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Pharmaceutical preparation containing palmitoyl-L-prolyl-L-prolyl-glycyl-L-tyrosine sodium and preparation method thereof

A technology of pharmaceutical preparations and sodium tyrosine, applied in the field of pharmaceutical preparations containing palmitoyl-L-prolyl-L-prolyl-glycyl-L-tyrosine sodium and its preparation, can solve the problem of Low water solubility, no effect, early recurrence and other problems

Pending Publication Date: 2022-05-27
BRIDGE BIOTHERAPEUTICS INC
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0004] For example, as an immunosuppressant, infliximab (infliximab) combines with tumor necrosis factor-α (TNF-α) to exert its effect and is used to treat ulcerative colitis and Crohn's disease, but this treatment method costs Expensive, and cause severe allergic reactions (rash, itching, edema, etc.) and various side effects such as chest pain in some patients
[0005] Also, the 5-aminosalicylic acid (5-ASA) series such as Sulfasalazine, which is used to block prostaglandins production, has the least side effects among ulcerative colitis therapeutic agents medication, but still have side effects
For example, sulfasalazine is known to cause dyspepsia, headache, drug-induced connective tissue disorder, interstitial nephritis, anemia, reversible male infertility, nausea, vomiting, Side effects such as skin rash, liver disease, and leukopenia
[0006] If 5-aminosalicylic acid (5-ASA) is not adequately administered, short-term corticosteroids are administered, but less than 3 weeks of steroid administration in active ulcerative colitis may lead to early Risk of relapse, early treatment is ineffective if the dose is less than 15 mg / day of prednisolone
However, palmitoyl-L-prolyl-L-prolyl-glycyl-L-tyrosine has low water solubility and cannot exert sufficient pharmacodynamics when administered in vivo, especially from the naturally occurring palmitoyl The above-mentioned compound formed by acid (palmitic acid) and natural amino acid (natural amino acid) has the problem of being easily affected by gastric acid and various digestive enzymes, so the inventors have long been committed to studying palmitoyl-L-prolyl-L-pro Novel salt forms of aminoacyl-glycyl-L-tyrosine and formulations capable of effective delivery to the colon when administered orally lead to the completion of the present invention

Method used

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  • Pharmaceutical preparation containing palmitoyl-L-prolyl-L-prolyl-glycyl-L-tyrosine sodium and preparation method thereof
  • Pharmaceutical preparation containing palmitoyl-L-prolyl-L-prolyl-glycyl-L-tyrosine sodium and preparation method thereof
  • Pharmaceutical preparation containing palmitoyl-L-prolyl-L-prolyl-glycyl-L-tyrosine sodium and preparation method thereof

Examples

Experimental program
Comparison scheme
Effect test

preparation example 1

[0063] Preparation of palmitoyl-L-prolyl-L-prolyl-glycyl-L-tyrosine (compound II)

[0064] chemical formula II

[0065]

[0066] Palmitoyl-L-prolyl-L-prolyl-glycyl-L-tyrosine, which is the compound of formula II above, was prepared according to the method described in US Patent Application No. 15 / 205853, which includes the above The entire contents of the patent are incorporated by reference.

preparation example 2

[0068] Preparation of sodium palmitoyl-L-prolyl-L-prolyl-glycyl-L-tyrosinate (compound I)

[0069] chemical formula I

[0070]

[0071] Use as Na 2 CO 3 , NaHCO3 Alternatively palmitoyl-L-prolyl-L-prolyl-glycyl-L-tyrosine is treated with a sodium base like NaOH to convert it to palmitoyl-L-prolyl-L-proline Sodium acyl-glycyl-L-tyrosinate (Compound I).

[0072] For example, 8.6 kg of NaHCO 3 After being placed in Reactor 1, 452 kg of water was added. NaHCO in Reactor 1 3 After the aqueous solution was transferred to another container A, 45 kg of palmitoyl-L-prolyl-L-prolyl-glycyl-L-tyrosine was added to the reactor 1 . 368 kg of the solution in the above-mentioned vessel A was added to the reactor 1, and the mixture was stirred at a temperature of 20°C to 30°C for 1 hour to 3 hours. 82 kg of the solution in container A was added to reactor 1, and stirred at a temperature of 20°C to 30°C for 1 hour to 5 hours. The temperature was raised to 45°C to 55°C and then stirre...

preparation example 3

[0076] Preparation of disodium palmitoyl-L-prolyl-L-prolyl-glycyl-L-tyrosine

[0077] chemical formula III

[0078]

[0079] In the above preparation method of compound I, excess NaOH (for example, 4 equivalents) was added to prepare disodium palmitoyl-L-prolyl-L-prolyl-glycyl-L-tyrosine, but due to hygroscopicity The property is very strong, and it is confirmed that it cannot maintain a solid form.

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PUM

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Abstract

The present invention relates to a pharmaceutical preparation containing palmitoyl-L-prolyl-L-prolyl-glycyl-L-tyrosine sodium (compound I) as an active ingredient, which has excellent bioavailability and stability. The compound I as an active ingredient of the pharmaceutical formulation of the present invention is not decomposed in the stomach but is released in the intestine, and thus can be effectively used as a dosage form for treating inflammatory bowel disease and the like.

Description

technical field [0001] The present invention relates to a pharmaceutical formulation comprising palmitoyl-L-prolyl-L-prolyl-glycyl-L-tyrosinate sodium, which has excellent bioavailability and stability. Using the pharmaceutical formulation of the present invention, a pharmaceutical dosage form in which the active ingredient is not decomposed in the stomach but is stably released in the intestine can be prepared. Background technique [0002] Inflammatory bowel disease can be roughly divided into ulcerative colitis (ulcerative colitis) and Crohn's disease (Crohn's disease). Specifically, colitis is an inflammatory disease limited to the mucosa or submucosa of the colon. Inflammation or ulceration begins in the rectum close to the anus and gradually develops to the entire colon, causing bloody stools, mucus and bloody stools, diarrhea, abdominal pain, and in severe cases Systemic symptoms such as fever, weight loss, and anemia were manifested. Although acute onset occurs, mo...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): A61K38/07A61P1/00C07K5/117
CPCA61K38/07A61K9/0053C07K5/1024A61P1/00A61P29/00A61K9/4891A61K9/5026A61K9/4858A61K9/2846A61K9/2886A61K9/2027A61K9/5073A61K47/542A61K9/2054A61K31/166A61K31/4025
Inventor 姜相旭
Owner BRIDGE BIOTHERAPEUTICS INC