): 690-2)

U.S. Patent Nos. 7,713,929 and 7,718,609 disclose compositions comprising fast or intermediate insulin in combination with sustained insulin, wherein the pH of the composition is adjusted to a pH of 3.8 to 4.2 to solubilize the sustained insulin do.

U.S. Patent No. 8,084,420 discloses injectable formulations containing fast acting, fast acting or very fast acting insulin, including chelators and solubilizers, in combination with intermediate insulin in a form suitable for subcutaneous administration. The patent discloses that Lantus ™ (insulin glargine) is mixed with Viaject ™ (fast acting insulin) and that the compatibility of these agents is due to the pH similarity of the Lantus and Viaject compositions. The '420 patent discloses that when administered to a patient, such a composition, Lantus ™, had a shorter duration of action when presented in a single shot with Viaject ™.

U.S. Patent Application No. 20130065826 discloses a pharmaceutical composition comprising at least a) a basal insulin, the isoelectric point of its pI being 5.8 to 8.5; And b) a composition in the form of an injectable aqueous solution comprising a modified dextran polymer, the pH of which is 6.0 to 8.0. The composition may additionally comprise meal insulin.

PCT Publication Nos. 2009021956A1 and 2009021955A1 disclose pharmaceutical compositions comprising a novel fast acting insulin analog in a mixture with a sustained insulin analog. Mixing with persistent insulin analogues is accomplished through the substitution of Zn-linked His with Ile, Val, Ala or Phe at position B-10 of human insulin.

PCT Publication No. 2007041481 initiates the injection of insulin glazin with a dose equivalent to the daily use of the subject's basal insulin mixed with VIAJECT ™.

PCT Publication No. 2011094632 discloses that in various embodiments, one or more of the insulin analogues comprises a combination with a sustained-acting insulin analogue in combination with a fast-acting insulin analog.

Any prior art optionally comprises an easily dissociable molecular aggregate formed by combining, with one or more excipients, one or more insulin analogs or derivatives having an isoelectric point of 4.0 to 5.7 with an insulin analog or derivative having an isoelectric point of 5.8 to 8.5. Ready-to-use premixed two-phase pharmaceutical composition, wherein the particle agglomerate has an average particle size of about 5 [mu] m to about 20 [mu] m. The formulation does not contain any chemical modifications to the insulin chain to make two compatible insulins. Insulin glargine has an isoelectric point (pI) at pH 6.8.

Thus, insulin glargine is dissolved at acidic pH and precipitated at neutral pH. On the other hand, all other fast acting, short acting or intermediate insulin remains isozymes at pH 5.5-5.8 and solubilized at neutral pH. Thus, it is a challenge for the formulator to prepare a pharmaceutical composition in which the active agent has a different pi. In addition, insulin is known to be a very sensitive molecule, where small changes in the formulation can cause profound changes in surface morphology and molecular structure, which can alter formulation activity. Thus, there is a need for a pharmaceutical composition which can be mixed with insulin with different isoelectric points to have a stable and biologically available preparation, wherein the release can be controlled and defined.

SUMMARY OF THE INVENTION

As used herein, the term "easily dissociable molecular aggregate " refers to loosely bound molecular aggregates that dissociate directly into individual particles upon shaking the formulation or in vivo administration of the agent.

As used herein, the term "fast acting or short acting insulin" is rapidly absorbed within < 30 min after injection compared to regular human insulin and takes a short time of 1 h to peak insulin concentration and 3-4 h Of insulin with a shorter duration of action.

As used herein, the term "intermediate insulin" refers to the type of insulin that begins to lower blood glucose within 1 to 2 hours after injection and has its strongest effect at 6 to 12 hours.

As used herein, the term "pharmaceutical composition" is intended to encompass a mixture comprising a therapeutic compound to be administered to a mammal, such as a human, in order to prevent, treat or control a particular disease or disorder affecting the mammal .

As used herein, the term "buffer" refers to a solution containing a weak acid and its salt or a weak base and its salt, which is resistant to pH changes.

As used herein, "preservative" refers to a compound that can be used to prevent the growth of fungi and other microorganisms.

As used herein, an "isotonic agent" refers to a compound that is physiologically tolerated and provides the formulation with a tonicity suitable for preventing net flow of water across the cell membrane in contact with the agent. Quot;

As used herein, "pH modifier" refers to a combination of acid and alkali.

As used herein, "solubilizing agent" refers to a material that is capable of solubilizing or partially solubilizing therapeutic compounds and / or polymers.

As used herein, "chelator" refers to a ligand capable of forming a chelate with a metal atom.

As used herein, "acidifying agent" refers to a species that donates a proton or hydrogen ion and / or accepts an electron.

As used herein, "lack of chelator" means that the chelator is present at a concentration of less than 0.01% w / v of the final formulation.

As used herein, "oxidizing agent deficient" means that the oxidizing agent is present at a concentration of less than 0.01% w / v of the final formulation.

As used herein, "dextran-deficient" means that the dextran polymer is not present in the formulation.

One aspect of the present invention is a method for the treatment of insulin, insulin analogs, derivatives or metabolites having an isoelectric point of from 5.8 to 8.5 with one or more insulins, insulin analogues, derivatives or metabolites having an isoelectric point of 4.0 to 5.7, optionally with one or more excipients Water, wherein the molecular aggregate has an average particle size of about 5 [mu] m to about 20 [mu] m.

Another aspect of the present invention provides a method for treating Type I and Type II diabetes mellitus in a patient, which method comprises, optionally in combination with one or more excipients, one or more insulin with an isoelectric point between 4.0 and 5.7, Comprising administering to said patient a pharmaceutical composition comprising an easily dissociable molecular aggregate formed by combining an insulin, insulin analog, derivative or metabolite having an isoelectric point of from 5.8 to 8.5 with an analog, derivative, or metabolite thereof, Wherein the molecular aggregate has an average particle size of from about 5 [mu] m to about 20 [mu] m.

Another aspect of the invention provides a method of prolonging the duration of sustained insulin action in the treatment of Type I and Type II diabetes mellitus in a patient, said method optionally comprising administering a therapeutically effective amount of A pharmaceutical composition comprising an easily dissociable molecular aggregate formed by combining at least one insulin, insulin analog, derivative or metabolite having an isoelectric point with an insulin, insulin analogue, derivative or metabolite having an isoelectric point of 5.8 to 8.5, Wherein the molecular aggregate has an average particle size of from about 5 [mu] m to about 20 [mu] m.

Another aspect of the present invention provides a method of reducing nocturnal hypoglycemia in a patient suffering from Type I and Type II diabetes mellitus, said method optionally further comprising administering to said patient one or more excipients with an isoelectric point between 4.0 and 5.7, Comprising administering to said patient a pharmaceutical composition comprising an easily dissociable molecular aggregate formed by combining insulin, insulin analogs, derivatives or metabolites thereof having an isoelectric point of from 5.8 to 8.5 with an insulin, insulin analog, derivative or metabolite Wherein the molecular aggregate has an average particle size of about 5 [mu] m to about 20 [mu] m.

Another aspect of the present invention provides a method for obtaining a flattened insulin serum concentration versus time profile in a patient, the method optionally including, in combination with one or more excipients, one or more insulin with an isoelectric point between 4.0 and 5.7, Comprising administering to a patient in need thereof a pharmaceutical composition comprising an easily dissociable molecular aggregate formed by combining an insulin, insulin analog, derivative or metabolite having an isoelectric point of from 5.8 to 8.5 with a derivative or metabolite , Wherein the molecular aggregate has an average particle size of about 5 [mu] m to about 20 [mu] m.

Another aspect of the invention is a method for the treatment of insulin, insulin analogs, derivatives or metabolites having an isoelectric point of from 5.8 to 8.5 with one or more insulins, insulin analogues, derivatives or metabolites having an isoelectric point of 4.0 to 5.7, optionally with one or more excipients Wherein the molecular aggregate has an average particle size of from about 5 [mu] m to about 20 [mu] m, the process comprising: (a) preparing a pharmaceutical composition comprising an easily dissociable molecular aggregate formed by combining

a) preparing a pharmaceutical composition comprising 100 IU-1000 IU of an insulin analog or derivative having an isoelectric point of 5.8 to 8.5, wherein the pH of the composition is 3.0-4.5,

b) preparing a pharmaceutical composition comprising at least one 100 IU-1000 IU immediate-acting, short-acting or intermediate insulin, wherein the pH of the composition is 6.0-8.0,

c) a composition of insulin, insulin analogue, derivative or metabolite composition having an isoelectric point of 5.8 to 8.5 of step a), such that the final pH of the composition is between pH 6.5-8.0, with a rapid acting, short acting or intermediate insulin composition of step b) &Lt; / RTI &gt;

One aspect of the invention is directed to a pharmaceutical composition comprising one or more insulins, insulin analogs, derivatives or metabolites having an isoelectric point of from 4.0 to 5.7, one or more stabilizers and an isoelectric point of from 5.8 to 8.5, optionally in combination with one or more excipients or combinations thereof Wherein the molecular aggregate has an average particle size of about 5 [mu] m to about 20 [mu] m, wherein the molecular aggregate has an average particle size of about 5 [mu] m to about 20 [mu] m.

DETAILED DESCRIPTION OF THE INVENTION

In developing a formulation comprising a combination of other insulin analogs and insulin glargine, the inventors of the present application have found that when the insulin glargine is made into one or more fast acting, short acting or intermediate insulin, wherein the pH of the composition is from 6.0 to 8.0 Lt; / RTI &gt; It was surprisingly found that the resulting formulation is stable. This formulation is easy to make and easy to use. In addition, the content uniformity of the formulation can be achieved by simultaneously mixing two different formulations at the filling time. This formulation produces an anti-diabetic effect over an extended period of time, i.e. over 24 hours. The present invention has the effect of an extended period of time.

One aspect of the invention is a pharmaceutical composition comprising, in combination with one or more excipients or combinations thereof, one or more insulin, an insulin analogue, derivative or metabolite having an isoelectric point of 4.0 to 5.7 and an insulin having an isoelectric point of 5.8 to 8.5, , Derivative or metabolite thereof, wherein the molecular aggregate has an average particle size of from about 5 [mu] m to about 20 [mu] m and the pH of the composition is from 3.0 to 8.0 and adjusted to pH.

One aspect of the present invention is a method for the treatment of insulin, insulin analogs, derivatives or metabolites having an isoelectric point of from 5.8 to 8.5 with one or more insulins, insulin analogues, derivatives or metabolites having an isoelectric point of 4.0 to 5.7, optionally with one or more excipients Water, wherein the molecular aggregate has an average particle size of from about 5 [mu] m to about 20 [mu] m and the pH of the composition is adjusted to a pH of from 6.0 to 8.0 .

One aspect of the invention is a pharmaceutical composition comprising, together with optionally one or more excipients, at least one 100 IU to 1000 IU of insulin, insulin analogue, derivative or metabolite having an isoelectric point of 4.0 to 5.7 and 100 IU To 1000 IU of an insulin, insulin analog, derivative or metabolite, wherein the molecular aggregate has an average particle size of from about 5 [mu] m to about 20 [mu] m.

One or more insulin, insulin analogs, derivatives or metabolites are present in a concentration range of 40 IU to 1000 IU per ml.

According to the present invention, one or more insulin analogues or derivatives having an isoelectric point of 4.0 to 5.7 are selected from the group consisting of recombinant human insulin, insulin NPH, insulin lispro, insulin lispro protamine, insulin glutinine and insulin aspartate, insulin aspartot protamine, A21 Gly insulin, A21Gly B28Lys insulin , A21Gly B28Lys B29Pro, A21Gly B28Asp or Viaject (fast acting insulin).

An insulin analog or derivative having an isoelectric point of 4.0 to 5.7 is insulin aspartate.

An insulin analog or derivative having an isoelectric point of 4.0 to 5.7 is A21 Gly insulin.

One or more insulin, insulin analogs, derivatives or metabolites having an isoelectric point of from 5.8 to 8.5 include insulin glargine or A21Gly B31Arg insulin.

The at least one insulin, insulin analog, derivative or metabolite having an isoelectric point of from 5.8 to 8.5 is insulin glargine.

The composition of the present invention is a two-phase composition.

One aspect of the invention is a pharmaceutical composition comprising, together with optionally one or more excipients, at least one 100 IU to 1000 IU of insulin, insulin analogue, derivative or metabolite having an isoelectric point of 4.0 to 5.7 and 100 IU To 1000 IU of an insulin, insulin analog, derivative or metabolite, wherein the molecular aggregate has an average particle size of about 5 [mu] m to about 20 [mu] m, The pH is 6.0 to 8.0.

One aspect of the invention is a pharmaceutical composition comprising, together with optionally one or more excipients, at least one 100 IU to 1000 IU of insulin, insulin analogue, derivative or metabolite having an isoelectric point of 4.0 to 5.7 and 100 IU To 1000 IU of an insulin, insulin analog, derivative or metabolite, wherein the molecular aggregate has an average particle size of about 5 [mu] m to about 20 [mu] m, The pH is 6.5 to 7.5.

One aspect of the invention is a method for the treatment of one or more insulins, insulin analogues, derivatives &lt; RTI ID = 0.0 &gt; (I) &lt; / RTI &gt; having an isoelectric point of 4.0 to 5.7 selected from the group consisting of insulin aspirate, insulin lispro, insulin glulisine or A21 Gly insulin, Or an easily dissociable molecular aggregate formed by combining a metabolite and insulin glargine, said molecular aggregate having an average particle size of about 5 [mu] m to about 20 [mu] m.

Another aspect of the invention is a method for the treatment or prophylaxis of one or more insulin, insulin analogues, derivatives or analogs thereof having an isoelectric point of 4.0 to 5.7, selected from the group consisting of insulin aspirate, insulin lispro, insulin glulisine or A21 Gly insulin, A pharmaceutical composition comprising an easily dissociable molecular aggregate formed by combining a metabolite and insulin glargine, wherein the molecular aggregate has an average particle size of about 5 [mu] m to about 20 [mu] m.

Yet another aspect of the present invention provides a pharmaceutical composition comprising a readily dissociable molecular aggregate formed by combining insulin aspirate and insulin glargine, wherein the molecular aggregate has an average particle size of about 5 [mu] m to about 20 [mu] m.

Yet another aspect of the present invention provides a pharmaceutical composition comprising a readily dissociable molecular aggregate formed by combining A21Gly insulin and insulin glargine, wherein the molecular aggregate has an average particle size of about 5 [mu] m to about 20 [mu] m.

Yet another aspect of the present invention relates to a pharmaceutical composition comprising an easily dissociable molecular aggregate formed by combining 100 IU to 1000 IU of insulin aspartate and 100 IU to 1000 IU of insulin glazine, And an average particle size of from about 5 [mu] m to about 20 [mu] m.

Yet another aspect of the present invention relates to a pharmaceutical composition comprising an easily dissociable molecular aggregate formed by combining 100 IU to 1000 IU of insulin lispro and 100 IU to 1000 IU of insulin glazine, And an average particle size of from about 5 [mu] m to about 20 [mu] m.

Yet another aspect of the present invention relates to a pharmaceutical composition comprising an easily dissociable molecular aggregate formed by combining 100 IU to 1000 IU of insulin glulisine and 100 IU to 1000 IU of insulin glazine, And has an average particle size of about 5 [mu] m to about 20 [mu] m.

Yet another aspect of the present invention relates to a pharmaceutical composition comprising an easily dissociable molecular aggregate formed by combining 100 IU to 1000 IU of A21Gly insulin and 100 IU to 1000 IU of insulin glazine, And an average particle size of from about 5 [mu] m to about 20 [mu] m.

One aspect of the invention is a pharmaceutical composition comprising, together with optionally one or more excipients, at least one 100 IU to 1000 IU of insulin, insulin analogue, derivative or metabolite having an isoelectric point of 4.0 to 5.7 and 100 IU To 1000 IU of an insulin, insulin analog, derivative or metabolite, wherein the molecular aggregate has an average particle size of about 5 [mu] m to about 20 [mu] m, wherein the composition Is adjusted to a pH of 6.0 to 8.0.

Insulin analogs, insulin analogues, derivatives or metabolites of 100 IU-1000 IU with an isoelectric point of 5.8 to 8.5 in 1 ml and insulin, insulin analogs, derivatives or metabolites of 100 IU-1000 IU with an isoelectric point of 4.0 to 5.7 in 1 ml, Derivatives or metabolites have been developed. Thus, the total amount of insulin, insulin analog, derivative or metabolite having an isoelectric point of 5.8 to 8.5 and insulin analogue, derivative or metabolite having an isoelectric point of 4.0 to 5.7 in the formulation is 200 to 1000 IU / ml. Insulin analogs, derivatives or metabolites having an isoelectric point of 5.8 to 8.5 in a single vial having a reduced volume for injection and a combination of insulin, insulin analogues, derivatives or metabolites having an isoelectric point of 4.0 to 5.7 , The formulation requires fewer injections per day. This increases patient compliance.

One aspect of the invention is a pharmaceutical composition comprising, together with optionally one or more excipients, at least one 100 IU to 1000 IU of insulin, insulin analogue, derivative or metabolite having an isoelectric point of 4.0 to 5.7 and 100 IU To 1000 IU of an insulin, insulin analog, derivative or metabolite, wherein the molecular aggregate has an average particle size of about 5 [mu] m to about 20 [mu] m, wherein the composition Is adjusted to a pH of 6.8 to 7.2.

An insulin, insulin analog, derivative or metabolite having an isoelectric point of 5.8 to 8.5 and at least one insulin, insulin analogue, derivative or metabolite having an isoelectric point of 4.0 to 5.7 is present in the pharmaceutical composition in a ratio of 1:99 to 99: 1 do.

One aspect of the invention is a pharmaceutical composition comprising, together with optionally one or more excipients, at least one 100 IU to 1000 IU of insulin, insulin analogue, derivative or metabolite having an isoelectric point of 4.0 to 5.7 and 100 IU To 1000 IU of an insulin, insulin analog, derivative or metabolite, wherein the molecular aggregate has an average particle size of about 5 [mu] m to about 20 [mu] m, wherein the composition There is no chelator.

Suitable chelates as used herein include, but are not limited to, ethylenediaminetetraacetic acid (EDTA), citric acid, dimercaprol (BAL), penicillamine, alginic acid, chlorella, cilantro, alpha lipoic acid, dimercaptosuccinic acid (DMSA) Dimercaptopropane sulfonate (DMPS), and oxalic acid.

One aspect of the invention is a pharmaceutical composition comprising, together with optionally one or more excipients, at least one 100 IU to 1000 IU of insulin, insulin analogue, derivative or metabolite having an isoelectric point of 4.0 to 5.7 and 100 IU To 1000 IU of an insulin, insulin analog, derivative or metabolite, wherein the molecular aggregate has an average particle size of about 5 [mu] m to about 20 [mu] m, wherein the composition The oxidizing agent is lacking.

Suitable oxidizing agents include, but are not limited to, those agents in solid particulate form, such as formic acid, ascorbic acid, aspartic acid, benzenesulfonic acid, benzoic acid, hydrochloric acid, sulfuric acid, phosphoric acid, nitric acid, tartaric acid, diatribosonic acid, glutamic acid, lactic acid, malic acid, , Citric acid or anhydrous citric acid.

One aspect of the invention is a pharmaceutical composition comprising, together with optionally one or more excipients, at least one 100 IU to 1000 IU of insulin, insulin analogue, derivative or metabolite having an isoelectric point of 4.0 to 5.7 and 100 IU To 1000 IU of an insulin, insulin analog, derivative or metabolite, wherein the molecular aggregate has an average particle size of about 5 [mu] m to about 20 [mu] m, wherein the composition Lt; / RTI &gt; lacks dextran polymer.

Dextran polymer refers to the dextran polymer claimed in U.S. Patent Application 20130065826, which is incorporated herein.

One aspect of the present invention provides a method for obtaining a flattened insulin serum concentration versus time profile in a patient, the method comprising, optionally with one or more excipients, one or more insulin with an isoelectric point of 4.0 to 5.7, , A derivative or metabolite thereof and an easily dissociable molecular aggregate formed by combining an insulin, an insulin analog, a derivative or a metabolite having an isoelectric point of 5.8 to 8.5, to a patient in need thereof , Wherein the molecular aggregate has an average particle size of about 5 [mu] m to about 20 [mu] m, and the composition is administered via the subcutaneous, intramuscular, or intravenous route.

Another aspect of the present invention provides a method for obtaining a flattened insulin serum concentration versus time profile in a patient, the method optionally including, in combination with one or more excipients, one or more insulin with an isoelectric point between 4.0 and 5.7, Comprising administering to a patient in need thereof a pharmaceutical composition comprising an easily dissociable molecular aggregate formed by combining an insulin, insulin analogue, derivative or metabolite having an isoelectric point of from 5.8 to 8.5 with an insulin analog, derivative or metabolite, Wherein the molecular aggregate has an average particle size of about 5 [mu] m to about 20 [mu] m and the composition is administered subcutaneously.

The pharmaceutical composition of the present invention is a liquid or lyophilized preparation.

The pharmaceutical compositions of the invention are for oral, mucosal, nasal or parenteral administration.

The pharmaceutical composition of the present invention is for parenteral administration.

The pharmaceutical compositions of the invention are administered as subcutaneous or intravenous infusion or intravenous infusion.

In one aspect of the present invention there is provided a pharmaceutical composition comprising, in combination with one or more excipients, one or more insulin, an insulin analogue, derivative or metabolite having an isoelectric point of 4.0 to 5.7 and an insulin, insulin analogue, derivative or metabolite There is provided a pharmaceutical composition comprising an easily dissociable molecular aggregate formed by combining water, wherein the molecular aggregate has an average particle size of from about 5 [mu] m to about 20 [mu] m and the excipient is an isotonic agent, a surfactant, a buffer, Salts, preservatives, pH modifiers, stabilizers, solubilizing agents, and combinations of the above-mentioned excipients.

In one aspect of the present invention, there is provided a pharmaceutical composition comprising, in combination with one or more excipients, one or more insulin, insulin analogs, derivatives or metabolites of 100 IU to 1000 IU having an isoelectric point of 4.0 to 5.7 and 100 IU - 1000 IU of insulin, insulin analogs, derivatives or metabolites, wherein the molecular aggregates have an average particle size of about 5 [mu] m to about 20 [mu] m, wherein the excipient Is selected from the group consisting of isotonic agents, surfactants, buffers, zinc or its salts, preservatives, pH modifiers, stabilizers and solubilizers.

Excipients include, but are not limited to, isotonic agents, surfactants, buffers, zinc or its salts, preservatives, pH modifiers, solubilizers, stabilizers, and combinations thereof.

"Isotonic" is a compound commonly used for this purpose at known concentrations, such as glycerin. Other potential isotopes include salts, such as sodium chloride, dextrose, or lactose.

&Quot; Surfactant "as used herein refers to a portion of polyhydric alcohols such as glycerol, sorbitol, and fatty acid esters and ethers (Span ^® , Tween ^® , especially Tween ^® 20 and Tween ^® 80, Myrj ^® , Brij ^® , Cremophore ^® Or Poloxamer, Pluronics ^® and Tetronics ^® ), Polysorbate (Tween ™), Sodium Dodecyl Sulfate (Sodium Lauryl Sulfate), Lauryl Dimethylamine Oxide, Cetyltrimethylammonium Bromide (CTAB), Polyethoxylated Alcohol Polyethylene Sorbitan, Triton X100 ™, N, N-dimethyldodecylamine-N-oxide, hexadecyltrimethylammonium bromide (HTAB), polyoxyl 10 lauryl ether, Brij 721 ™, (Cholamophor ™), nonylphenol ethoxylate (Tergitol ™), cyclodextrin, lecithin, and methylbenzethonium chloride (Hyamine ™). It includes, but is not limited to this.

As used herein, a "buffer" refers to a phosphate, acetate, citrate, arginine, glycylglycine or TRIS (i.e., 2-amino-2-hydroxymethyl-l, 3- propanediol) But are not limited thereto.

"Preservative ", as used herein, refers to benzoic acid, butylparaben, ethylparaben, methylparaben, propylparaben, sodium benzoate, sodium propionate, benzalkonium chloride, benzethonium chloride, benzyl alcohol, But are not limited to, sodium chloride, chloro butanol, phenol, phenylethyl alcohol, 2-phenoxyethanol, phenylmercuric nitrate, thimerosal, metacresol or combinations thereof.

As used herein, a "pH modifier" refers to a pH modifier consisting of o-phosphoric acid, citric acid, acetic acid, succinic acid, lactic acid, gluconic acid, tartaric acid, 1,2,3,4-butanetetracarboxylic acid, fumaric acid or malic acid Can be selected from the group. The alkali is selected from the group consisting of sodium hydroxide, potassium hydroxide, sodium hydroxide, ammonium hydroxide, magnesium oxide, calcium hydroxide, calcium carbonate, magnesium carbonate, magnesium aluminum silicate, diethanolamine, monoethanol Amine, sodium carbonate, sodium bicarbonate or triethanolamine.

As used herein, "antioxidants" include ascorbate (sodium / acid), bisulfite sodium, butylated hydroxyanisole (bha), butylated hydroxytoluene (bht), cysteine / , Dithionite sodium (na hydrolysulfate, na sulfoxylate), gentisic acid, gentisic acid ethanolamine, glutamate monosodium, glutathione, formaldehyde sulfoxylate sodium, methasulfite potassium, metabisulfite sodium, May be selected from the group consisting of methionine, monothioglycerol (thioglycerol), propyl gallate, sulfite sodium, tocopherol alpha, alpha tocopherol hydrogensuccinate, thioglycolate sodium or combinations thereof.

As used herein, "solubilizing agent" includes humectants such as polysorbates and poloxamers, non-ionic and ionic surfactants, food acids and bases (such as sodium bicarbonate), polyhydric alcohols and alcohols, But is not limited thereto.

"Stabilizer " as used herein includes, but is not limited to, surfactants, antioxidants, preservatives, solubilizers, esterase inhibitors and combinations thereof. Stabilizers include polyhydric alcohols such as glycerol, sorbitol and the like and fatty acid esters and ethers (Span ^® , Tween ^® , especially Tween ^® 20 and Tween ^® 80, Myrj ^® , Brij ^® , Cremophore ^® or Poloxamer, Pluronics ^® and Tetronics ^® ), Polysorbates (Tween ™), sodium dodecyl sulfate (sodium lauryl sulfate), lauryldimethylamine oxide, cetyltrimethylammonium bromide (CTAB), polyethoxylated alcohol polyethylene sorbitan, Triton X100 (Sodium deoxycholate, sodium cholate), polyoxyethylenediamine, polyoxyethylenediaminetetraamine, polyoxyethyleneglycol ethers, polyoxyethyleneglycol ethers, polyoxyethylene Such as castor oil, castor oil, cremophor, nonylphenol ethoxylate, cyclodextrin, lecithin, and methyl benzethonium chloride, But are not limited to, parabens, propylparaben, sodium benzoate, sodium propionate, benzalkonium chloride, benzethonium chloride, benzyl alcohol, cetaphyridinium chloride, chlorobutanol, phenol, phenylethyl alcohol, Butylated hydroxyanisole (BHA), butylated hydroxytoluene (BHT), cysteine / cysteinate HCl &lt; RTI ID = 0.0 &gt; , Sodium dithionite (sodium hydrosulfite, sodium sulfoxylate), gentisic acid, gentisic acid ethanolamine, glutamate monosodium, glutathione, formaldehyde sulfoxylate sodium, methasulfite potassium, metabisulfite sodium, Methionine, monothioglycerol (thioglycerol), propyl gallate, sodium sulfite, tocopherol alpha, alpha tocopherol hydrogensuccinate, Thioglycolate sodium, an esterase inhibitor, such as a pancreatic secretion inhibitor, a protease inhibitor, and a serine esterase inhibitor, such as aprotinin.

Another aspect of the present invention provides a method for treating Type I and Type II diabetes mellitus in a patient, the method comprising, optionally in combination with one or more excipients, one or more insulin with an isoelectric point between 4.0 and 5.7, , A derivative or metabolite thereof, and an easily dissociable molecular aggregate formed by combining an insulin, an insulin analog, a derivative or a metabolite having an isoelectric point of 5.8 to 8.5, Molecular aggregates have an average particle size of about 5 [mu] m to about 20 [mu] m, and the compositions are premixed two-phase formulations for immediate use.

Another aspect of the present invention provides a method for treating Type I and Type II diabetes mellitus in a patient, the method comprising, optionally in combination with one or more excipients, one or more insulin with an isoelectric point between 4.0 and 5.7, , A derivative or metabolite thereof, and an easily dissociable molecular aggregate formed by combining an insulin, an insulin analog, a derivative or a metabolite having an isoelectric point of 5.8 to 8.5, The molecular aggregate has an average particle size of about 5 [mu] m to about 20 [mu] m and the pH of the composition is adjusted to a pH of 6.5 to 8.0.

Another aspect of the invention provides a method for treating Type I and Type II diabetes mellitus in a patient, wherein the method optionally comprises administering one or more 100 IU-1000 with an isoelectric point between 4.0 and 5.7, A pharmaceutical composition comprising a readily dissociable molecular aggregate formed by combining an insulin, insulin analog, derivative or metabolite of IU with an insulin, insulin analogue, derivative or metabolite of 100 IU-1000 IU having an isoelectric point of 5.8 to 8.5 Wherein the molecular aggregate has an average particle size of from about 5 [mu] m to about 20 [mu] m and the pH of the composition is adjusted to a pH of from 6.5 to 8.0.

Another aspect of the invention provides a method of prolonging the duration of sustained insulin action in the treatment of Type I and Type II diabetes mellitus in a patient, said method optionally comprising administering a therapeutically effective amount of Insulin analogs, derivatives or metabolites of one or more 100 IU-1000 IU having an isoelectric point and 100 IU-1000 IU insulin analogs, derivatives or metabolites having an isoelectric point of 5.8 to 8.5, Comprising administering to said patient a pharmaceutical composition comprising a possible molecular aggregate, wherein said molecular aggregate has an average particle size of from about 5 [mu] m to about 20 [mu] m.

Another aspect of the invention provides a method of prolonging the duration of sustained insulin action in the treatment of Type I and Type II diabetes mellitus in a patient, said method optionally comprising administering a therapeutically effective amount of Insulin analogs, derivatives or metabolites of one or more 100 IU-1000 IU having an isoelectric point and 100 IU-1000 IU insulin analogs, derivatives or metabolites having an isoelectric point of 5.8 to 8.5, Comprising administering to said patient a pharmaceutical composition comprising a possible molecular aggregate, wherein said molecular aggregate has an average particle size of from about 5 [mu] m to about 20 [mu] m and a pH of from 6.0 to 8.0.

In one aspect of the present invention there is provided a pharmaceutical composition comprising, in combination with one or more excipients, one or more insulin, an insulin analogue, derivative or metabolite having an isoelectric point of 4.0 to 5.7 and an insulin, insulin analogue, derivative or metabolite There is provided a process for preparing a pharmaceutical composition comprising an easily dissociable molecular aggregate formed by combining water wherein the molecular aggregate has an average particle size of from about 5 [mu] m to about 20 [mu] m, the process comprising :

a) preparing a pharmaceutical composition comprising 100 IU-1000 IU of insulin glargine, wherein the pH of the composition is 3.0-4.5,

b) preparing a pharmaceutical composition comprising at least one 100 IU-1000 IU immediate-acting, short-acting or intermediate insulin, wherein the pH of the composition is 6.0-8.0,

c) mixing the insulin glargine composition of step a) with the composition of the fast acting, short acting or intermediate insulin of step b) so that the final pH of the composition is between pH 6.5-8.0.

In one aspect of the present invention there is provided a pharmaceutical composition comprising, in combination with one or more excipients, one or more insulin, an insulin analogue, derivative or metabolite having an isoelectric point of 4.0 to 5.7 and an insulin, insulin analogue, derivative or metabolite There is provided a process for preparing a pharmaceutical composition comprising an easily dissociable molecular aggregate formed by combining water wherein the molecular aggregate has an average particle size of from about 5 [mu] m to about 20 [mu] m, the process comprising :

a) preparing a pharmaceutical composition comprising 100 IU-1000 IU of insulin glargine, wherein the pH of the composition is 3.0-4.5,

b) preparing a pharmaceutical composition comprising at least one 100 IU-1000 IU immediate-acting, short-acting or intermediate insulin, wherein the pH of the composition is 6.0-8.0,

c) simultaneously mixing the insulin glazin composition of step a) with the composition of the fast acting, short acting or intermediate insulin of step b) into the vial or cartridge so that the final pH of the composition is between pH 6.5-8.0.

In one aspect of the present invention there is provided a pharmaceutical composition comprising, in combination with one or more excipients, one or more insulin, an insulin analogue, derivative or metabolite having an isoelectric point of 4.0 to 5.7 and an insulin, insulin analogue, derivative or metabolite There is provided a process for preparing a pharmaceutical composition comprising an easily dissociable molecular aggregate formed by combining water wherein the molecular aggregate has an average particle size of from about 5 [mu] m to about 20 [mu] m, the process comprising :

a) preparing a pharmaceutical composition comprising 100 IU-1000 IU of insulin glargine, wherein the pH of the composition is 3.0-4.5,

b) preparing a pharmaceutical composition comprising at least one 100 IU-1000 IU immediate-acting, short-acting or intermediate insulin, wherein the pH of the composition is 6.0-8.0,

c) adding the insulin glazin composition of step a) to the vial,

d) adding a composition of the fast acting, short-acting or intermediate insulin of step b) to the vial of step c) containing the insulin glazin composition of step a) so that the final pH of the composition is between pH 6.5-8.0.

In one aspect of the present invention there is provided a pharmaceutical composition comprising, in combination with one or more excipients, one or more insulin, an insulin analogue, derivative or metabolite having an isoelectric point of 4.0 to 5.7 and an insulin, insulin analogue, derivative or metabolite There is provided a process for preparing a pharmaceutical composition comprising an easily dissociable molecular aggregate formed by combining water wherein the molecular aggregate has an average particle size of from about 5 [mu] m to about 20 [mu] m, the process comprising :

a) preparing a pharmaceutical composition comprising 100 IU-1000 IU of insulin glargine, wherein the pH of the composition is 3.0-4.5,

b) preparing a pharmaceutical composition comprising at least one 100 IU-1000 IU immediate-acting, short-acting or intermediate insulin, wherein the pH of the composition is 6.0-8.0,

c) mixing the insulin glazin composition of step a) with the composition of the fast acting, short acting or intermediate insulin of step b) so that the final pH of the composition is between pH 6.5-8.0 and the total volume of the composition is 1 ml.

The examples given below serve to illustrate embodiments of the present invention. However, this is not intended to limit the scope of the invention.

Example  1: pharmaceutical composition

A. Glazin  Preparation of solution

The amount of zinc chloride added to the formulation depends on the amount of zinc in the insulin glaze used. The target amount for zinc in the formulation is 30.0 μg per 100 IU insulin glargine.

Procedure: The pharmaceutical composition described in Table 1 was prepared according to the procedure detailed below:

Step 1: Preparation of API solution

The zinc-containing crystals of insulin glargine were dissolved in distilled water injected with a few microliters of 1M HCl. The endogenous zinc levels were supplemented by the addition of an appropriate volume of zinc chloride solution (1% w / v).

Step 2: Preparation of preservative / stabilizer solution

A preservative / stabilizer solution was prepared by dissolving metacresol and glycerol in distilled water for injection to obtain final concentrations of 25 mM m -cresol and 217 mM glycerol in 85%.

Step 3: Preparation of final solution

Both the API solution of step 1 and the preservative / stabilizer solution of step 2 were diluted to the final concentration after mixing and the pH was adjusted to 4.0 ± 0.1 with 1 M HCl or 1 M NaOH. The solution was then filtered through a sterile container using a 0.2 micron filter.

B. Insulin Aspard  Preparation of solution

Procedure: The pharmaceutical composition described in Table 2 was prepared according to the procedure detailed below:

Step 1: Preparation of API solution

An insulin aspartate solution was prepared by dissolving insulin aspartate in distilled water for injection with the help of a few microliters of 1M HCl.

Step 2: Preparation of buffer solution

Buffer solutions were prepared by dissolving metacresol, phenol, disodium hydrogenphosphate and glycerol in distilled water for injection to obtain final concentrations as 14 mM m -cresol, 18 mM phenol, 7 mM disodium hydrogen phosphate and 174 mM glycerol.

Step 3: Preparation of final solution

Both the API solution of step 1 and the buffer solution of step 2 were diluted to the final concentration after mixing and the pH was adjusted to 7.2 + -0.2 with 1 M HCl or 1 M NaOH. The solution was then filtered through a sterile container using a 0.2 micron filter.

C. Mix of Glazin and Aspartate

A solution of insulin aspartate was slowly added to the insulin glazin solution to obtain a ratio of 20:80 (insulin aspirate: insulin glargine). The suspension was thoroughly mixed. The pH of the suspension was 7.2. The preparation was placed in a vial and a stability test was performed.

Example 2: Insulin Glazine crystal image

The formulation of Example 1 (Combo NTE 1001) and 300 IU / mL of the insulin glazin composition were observed under an optical microscope (Olympus BX40). Samples were prepared in the following manner:

1. The pH of the insulin glargine 300 IU / mL sample was raised by the addition of phosphate buffer at pH 9.5. The sample was placed on a glass slide and observed with a 100X infusion microscope (Olympus BX40). Figure 1 shows a micrograph of insulin glargine at 300 IU / ml.

2. Microscopy of the formulation of Example 1 (Combo NTE 1001) with pH 7.2 was taken and is shown in FIG.

Claims (19)

An insulin analog, derivative or metabolite having an isoelectric point in the range of 5.8 to 8.5 with one or more insulin, insulin analogues, derivatives or metabolites having an isoelectric point of 4.0 to 5.7, optionally in combination with one or more excipients, Wherein the molecular aggregate has an average particle size of from about 5 [mu] m to about 20 [mu] m. 2. The pharmaceutical composition according to claim 1, wherein the pH of the composition is adjusted to a pH of from 6.0 to 8.5. 2. The pharmaceutical composition according to claim 1, wherein the insulin, insulin analog, derivative or metabolite is present in a concentration range of 100 IU-1000 IU / ml. The pharmaceutical composition according to claim 1, wherein the insulin, insulin analogue, derivative or metabolite having an isoelectric point of 5.8 to 8.5 is insulin glargine. The method of claim 1, wherein the at least one insulin analog or derivative having an isoelectric point of 4.0 to 5.7 is selected from the group consisting of recombinant human insulin, insulin NPH, insulin lispro, insulin lispro protamine, insulin glulisine and insulin aspartate, insulin aspartate protamine, A21 Gly insulin, A21Gly B28Lys insulin, A21Gly B28Lys B29Pro, A21Gly B28Asp and Viaject (fast acting insulin). 6. The pharmaceutical composition according to claim 5, wherein the at least one insulin, insulin analog, derivative or metabolite having an isoelectric point of 4.0 to 5.7 is insulin aspartate or A21Gly insulin. 2. The pharmaceutical composition according to claim 1, wherein the composition lacks dextran polymer. The pharmaceutical composition of claim 1, wherein the composition further comprises an excipient selected from the group consisting of isotonic agents, surfactants, buffers, zinc or its salts, preservatives, pH modifiers, stabilizers, and solubilizers. The insulin, insulin analog, derivative or metabolite having an isoelectric point of 5.8 to 8.5 is insulin glazine and the insulin, insulin analogue, derivative or metabolite having an isoelectric point of 4.0 to 5.7 is insulin aspartate or A21Gly insulin &Lt; / RTI &gt; 10. The pharmaceutical composition according to claim 9, wherein the composition comprises 100 IU - 300 IU / ml insulin glargine and 100 IU - 300 IU / ml insulin aspirate or A21 Gly insulin. 10. The pharmaceutical composition according to claim 9, wherein the composition comprises 100 IU / ml insulin glargine and 100 IU / ml insulin aspirate or A21Gly insulin. An insulin analog, derivative or metabolite having an isoelectric point in the range of 5.8 to 8.5 with one or more insulin, insulin analogues, derivatives or metabolites having an isoelectric point of 4.0 to 5.7, optionally in combination with one or more excipients, A method for preparing a pharmaceutical composition comprising a possible molecular aggregate, wherein the molecular aggregate has an average particle size of from about 5 [mu] m to about 20 [mu] m, the method comprising:
a. Preparing a pharmaceutical composition comprising 100 IU-1000 IU of an insulin analog or derivative having an isoelectric point of 5.8 to 8.5, wherein the pH of the composition is 3.0-4.5,
b. Preparing a pharmaceutical composition comprising at least one 100 IU-1000 IU insulin analog or derivative having an isoelectric point of 4.0 to 5.7, wherein the pH of the composition is 6.0-8.0.
c. Adding a composition of the rapid, short-acting or intermediate insulin of step b. To an insulin analog or derivative composition having an isoelectric point of 5.8 to 8.5 in step a. Such that the final pH of the composition is between pH 6.0-8.0. 13. The method of claim 12, wherein the at least one insulin analog or derivative having an isoelectric point of 4.0 to 5.7 is selected from the group consisting of recombinant human insulin, insulin NPH, insulin lispro, insulin lispro protamine, insulin glulisine and insulin aspartate, insulin aspirat protamine, A21 Gly insulin, A21Gly B28Lys insulin, A21Gly B28Lys B29Pro, A21Gly B28Asp and Viaject (fast acting insulin). 14. The method of claim 13, wherein the at least one insulin, insulin analog, derivative or metabolite having an isoelectric point of 4.0 to 5.7 is insulin aspartate or A21Gly insulin. 13. The method according to claim 12, wherein the insulin, insulin analog, derivative or metabolite having an isoelectric point of 5.8 to 8.5 is insulin glargine. 13. The method of claim 12, wherein the at least one excipient is selected from the group consisting of isotonic agents, surfactants, buffers, zinc or salts thereof, preservatives, pH modifiers, stabilizers, and solubilizers. A method for treating Type I and Type II diabetes mellitus in a patient, the method optionally comprising administering to the patient one or more insulin, insulin analogs, derivatives or metabolites having an isoelectric point of 4.0 to 5.7, The method comprising administering to the patient a pharmaceutical composition comprising an easily dissociable molecular aggregate formed by combining insulin, insulin analogs, derivatives or metabolites having an isoelectric point of from about 0.5 to about 8.5, &Lt; / RTI &gt; having an average particle size of about 20 mu m. A method of prolonging the duration of sustained action insulin in the treatment of Type I and Type II diabetes mellitus in a patient, the method comprising, optionally in combination with one or more excipients, one or more insulin with an isoelectric point between 4.0 and 5.7, Comprising administering to said patient a pharmaceutical composition comprising an easily dissociable molecular aggregate formed by combining an insulin, insulin analog, derivative or metabolite having an isoelectric point of from 5.8 to 8.5 with an analog, derivative, or metabolite thereof, Wherein the molecular aggregate has an average particle size of from about 5 [mu] m to about 20 [mu] m. A method of reducing nocturnal hypoglycemia in a patient suffering from Type I and Type II diabetes mellitus comprising administering to the subject in need thereof one or more insulin, an insulin analogue, derivative or derivative thereof having an isoelectric point of from 4.0 to 5.7, Comprising administering to said patient a pharmaceutical composition comprising an easily dissociable molecular aggregate formed by the combination of a metabolite and an insulin, insulin analog, derivative or metabolite having an isoelectric point of 5.8 to 8.5, wherein said molecular aggregate &Lt; / RTI &gt; has an average particle size of from about 5 microns to about 20 microns.

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