Stable Glucagon Peptide Formulations

Abstract

There is provided glucagon formulations suitable for preparing coatings on microneedle patches for the transdermal delivery of glucagon. The coated patches may be used for the treatment of low blood sugar in diabetic patients. Also provided are glucagon loaded patches, methods for their preparation, and methods of their use.

1 - 29 . (canceled) 
     
     
         30 . A liquid pharmaceutical formulation, comprising glucagon or a glucagon-like peptide and a stabilizing agent wherein the stabilizing agent is present in an amount down to 8 fold less, by weight, than the amount of glucagon or glucagon-like peptide. 
     
     
         31 . The liquid pharmaceutical formulation of  claim 30 , further comprising an amino acid, an organic acid, and a pharmaceutically acceptable diluent. 
     
     
         32 . The liquid pharmaceutical formulation of  claim 30 , wherein the formulation has a pH which is not between about 4 and about 8. 
     
     
         33 . The liquid pharmaceutical formulation of  claim 30 , wherein the formulation has a pH between about 2.8 and about 3.2. 
     
     
         34 . The liquid pharmaceutical formulation of  claim 30 , wherein the stabilizing agent is a cationic surfactant or a neutral surfactant. 
     
     
         35 . The liquid pharmaceutical formulation of  claim 34 , wherein the stabilizing agent is selected from the group consisting of lyso-myristoyl phosphatidylcholine (LMPC), glucose, sucrose, trehalose, dextrose, a derivative thereof substituted with a C8-C12 alkyl chain, and a combination of any of the foregoing. 
     
     
         36 . The liquid pharmaceutical formulation of  claim 31 , wherein glucagon or glucagon like peptide is present in amount of about 15-20% (w/w), wherein the stabilizing agent is present in an amount of about 7.5-10% (w/w), wherein the amino acid is present in an amount of about 3.75-5% (w/w) and the organic acid is present in an amount of about 3.75-5% (w/w). 
     
     
         37 . The liquid pharmaceutical formulation of  claim 31 , further comprising a carboxymethyl cellulose. 
     
     
         38 . The liquid pharmaceutical formulation of  claim 31 , wherein:
 a. the amino acid is glutamine or glycine,   b. the stabilizing agent is selected from the group consisting of lyso-myristoyl phosphatidylcholine (LMPC), glucose, sucrose, trehalose, dextrose, a derivative thereof substituted with a C8-C12 alkyl chain, and a combination of any of the foregoing, and   c. the organic acid is selected from the group consisting of methanoic acid, ethanoic acid, tartaric acid, malonic acid, glycolic acid, malic acid, gluconic acid, citric acid, caproic acid, benzoic acid, lactic acid, propionic acid, sorbic acid, and a combination of any of the foregoing.   
     
     
         39 . The liquid pharmaceutical formulation of  claim 38 , further comprising sodium carboxymethyl cellulose in a concentration from about 0.1 mg/mL to about 1.0 mg/mL. 
     
     
         40 . The liquid pharmaceutical formulation of  claim 39 , comprising about 200 mg/mL glucagon, about 100 mg/mL LMPC, about 50 mg/mL glutamine, and about 50 mg/mL tartaric acid. 
     
     
         41 . The liquid pharmaceutical formulation of  claim 39 , comprising about 200 mg/mL glucagon, about 100 mg/mL decanoyl sucrose (DS), about 50 mg/mL glutamine, and about 50 mg/mL tartaric acid. 
     
     
         42 . A pharmaceutical formulation, comprising:
 a. glucagon or a glucagon-like peptide;   b. a stabilizing agent selected from either a cationic or neutral surfactant;   c. an amino acid; and   d. an organic acid,   wherein the amount of the cationic or neutral surfactant is present in an amount which is greater than an amount which is 8 fold less by weight than the amount of glucagon or glucagon-like peptide.   
     
     
         43 . The pharmaceutical formulation of  claim 42  further comprising a carboxymethyl cellulose. 
     
     
         44 . The pharmaceutical formulation of  claim 43 , wherein the carboxymethyl cellulose is sodium carboxymethyl cellulose. 
     
     
         45 . The pharmaceutical formulation of  claim 44 , where the formulation is a liquid formulation and the sodium carboxymethyl cellulose is present in a concentration of from about 0.1 mg/ml to about 1 mg/ml. 
     
     
         46 . The pharmaceutical formulation of  claim 44 , wherein the sodium carboxymethyl cellulose is present in a concentration of about 0.5 mg/ml. 
     
     
         47 . The pharmaceutical formulation of  claim 42 , further comprising trehalose. 
     
     
         48 . The pharmaceutical composition of  claim 47 , wherein the formulation is a liquid formulation, and the trehalose is present in an amount of about 50 mg/ml. 
     
     
         49 . The pharmaceutical formulation of  claim 42 , wherein the surfactant is a phospholipid. 
     
     
         50 . The pharmaceutical formulation of  claim 49 , wherein the phospholipid is lyso-myristoyl phosphatidylcholine. 
     
     
         51 . The pharmaceutical formulation of  claim 42 , wherein the surfactant is decanoyl sucrose. 
     
     
         52 . The pharmaceutical formulation of  claim 42 , wherein the amino acid is selected from the group consisting of glutamine and glycine. 
     
     
         53 . The pharmaceutical formulation of  claim 42 , wherein the organic acid is selected from the group consisting of methanoic acid, ethanoic acid, tartaric acid, malonic acid, glycolic acid, malic acid, gluconic acid, citric acid, caproic acid, benzoic acid, lactic acid, propionic acid, and sorbic acid. 
     
     
         54 . The pharmaceutical formulation of  claim 42 , wherein the organic acid is tartaric acid. 
     
     
         55 . The formulation of  claim 42  wherein the formulation is a liquid formulation comprising a pharmaceutically acceptable diluent, and wherein the formulation has a pH which is not between 4 and 8. 
     
     
         56 . The formulation of  claim 55 , comprising:
 a. 15-20% (w/w) of the glucagon or glucagon like peptide;   b. 7.5-10% (w/w) of the cationic or neutral surfactant;   c. 3.75-5% (w/w) of the amino acid; and   d. 3.75-5% (w/w) of the organic acid.   
     
     
         57 . The formulation of  claim 56 , wherein the pH of the liquid formulation is between 2.8 and 3.2. 
     
     
         58 . The formulation of  claim 56 , further comprising a property selected from the group consisting of:
 a. the surfactant is a phospholipid;   b. the surfactant is lyso-myristoyl phosphatidylcholine;   c. the surfactant is decanoyl sucrose;   d. the amino acid is glutamine;   e. the amino acid is glycine;   f. the organic acid is selected from the group consisting of methanoic acid, ethanoic acid, tartaric acid, malonic acid, glycolic acid, malic acid, gluconic acid, citric acid, caproic acid, benzoic acid, lactic acid, propionic acid, and sorbic acid;   g. the organic acid is methanoic acid; and   h. the organic acid is tartaric acid.   
     
     
         59 . The formulation of  claim 58 , comprising:
 a. glucagon or glucagon-like peptide at a concentration of about 200 mg/ml;   b. lyso-myristoyl phosphatidylcholine at a concentration of about 100 mg/ml;   c. tartaric acid at a concentration of about 50 mg/ml;   d. glycine at a concentration of about 50 mg/ml;   e. trehalose at a concentration of about 50 mg/ml; and   f. sodium carboxymethyl cellulose at a concentration of about 0.5 mg/ml.   
     
     
         60 . A medical device, comprising an array of microneedles having coated thereon a solid composition according to  claim 30 . 
     
     
         61 . The medical device of  claim 60 , wherein the solid composition comprises:
 a. 40-50% (w/w) of the glucagon or a glucagon-like peptide;   b. 20-25% (w/w) of the cationic or neutral surfactant;   c. 10-12.5% (w/w) of the amino acid; and   d. 10-12.5% (w/w) of the organic acid.   
     
     
         62 . The medical device of  claim 61 , wherein the solid composition further comprises a property selected from the group consisting of:
 a. the surfactant is a phospholipid;   b. the surfactant is lyso-myristoyl phosphatidylcholine;   c. the surfactant is decanoyl sucrose;   d. the amino acid is glutamine;   e. the amino acid is glycine;   f. the organic acid is selected from the group consisting of methanoic acid, ethanoic acid, tartaric acid, malonic acid, glycolic acid, malic acid, gluconic acid, citric acid, caproic acid, benzoic acid, lactic acid, propionic acid, and sorbic acid;   g. the organic acid is methanoic acid; and   h. the organic acid is tartaric acid.   
     
     
         63 . The medical device of  claim 62 , wherein the solid composition comprises:
 a. about 44% w/w glucagon or glucagon-like peptide;   b. about 22% w/w lyso-myristoyl phosphatidylcholine;   c. about 11% tartaric acid;   d. about 11% glycine;   e. about 11% trehalose; and   f. carboxymethyl cellulose.   
     
     
         64 . An intracutaneous delivery system, comprising a patch having a plurality of microprojections that are adapted to penetrate or pierce the stratum corneum of a human subject, the microprojections having a solid formulation coating thereon, wherein:
 a. the coating comprises about 40-50% (w/w) of glucagon or a glucagon-like peptide and about 20-25% (w/w) of a stabilizing agent,   b. upon piercing the stratum corneum layer of the skin, the coating is dissolved by body fluids thereby releasing the glucagon or glucagon-like peptide into the skin for absorption to the blood stream.   
     
     
         65 . The system of  claim 64 , wherein the glucagon or glucagon-like peptide is present in a therapeutic dose ranging from about 0.25 mg to about 2.0 mg. 
     
     
         66 . The system of  claim 64 , wherein the patch delivers from about 0.25 mg/patch to about 2.0 mg/patch of glucagon or glucagon-like peptide. 
     
     
         67 . The system of  claim 64 , wherein the patch delivers from about 0.5 mg/patch to about 1.0 mg/patch of glucagon or glucagon-like peptide. 
     
     
         68 . The system of  claim 64 , wherein the comprises a microprojection array of about 2.5 cm 2  to about 8 cm 2 . 
     
     
         69 . The system of  claim 64  used for treatment of low blood sugar in a patient, wherein the patient may require the application of one patch per occurrence. 
     
     
         70 . The system of  claim 64 , wherein the patient may require the application of several patches simultaneously or sequentially until the blood sugar has reached a normal range of glucose serum concentration. 
     
     
         71 . The system of  claim 64 , wherein glucagon or glucagon-like peptide is completely released from the patch within from about 1 minute to about 30 minutes of application. 
     
     
         72 . A method for treating a patient having low blood sugar, wherein the method comprises applying a patch having a plurality of microprojections that are adapted to penetrate or pierce the stratum corneum of the patient, the microprojections having a solid formulation coating thereon, wherein:
 a. the coating comprises about 40-50% (w/w) of glucagon or a glucagon-like peptide, about 20-25% (w/w) of a stabilizing agent, about 10-12.5% (w/w) of an amino acid, and about 10-12.5% (w/w) of an organic acid, and   b. upon piercing the stratum corneum layer of the skin, the coating is dissolved by body fluids thereby releasing the glucagon or glucagon-like peptide into the skin for absorption to the blood stream.   
     
     
         73 . The method of  claim 72 , wherein blood serum Cmax of glucagon or glucagon-like peptide is reached in less than about 30 minutes following application of the patch to the skin of the patient. 
     
     
         74 . The method of  claim 73 , wherein the blood serum Cmax of glucagon or glucagon-like peptide reaches at least 5 ng/mL. 
     
     
         75 . The method of  claim 73 , wherein the blood serum Cmax of glucagon or glucagon-like peptide reaches about 20 ng/mL. 
     
     
         76 . A method for treating a patient having low blood sugar, wherein the method comprises applying a patch carrying a plurality of microprojections that are adapted to penetrate or pierce the stratum corneum of the patient, the microprojections having a solid formulation coating thereon, wherein:
 a. the coating comprises about 15-20% (w/w) of glucagon and about 7.5-10% (w/w) of a stabilizing agent, about 3.75-5% (w/w) of an amino acid, and about 3.75-5% (w/w) of an organic acid, and   b. upon piercing the stratum corneum layer of the skin, the coating is dissolved by body fluids thereby releasing the glucagon into the skin for absorption to the blood stream.   
     
     
         77 . The method of  claim 76 , wherein blood serum Cmax of glucagon is reached in less that about 30 minutes following application of the patch to the skin of the patient. 
     
     
         78 . The method of  claim 77 , wherein the blood serum Cmax of glucagon reaches at least 5 ng/mL. 
     
     
         79 . The method of  claim 77 , wherein the blood serum Cmax of glucagon reaches about 20 ng/mL.