CA2037531A1 - Preparation, which stimulates the immune system, can be applied parenterally and has a long shelf life, and method forproducing it - Google Patents
Preparation, which stimulates the immune system, can be applied parenterally and has a long shelf life, and method forproducing itInfo
- Publication number
- CA2037531A1 CA2037531A1 CA002037531A CA2037531A CA2037531A1 CA 2037531 A1 CA2037531 A1 CA 2037531A1 CA 002037531 A CA002037531 A CA 002037531A CA 2037531 A CA2037531 A CA 2037531A CA 2037531 A1 CA2037531 A1 CA 2037531A1
- Authority
- CA
- Canada
- Prior art keywords
- solution
- preparation
- splenopentine
- peptide
- buffered
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Abandoned
Links
- 238000002360 preparation method Methods 0.000 title claims abstract description 13
- 210000000987 immune system Anatomy 0.000 title claims 3
- 238000004519 manufacturing process Methods 0.000 title claims 2
- 238000000034 method Methods 0.000 claims abstract description 8
- 150000002148 esters Chemical class 0.000 claims abstract description 3
- 239000000243 solution Substances 0.000 claims description 17
- 108090000765 processed proteins & peptides Proteins 0.000 claims description 14
- DNIAPMSPPWPWGF-UHFFFAOYSA-N Propylene glycol Chemical compound CC(O)CO DNIAPMSPPWPWGF-UHFFFAOYSA-N 0.000 claims description 9
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims description 7
- QSJXEFYPDANLFS-UHFFFAOYSA-N Diacetyl Chemical group CC(=O)C(C)=O QSJXEFYPDANLFS-UHFFFAOYSA-N 0.000 claims description 4
- QNAYBMKLOCPYGJ-REOHCLBHSA-N L-alanine Chemical compound C[C@H](N)C(O)=O QNAYBMKLOCPYGJ-REOHCLBHSA-N 0.000 claims description 3
- 235000004279 alanine Nutrition 0.000 claims description 3
- 239000002253 acid Substances 0.000 claims description 2
- 239000007864 aqueous solution Substances 0.000 claims description 2
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims 4
- -1 hydroxybenzoate ester Chemical class 0.000 claims 3
- FJKROLUGYXJWQN-UHFFFAOYSA-N 4-hydroxybenzoic acid Chemical compound OC(=O)C1=CC=C(O)C=C1 FJKROLUGYXJWQN-UHFFFAOYSA-N 0.000 claims 2
- FBPFZTCFMRRESA-KVTDHHQDSA-N D-Mannitol Chemical compound OC[C@@H](O)[C@@H](O)[C@H](O)[C@H](O)CO FBPFZTCFMRRESA-KVTDHHQDSA-N 0.000 claims 2
- 229930195725 Mannitol Natural products 0.000 claims 2
- 239000000872 buffer Substances 0.000 claims 2
- 239000000594 mannitol Substances 0.000 claims 2
- 235000010355 mannitol Nutrition 0.000 claims 2
- 239000003960 organic solvent Substances 0.000 claims 2
- 239000002904 solvent Substances 0.000 claims 2
- 238000004108 freeze drying Methods 0.000 claims 1
- 230000001900 immune effect Effects 0.000 abstract description 3
- 239000003814 drug Substances 0.000 abstract 1
- 239000007788 liquid Substances 0.000 abstract 1
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 5
- 150000002500 ions Chemical class 0.000 description 4
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 3
- 239000012528 membrane Substances 0.000 description 3
- 238000003756 stirring Methods 0.000 description 3
- DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical compound C[C@@H]1CC[C@@]2(CC[C@@]3(C(=CC[C@H]4[C@]3(CC[C@@H]5[C@@]4(CC[C@@H](C5(C)C)OS(=O)(=O)[O-])C)C)[C@@H]2[C@]1(C)O)C)C(=O)O[C@H]6[C@@H]([C@H]([C@@H]([C@H](O6)CO)O)O)O.[Na+] DGAQECJNVWCQMB-PUAWFVPOSA-M 0.000 description 2
- 238000009472 formulation Methods 0.000 description 2
- ZZUFCTLCJUWOSV-UHFFFAOYSA-N furosemide Chemical compound C1=C(Cl)C(S(=O)(=O)N)=CC(C(O)=O)=C1NCC1=CC=CO1 ZZUFCTLCJUWOSV-UHFFFAOYSA-N 0.000 description 2
- LXCFILQKKLGQFO-UHFFFAOYSA-N methylparaben Chemical compound COC(=O)C1=CC=C(O)C=C1 LXCFILQKKLGQFO-UHFFFAOYSA-N 0.000 description 2
- 239000000203 mixture Substances 0.000 description 2
- 102000004196 processed proteins & peptides Human genes 0.000 description 2
- 229910052708 sodium Inorganic materials 0.000 description 2
- 239000011734 sodium Substances 0.000 description 2
- 239000008215 water for injection Substances 0.000 description 2
- 208000030507 AIDS Diseases 0.000 description 1
- HRPVXLWXLXDGHG-UHFFFAOYSA-N Acrylamide Chemical compound NC(=O)C=C HRPVXLWXLXDGHG-UHFFFAOYSA-N 0.000 description 1
- 239000005711 Benzoic acid Substances 0.000 description 1
- 101000867232 Escherichia coli Heat-stable enterotoxin II Proteins 0.000 description 1
- 241001174911 Iasis Species 0.000 description 1
- 206010061598 Immunodeficiency Diseases 0.000 description 1
- 208000029462 Immunodeficiency disease Diseases 0.000 description 1
- 206010028980 Neoplasm Diseases 0.000 description 1
- 206010033799 Paralysis Diseases 0.000 description 1
- MKUXAQIIEYXACX-UHFFFAOYSA-N aciclovir Chemical compound N1C(N)=NC(=O)C2=C1N(COCCO)C=N2 MKUXAQIIEYXACX-UHFFFAOYSA-N 0.000 description 1
- 235000001014 amino acid Nutrition 0.000 description 1
- 150000001413 amino acids Chemical class 0.000 description 1
- 210000000988 bone and bone Anatomy 0.000 description 1
- 201000011510 cancer Diseases 0.000 description 1
- 238000002512 chemotherapy Methods 0.000 description 1
- 230000007423 decrease Effects 0.000 description 1
- 230000009977 dual effect Effects 0.000 description 1
- 230000000694 effects Effects 0.000 description 1
- 230000007813 immunodeficiency Effects 0.000 description 1
- 238000002347 injection Methods 0.000 description 1
- 239000007924 injection Substances 0.000 description 1
- 238000002665 ion therapy Methods 0.000 description 1
- 210000000056 organ Anatomy 0.000 description 1
- 125000000913 palmityl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 239000002244 precipitate Substances 0.000 description 1
- IOVGROKTTNBUGK-SJCJKPOMSA-N ritodrine Chemical compound N([C@@H](C)[C@H](O)C=1C=CC(O)=CC=1)CCC1=CC=C(O)C=C1 IOVGROKTTNBUGK-SJCJKPOMSA-N 0.000 description 1
- HJHVQCXHVMGZNC-JCJNLNMISA-M sodium;(2z)-2-[(3r,4s,5s,8s,9s,10s,11r,13r,14s,16s)-16-acetyloxy-3,11-dihydroxy-4,8,10,14-tetramethyl-2,3,4,5,6,7,9,11,12,13,15,16-dodecahydro-1h-cyclopenta[a]phenanthren-17-ylidene]-6-methylhept-5-enoate Chemical compound [Na+].O[C@@H]([C@@H]12)C[C@H]3\C(=C(/CCC=C(C)C)C([O-])=O)[C@@H](OC(C)=O)C[C@]3(C)[C@@]2(C)CC[C@@H]2[C@]1(C)CC[C@@H](O)[C@H]2C HJHVQCXHVMGZNC-JCJNLNMISA-M 0.000 description 1
- 239000003381 stabilizer Substances 0.000 description 1
- 230000001954 sterilising effect Effects 0.000 description 1
- 238000004659 sterilization and disinfection Methods 0.000 description 1
- 230000004936 stimulating effect Effects 0.000 description 1
- 238000002054 transplantation Methods 0.000 description 1
Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K38/00—Medicinal preparations containing peptides
- A61K38/16—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
- A61K38/17—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
- A61K38/22—Hormones
- A61K38/32—Thymopoietins
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
- A61K47/08—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing oxygen, e.g. ethers, acetals, ketones, quinones, aldehydes, peroxides
- A61K47/14—Esters of carboxylic acids, e.g. fatty acid monoglycerides, medium-chain triglycerides, parabens or PEG fatty acid esters
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/0012—Galenical forms characterised by the site of application
- A61K9/0019—Injectable compositions; Intramuscular, intravenous, arterial, subcutaneous administration; Compositions to be administered through the skin in an invasive manner
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
- A61P31/12—Antivirals
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P37/00—Drugs for immunological or allergic disorders
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P37/00—Drugs for immunological or allergic disorders
- A61P37/02—Immunomodulators
- A61P37/04—Immunostimulants
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
Landscapes
- Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Medicinal Chemistry (AREA)
- General Health & Medical Sciences (AREA)
- Veterinary Medicine (AREA)
- Public Health (AREA)
- Pharmacology & Pharmacy (AREA)
- Animal Behavior & Ethology (AREA)
- General Chemical & Material Sciences (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Organic Chemistry (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Engineering & Computer Science (AREA)
- Immunology (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Epidemiology (AREA)
- Communicable Diseases (AREA)
- Endocrinology (AREA)
- Pain & Pain Management (AREA)
- Rheumatology (AREA)
- Dermatology (AREA)
- Virology (AREA)
- Oil, Petroleum & Natural Gas (AREA)
- Oncology (AREA)
- Zoology (AREA)
- Gastroenterology & Hepatology (AREA)
- Proteomics, Peptides & Aminoacids (AREA)
- Medicinal Preparation (AREA)
- Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
- Medicines Containing Antibodies Or Antigens For Use As Internal Diagnostic Agents (AREA)
Abstract
Abstract of the Disclosure The invention is directed to a stable, liquid or lyophilized preparation for use as a stimulator of the immunological system in human medicine and to method suitable for producing it. The preparation is produced at a pH between 6 and 8 by com-bining splenopentine or splenopentine analogs with a hydroxbenoate ester and is distinguished by an improved and extended stability.
Description
7 .3 r-~
A PREPARATION, WHICH STII~UL~TEES THE IMMllNE
SYSTEM, ~::AN BE APPLIED P~RENTERALL~ AND HAS A LON~i;
SHLF LiFE, ~NS3 METHOl)S FOI:~ PRODlJClNG IT
The invention i~ directed to a prepara~ion, which stimulates the immune sy~tem, is suitable fur parenteral application and has a lon~ shelf life, arld to a method suitable for producing it. It finds application in the pharmaceutical ~ndustry.
Areas of indication for the prepar~ti~n are - immunodeficiency of HIV/AIDS patients;
- restoration of the ahility of the ~m~unological ~ystem to function in cancer patients after chemotherapy or radia~ion therapy;
- paralysis of the immuno]ogical system in the case of organ transpiantation;
restoration of the ability of the immunological system to function a~ter a bone mar~ow transplantation;
- rheumatoid ar~hritis;
pso~iasis with severe joint involvement.
As a rule, peptides are unstable, particularly in aqueous solutions. The hy~rolysis o~ th~ peptldc bonds leads to the splitt}ng of the molecule Int~ ~neffective p~ptidc fra~ment$. Hlgher temperatures, particularly in the presence of water, ]e~d to d~n~tur~ti~n ~nd, with that, t~ the ~ccurr~nce of precipitates, which make paren~
ter~l appllcatlon in~possible, Depending on the amino acid ~equencç of the peptide, , ~ . . .
.
, , . -:,, . .: , ;
, . ... . ;.
~ 7~
extensive experiment~ are always required irl order t~ develop an indiv~dual, opti-mum formulation, which ensures adequate stab;lity of the prepaIatiorl during thetime period, in which it can bc used.
Like other peptides, ~pienopentine and its analogs ~re unstable. According to monographs and expert, phqrmaceutica] opinion, diacetyl splenopentine hydro-chJoride ~ust be stored under ~rery cool conditions while protected against the effects of light and moisture, Expenence has showrl that the stability decreases in the presence of water or durin~ the Iyophilization.
Preparations with a stimulating effect on the immunolog~cal sy~tem, which have a10ng sheIf life, can be applied parenterally and ars based on sple~opentine or its anal~s, have not pre~ously been known.
It is an object of the invention to p~oduce a stable prepzration, which ha~ a stimu-Iating e~ect on the immunologica~ system, can be appliod parenterally and is ~ased on splenopentine or its ana]ogs.
Tt~e invention is based on the task of providing a prep~ration, which contains splenopentine or its analogs in a parenserally applicable form of lon~ shelf life AS
a stimulator of the immunological system.
Purcuant to the inventioII, this objective is accornplished ~wing to the fact that, whlle usin~ splenopentine or splenopentine an~logs ~nd avoidin~ the p~ecipitation ~an~e, th~ p}~ is adju~ted to B va]Ue bet~cen 6.0 and ~.0 and preferably to a vRIue betw~erl 6.S ~ncl 7.S, preferably diacetyI splenopentine hydrochlorido is used in a c~ncclltratiol1 of 1 t~ m~/mL a~ pcptide snd aqueous solutioI~s of hydro7y~
ben~oate est~rs, in a In~ng ratio of 1: 1 to 10: 1 arld preferably of 5: 1, which sre temp~red to 90~ to 95~, ar~ u~ed as stabilizers. l'he peptide is dissolved in û.l mole~lL of sodium hydroxidç solution and subseq-~en~ly mixcd with the hydro~y-benzoic acid solution, which hss becn tempere~ at 90 to 954C After the p~I ~s adju~ted, the solu~ion is filtered through a 0.2 ~m membrane filter for sterilization and filled into ~ mL ~Inpuls under aseptic conditions. Thc hydroxyben~oa~e esterpreferab~y is tlsed in a concentration of 0.1 to 10 nfg/L.
The peptide preparations, produced according to this procedure, have ~ good st~bility and thus also make a p~renteral app]ication pos~ible.
The use of h~droxybenzoate esters ~s solllbilizers and stabili~er~ for peptide~ is novel and the success is entir~ly surpnsing.
The invelltive solution mskes it possible to improve the stabili~ of an aqueous sollltion and of a corrosponding Iyophilisate, so that limitatiorls are no lon~er required with regard to the storage instructions and the re~ultin~ solutions can be applied even parenter~lly. The limitations imposed on the storage conditions (very cool storage and protection against moisture) for thi~ sctiv~ ingredient1 are nolonger applicable.
Example 1 cetyl spl~rlopentine hyclrochloride t27 g) 18 dissolved in ~00 mL of 0.02 moles/L
of ph~sphorlc acic~. ~ stan w~th, the pE~ is adjusted to a vRlue of 8.0 to ~,0 by ns of a~ ex~ess o~ sodium hydroxide. Afte~ stirrlng for 20 mlnutes, the pH i~
~ : . ; ., . :
. . .
, : :
A PREPARATION, WHICH STII~UL~TEES THE IMMllNE
SYSTEM, ~::AN BE APPLIED P~RENTERALL~ AND HAS A LON~i;
SHLF LiFE, ~NS3 METHOl)S FOI:~ PRODlJClNG IT
The invention i~ directed to a prepara~ion, which stimulates the immune sy~tem, is suitable fur parenteral application and has a lon~ shelf life, arld to a method suitable for producing it. It finds application in the pharmaceutical ~ndustry.
Areas of indication for the prepar~ti~n are - immunodeficiency of HIV/AIDS patients;
- restoration of the ahility of the ~m~unological ~ystem to function in cancer patients after chemotherapy or radia~ion therapy;
- paralysis of the immuno]ogical system in the case of organ transpiantation;
restoration of the ability of the immunological system to function a~ter a bone mar~ow transplantation;
- rheumatoid ar~hritis;
pso~iasis with severe joint involvement.
As a rule, peptides are unstable, particularly in aqueous solutions. The hy~rolysis o~ th~ peptldc bonds leads to the splitt}ng of the molecule Int~ ~neffective p~ptidc fra~ment$. Hlgher temperatures, particularly in the presence of water, ]e~d to d~n~tur~ti~n ~nd, with that, t~ the ~ccurr~nce of precipitates, which make paren~
ter~l appllcatlon in~possible, Depending on the amino acid ~equencç of the peptide, , ~ . . .
.
, , . -:,, . .: , ;
, . ... . ;.
~ 7~
extensive experiment~ are always required irl order t~ develop an indiv~dual, opti-mum formulation, which ensures adequate stab;lity of the prepaIatiorl during thetime period, in which it can bc used.
Like other peptides, ~pienopentine and its analogs ~re unstable. According to monographs and expert, phqrmaceutica] opinion, diacetyl splenopentine hydro-chJoride ~ust be stored under ~rery cool conditions while protected against the effects of light and moisture, Expenence has showrl that the stability decreases in the presence of water or durin~ the Iyophilization.
Preparations with a stimulating effect on the immunolog~cal sy~tem, which have a10ng sheIf life, can be applied parenterally and ars based on sple~opentine or its anal~s, have not pre~ously been known.
It is an object of the invention to p~oduce a stable prepzration, which ha~ a stimu-Iating e~ect on the immunologica~ system, can be appliod parenterally and is ~ased on splenopentine or its ana]ogs.
Tt~e invention is based on the task of providing a prep~ration, which contains splenopentine or its analogs in a parenserally applicable form of lon~ shelf life AS
a stimulator of the immunological system.
Purcuant to the inventioII, this objective is accornplished ~wing to the fact that, whlle usin~ splenopentine or splenopentine an~logs ~nd avoidin~ the p~ecipitation ~an~e, th~ p}~ is adju~ted to B va]Ue bet~cen 6.0 and ~.0 and preferably to a vRIue betw~erl 6.S ~ncl 7.S, preferably diacetyI splenopentine hydrochlorido is used in a c~ncclltratiol1 of 1 t~ m~/mL a~ pcptide snd aqueous solutioI~s of hydro7y~
ben~oate est~rs, in a In~ng ratio of 1: 1 to 10: 1 arld preferably of 5: 1, which sre temp~red to 90~ to 95~, ar~ u~ed as stabilizers. l'he peptide is dissolved in û.l mole~lL of sodium hydroxidç solution and subseq-~en~ly mixcd with the hydro~y-benzoic acid solution, which hss becn tempere~ at 90 to 954C After the p~I ~s adju~ted, the solu~ion is filtered through a 0.2 ~m membrane filter for sterilization and filled into ~ mL ~Inpuls under aseptic conditions. Thc hydroxyben~oa~e esterpreferab~y is tlsed in a concentration of 0.1 to 10 nfg/L.
The peptide preparations, produced according to this procedure, have ~ good st~bility and thus also make a p~renteral app]ication pos~ible.
The use of h~droxybenzoate esters ~s solllbilizers and stabili~er~ for peptide~ is novel and the success is entir~ly surpnsing.
The invelltive solution mskes it possible to improve the stabili~ of an aqueous sollltion and of a corrosponding Iyophilisate, so that limitatiorls are no lon~er required with regard to the storage instructions and the re~ultin~ solutions can be applied even parenter~lly. The limitations imposed on the storage conditions (very cool storage and protection against moisture) for thi~ sctiv~ ingredient1 are nolonger applicable.
Example 1 cetyl spl~rlopentine hyclrochloride t27 g) 18 dissolved in ~00 mL of 0.02 moles/L
of ph~sphorlc acic~. ~ stan w~th, the pE~ is adjusted to a vRlue of 8.0 to ~,0 by ns of a~ ex~ess o~ sodium hydroxide. Afte~ stirrlng for 20 mlnutes, the pH i~
~ : . ; ., . :
. . .
, : :
2 ~ 3 :~
adjusted to ~ value of 7.5 with 0.02 mv~es/l, of phosphori~ acid. Methyl hydroxybenzoate (1.5 ~) ;B dissolYed in 300 mL of water for inJcction ~n~ imunedi~tely combined with the above ~ormulation ~ith stirring. The pH is ~dju~ted to 6.~ - 7.1.
Subsequently, the formulation is diluted to 1 L, filtered through a 0.2 S~m membrane filter to ~terilize it and processed und~r ~terile conditions.
Example 2 Splenopentine hydrochloride (27 g) is dissolved in SOû mL of water for injection.
To begin with, the pH of the solution is adjusted to 8.0 to ~.0 with n~e~lurnine and, after stirring for 20 minute~, with 1 mole/L of hydrochloric acid to 7.5. Propylhydroxybenznate ~0-7~ B) is dissolved at ~0 to 95~C in 20Q mL of watel for iIljec-tion and mixed i~me~iately whh ~he peptide solu~ion with s~irring. After t~e addition of 200 g of propylene glycol, the formu]a~ion is made up to 1 L, ~terilized throu~h a 0.2 ~m fil~er and bottled under 3septic conditions.
Example 3 Diacetyl splenopentine hydrochlonde (20 ~) is dissolved in 450 mL of 0.05 mo~es/L
of aqueous sodium hydro?dde. ~u~sequently, 50 g of alanine are added.
Methyl hydroxybenzoate (1.5 g) is dissolved at ~0 to 95C in 450 mL of water for injection ancl mixed at once with ~he peptide solution. Ater stirring for ~0 minutes, the pH is adjust~d with hydrochloric acid to 7.5 and the volume made up to 1 L
with w~ter for injection.
jection ~olutiull, filte,red fc~r æt~rili~ation thrc)u~h R membrane ~qlter, i~ filled und~r a~eptic ~ondltiotl~ into inje~tions ~ and Iyophilize~ ~t temperatures up to 2so~.
,. .
: ` : : :~: ~ :
adjusted to ~ value of 7.5 with 0.02 mv~es/l, of phosphori~ acid. Methyl hydroxybenzoate (1.5 ~) ;B dissolYed in 300 mL of water for inJcction ~n~ imunedi~tely combined with the above ~ormulation ~ith stirring. The pH is ~dju~ted to 6.~ - 7.1.
Subsequently, the formulation is diluted to 1 L, filtered through a 0.2 S~m membrane filter to ~terilize it and processed und~r ~terile conditions.
Example 2 Splenopentine hydrochloride (27 g) is dissolved in SOû mL of water for injection.
To begin with, the pH of the solution is adjusted to 8.0 to ~.0 with n~e~lurnine and, after stirring for 20 minute~, with 1 mole/L of hydrochloric acid to 7.5. Propylhydroxybenznate ~0-7~ B) is dissolved at ~0 to 95~C in 20Q mL of watel for iIljec-tion and mixed i~me~iately whh ~he peptide solu~ion with s~irring. After t~e addition of 200 g of propylene glycol, the formu]a~ion is made up to 1 L, ~terilized throu~h a 0.2 ~m fil~er and bottled under 3septic conditions.
Example 3 Diacetyl splenopentine hydrochlonde (20 ~) is dissolved in 450 mL of 0.05 mo~es/L
of aqueous sodium hydro?dde. ~u~sequently, 50 g of alanine are added.
Methyl hydroxybenzoate (1.5 g) is dissolved at ~0 to 95C in 450 mL of water for injection ancl mixed at once with ~he peptide solution. Ater stirring for ~0 minutes, the pH is adjust~d with hydrochloric acid to 7.5 and the volume made up to 1 L
with w~ter for injection.
jection ~olutiull, filte,red fc~r æt~rili~ation thrc)u~h R membrane ~qlter, i~ filled und~r a~eptic ~ondltiotl~ into inje~tions ~ and Iyophilize~ ~t temperatures up to 2so~.
,. .
: ` : : :~: ~ :
Claims (12)
PROPERTY OR PRIVILEGE IS CLAIMED ARE DEFINED AS FOLLOWS:
1. A preparation, which stimulates the immune system, can be applied parenterally and has a long shelf life, characterized in that it consists of m aqueous solution of splenopentine or splenopentine analogs or of a solvent containing solution ofsplenopcntine or splenopentine analogs, to which an ester of hydroxybenzoic acid has been added and which is buffered to a pH between 6.0 and 8Ø
2. The preparation of claim 1, characterized in that it contains diacetyl spleno-pentine hydrochloride as peptide in a concentration of 0.1 to 10 mg/ml and hydroxybenzoate ester in concentrations of 0.1 to 10 mg/ml
3. The preparation of claims 1 and 2, characterized in that the peptide solutionis buffered with conventional, pharmaceutically and pharmacologically suitable buffers to a pH of 6.5 to 7.5.
4. The preparation of claims 1 to 3, characterized in that the mixing ratio of peptide solution to added hydroxybenzoic acid solution is 1: 10 to 10: 1 and preferably 5 1.
5. The preparation of claims 1 to 4, characterized in that the solution contains propylene glycol and/or ethanol as organic solvent.
e preparation of claims 1 to S, characterized in that the sultan contains 1 to 10% of a lyophllizlng vehicle, preferably mannitol or alanine, and is lyophilized at temperatures up to 30°C.
7. A method for producing a preparation, which stimulates the immune system, can be applied parenterally and has a long shelf life, characterized in that an aqueous or solvent-containing solution of splenopentine or splenopentine ana-logs, buffered to a pH between 6.0 and 8.0, is mixed with an aqueous hydroxy benzoate ester solution heated to 90°to 95°C and sterilized by conventional pharmaceutical technology and bottled or lyophilized.
8. The method of claims 7, characterized in that diacetyl splenopentine hydro-chloride is used as peptide in a concentration of 1 to 100 mg/mL and that the hydroxy benzoate ester is used in concentrations of 0.1 to 10 mg/mL
9. The method of claims 7 and 8, characterized in that the peptide solution is buffered with conventional, pharmaceutically and pharmacologically suitable buffers to a pH of 6.5 to 7.5.
10. The method of claims 7 to 9, characterized in that the mixing ratio of peptide solution to hydrobenzoic acid solution is 1: 1 to 10: 1 and preferably 5: 1.
11. The method of claims 7 to 10, characterized in that propylene glycol and/or ethanol are added to the solution as organic solvent.
12. The method of claims 7 to 11, characterized in that 1% to 10% of a lyophiliza-tion vehicle, preferably mannitol or alanine, is added to the solution, which issubsequently lyophilized at temperatures up to 30°C.
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| DD90338431A DD292382B5 (en) | 1990-03-06 | 1990-03-06 | METHOD FOR PRODUCING A PARENTERALLICALLY APPLICABLE STORAGE-RESISTANT IMMUNOSTIMULATING PREPARATION |
| DEWPA61K/3384311 | 1990-03-06 |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CA2037531A1 true CA2037531A1 (en) | 1991-09-07 |
Family
ID=5616877
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CA002037531A Abandoned CA2037531A1 (en) | 1990-03-06 | 1991-03-04 | Preparation, which stimulates the immune system, can be applied parenterally and has a long shelf life, and method forproducing it |
Country Status (7)
| Country | Link |
|---|---|
| EP (1) | EP0445581B1 (en) |
| JP (1) | JPH0692315B2 (en) |
| AT (1) | ATE88903T1 (en) |
| CA (1) | CA2037531A1 (en) |
| DD (1) | DD292382B5 (en) |
| DE (1) | DE59100098D1 (en) |
| ES (1) | ES2055469T3 (en) |
Families Citing this family (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| RU2010114022A (en) * | 2007-09-11 | 2011-10-20 | Мондобайотек Лабораториз Аг (Li) | The combination of splenopentin and thymopentin and their use in the drug |
| ITMI20081652A1 (en) * | 2008-09-16 | 2010-03-17 | Antica Ritrovati Medicinal I S A R M Srl Soc | TRANSDERMIC COMPOSITIONS FOR HYPOSENSIBILIZING SPECIFIC IMMUNOTHERAPY |
| RU2698707C1 (en) * | 2019-04-29 | 2019-08-29 | Федеральное государственное бюджетное научное учреждение "Федеральный Алтайский научный центр агробиотехнологий" (ФГБНУ ФАНЦА) | Biogenic preparations production method |
Family Cites Families (7)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| DE3146598A1 (en) * | 1981-11-25 | 1983-07-07 | Hoechst Ag, 6230 Frankfurt | "NEW PEPTIDES AND METHOD FOR THEIR PRODUCTION" |
| HU199878B (en) * | 1987-06-19 | 1990-03-28 | Berlin Chemie Veb | Process for producing acylated splenopentynes and pharmaceutical compositions comprising such compounds as active ingredient |
| DD271267A1 (en) * | 1988-03-31 | 1989-08-30 | Akad Wissenschaften Ddr | METHOD FOR PRODUCING A MEANS FOR NORMALIZING THE IMMUNE SYSTEM |
| DD263994A1 (en) * | 1987-07-09 | 1989-01-18 | Univ Halle Wittenberg | PROCESS FOR PREPARING OLIGODESOXYRIBONUCLEOTIDES FOR SPLENOPENTINE EXPRESSION |
| NZ229004A (en) * | 1988-05-19 | 1993-09-27 | Immunobiology Res Inst Inc | Tetrapeptides having t cell helper acitivity |
| DD273980B5 (en) * | 1988-07-12 | 1994-04-14 | Berlin Chemie Ag | Process for the preparation of insulin preparations for rectal use |
| DD296084A5 (en) * | 1989-07-27 | 1991-11-21 | Adw | PROCESS FOR THE MANUFACTURE OF HUMAN SPLENINE DERIVATIVES |
-
1990
- 1990-03-06 DD DD90338431A patent/DD292382B5/en unknown
-
1991
- 1991-02-20 EP EP91102431A patent/EP0445581B1/en not_active Expired - Lifetime
- 1991-02-20 DE DE9191102431T patent/DE59100098D1/en not_active Expired - Fee Related
- 1991-02-20 AT AT91102431T patent/ATE88903T1/en not_active IP Right Cessation
- 1991-02-20 ES ES91102431T patent/ES2055469T3/en not_active Expired - Lifetime
- 1991-03-04 CA CA002037531A patent/CA2037531A1/en not_active Abandoned
- 1991-03-05 JP JP3038808A patent/JPH0692315B2/en not_active Expired - Fee Related
Also Published As
| Publication number | Publication date |
|---|---|
| ATE88903T1 (en) | 1993-05-15 |
| DE59100098D1 (en) | 1993-06-09 |
| JPH0692315B2 (en) | 1994-11-16 |
| JPH04211611A (en) | 1992-08-03 |
| ES2055469T3 (en) | 1994-08-16 |
| EP0445581A1 (en) | 1991-09-11 |
| DD292382B5 (en) | 1994-03-24 |
| DD292382A5 (en) | 1991-08-01 |
| EP0445581B1 (en) | 1993-05-05 |
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Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| EEER | Examination request | ||
| FZDE | Discontinued |