CN105168115A - Oral medication path of somatostatin analogue polypeptide drug - Google Patents
Oral medication path of somatostatin analogue polypeptide drug Download PDFInfo
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- CN105168115A CN105168115A CN201510559263.0A CN201510559263A CN105168115A CN 105168115 A CN105168115 A CN 105168115A CN 201510559263 A CN201510559263 A CN 201510559263A CN 105168115 A CN105168115 A CN 105168115A
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- polypeptides
- lanreotide
- somatostatin analogue
- vapreotide
- octreotide
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Abstract
The invention provides an oral medication path of a somatostatin analogue polypeptide drug, and in particularly relates to an oral medication path of three somatostatin analogue polypeptides, including octreotide, vapreotide and lanreotide, belonging to the field of medicine. The invention provides the stability of the three somatostatin analogues in in-vitro artificial gastric juice and artificial intestinal juice, and the experiments prove that the three somatostatin analogue polypeptides are stable in the artificial gastric juice and can not be degraded; in the artificial intestinal juice, the three polypeptides are gradually degraded along with time, the sequences of the stabilities of the three polypeptides from high to low are as follows: octreotide, vapreotide and lanreotide. The invention further provides the absorbing states of the three polypeptides after the three polypeptides are given to a rat through intragastric administration, and describes the oral pharmacokinetic behaviors of the three polypeptides. According to the invention, on the basis of the original injection paths of the three polypeptides, the oral medication path of the three polypeptides is increased, so that the compliance of a patient is improved.
Description
Technical field
The present invention relates to the change of route of administration of somatostatin analogue polypeptide octreotide (octreotide), Lanreotide (lanreotide), vapreotide (vapreotide), specifically on the drug administration by injection approach basis of its routine, increase the approach of its oral administration, improve safety and the compliance of medicine use, belong to drug world.
Background technology
Along with the development of life sciences, active polypeptide class medicine has become pharmaceutical industry priority research areas, and the trend progressively accelerated has appearred in the research and development of polypeptide drug and listing.At present, the polypeptide drug of the granted listing in the whole world has exceeded 50, have an appointment 140 polypeptide drugs in clinical studies, and the polypeptide drug in clinical front development reaches 500 to 600.But due to polypeptide drugs oral time by itself the restriction of physicochemical properties, such as unstable in gastric acid, easily lost biological activity by the enzymatic degradation in gastrointestinal tract, not easily through gastrointestinal tract mucous etc., limit the oral administration of polypeptide drugs, reduce the compliance of patient, and seriously limit its market potential.
Somatostatin is at maincenter and peripheral nervous system, endocrinal glands, digestive system, the even peptide hormone of extensively distribution in some tumors, playing physiological action widely by combining with somatostatin receptor different subtype (sstr1-5), comprising and suppressing body of gland and hormone secretion, adjustment nerve conduction and cell differentiation etc.In addition to Tumor suppression, particularly neuroendocrine tumor also plays an important role.Natural somatostatin is unstable in vivo, the half-life short (2-3min).The somatostatin analogue of a series of synthetic such as octreotide, Lanreotide, vapreotide etc. remain the active group aminoacid sequence Phe-Trp-Lys-Thr of spontaneous growth chalone, and use alcoholization, amidatioon, D type aminoacid to modify polypeptide, to overcome the deficiency of spontaneous growth chalone, and become the comparatively successfully peptide medicament gone on the market.
The same with most peptide medicaments, the route of administration of somatostatin analogue polypeptide is drug administration by injection at present both at home and abroad.Because the compliance of patient to drug administration by injection is significantly less than oral administration, therefore the oral administration route of somatostatin analogue polypeptide is developed to patient, particularly to the patient needing Long-term taking medicine, as significant acromegaly, neuroendocrine tumor patient.
Summary of the invention
In view of this, the object of the present invention is to provide the oral administration route of feasible somatostatin analogue polypeptide octreotide, Lanreotide, vapreotide.
The ring-like polypeptide be by a disulfide bond connection of three kinds of somatostatin similar polypeptides, and all certain modification has been carried out to peptide backbone, the structure of octreotide is:
wherein the tryptophan of primary phenylalanine and the 4th is D type aminoacid, and the threonine of the 8th transform Soviet Union's ammonia alcohol as; The structure of vapreotide is:
wherein the tryptophan of primary phenylalanine and the 4th is D type aminoacid, and the 8th tryptophan is amidated; The structure of Lanreotide is
first is D type β naphthylalanine, and the tryptophan of the 4th is D type aminoacid, and the threonine of the 8th is amidated.The feature of peptide backbone circulus, and D type aminoacid, the introducing of alpha-non-natural amino acid etc., makes three peptide species in gastrointestinal tract, have certain resistance to enzymolysis ability, therefore can pass through oral administration.
The object of the invention is by the stability study to three kinds of somatostatin analogue polypeptide simulated gastric fluid and simulated intestinal fluid in vitro, after gastrointestinal administration in body blood drug level mensuration and calculate that the oral absolute bioavailability of medicine realizes.Three kinds of somatostatin analogue polypeptide are stable in containing pepsic simulated gastric fluid, in containing the simulated intestinal fluid of pancreatin, also can keep better stability within a period of time; Through gastric infusion 15,30, after 60mg/Kg, determination of plasma concentration shows that three peptide species medicines have obvious absorption in vivo.
This invention exploits the new route of administration of three kinds of somatostatin analogue polypeptide, the oral administration route demonstrated is feasible, expand the application of the single drug administration by injection approach of somatostatin analogue polypeptide to oral administration route, add the range of application of somatostatin analogue polypeptide.
Accompanying drawing illustrates:
Fig. 1: three kinds of somatostatin analogue polypeptide octreotides, vapreotide, Lanreotide stability in simulated gastric fluid
Fig. 2: three kinds of somatostatin analogue polypeptide octreotides, vapreotide, Lanreotide stability in simulated intestinal fluid
Fig. 3: the blood concentration-time curve of octreotide intravenous injection and gavage
Fig. 4: the blood concentration-time curve of vapreotide intravenous injection and gavage
Fig. 5: the blood concentration-time curve of Lanreotide intravenous injection and gavage
Detailed description of the invention
Below in conjunction with drawings and Examples, the present invention is further detailed.
Embodiment 1 three kinds of somatostatin analogue polypeptide octreotides, vapreotide, the stability of Lanreotide in simulated gastric fluid:
The first step: according to the formulated simulated gastric fluid of American Pharmacopeia.Concrete formula is as follows: in 1000mL simulated gastric fluid, NaCl2.0g, pepsin 3.2g, HCl adjust ph to 1.2, the pre-temperature of 37 DEG C incubate 30 minutes for subsequent use.
Second step: with the simulated gastric fluid in the first step respectively compound concentration be octreotide, vapreotide, the Lanreotide solution 1mL of 100 μ g/mL, parallel 3 parts, after 37 DEG C of temperature incubate the regular hour (0,10,30,60,120,180 minute), by 3mL ice acetonitrile cessation reaction, centrifugal 10 minutes of 30000g, gets supernatant LC-MS/MS and detects.
3rd step: calculate residual volume.Be 100% residual volume with the drug level of 0 minute, the ratio of the drug level of each time point and 0 minute concentration is the residual volume of each time point.The results are shown in Figure 1, three kinds of somatostatin analogue polypeptide octreotides, vapreotide, Lanreotides keep stable in simulated gastric fluid in 3 hours, do not occur signs of degradation.
Embodiment 2 three kinds of somatostatin analogue polypeptide octreotides, vapreotide, the stability of Lanreotide in simulated intestinal fluid:
The first step: according to the formulated simulated intestinal fluid of American Pharmacopeia.Concrete formula is as follows: in 1000mL simulated intestinal fluid, trypsin 10.0g, KH
2pO
46.8g, NaOH adjust ph to 7.5 ± 0.1, the pre-temperature of 37 DEG C incubate 30 minutes for subsequent use.
Second step: with the simulated intestinal fluid in the first step respectively compound concentration be octreotide, vapreotide, the Lanreotide solution 1mL of 100 μ g/mL, parallel 3 parts, after 37 DEG C of temperature incubate the regular hour (0,10,30,60,120,180 minute), by 3mL ice acetonitrile cessation reaction, centrifugal 10 minutes of 30000g, gets supernatant LC-MS/MS and detects.
3rd step: calculate residual volume.Be 100% residual volume with 0 minute drug level, the ratio of the drug level of each time point and 0 minute concentration is the residual volume of each time point.The results are shown in Figure 2, kind somatostatin analogue polypeptide octreotide, vapreotide, Lanreotide have the phenomenon of slowly degraded in simulated intestinal fluid, and the stability strong or weak relation of three peptide species is octreotide > vapreotide > Lanreotide.
Blood drug level after embodiment 3 rat intravenous injection and gavage three kinds of somatostatin analogue polypeptide through time process:
The first step: by 30 male SD rats, 180-200g, is divided into 6 groups at random, often organizes 5, is respectively octreotide intravenous injection group, octreotide gavage group, vapreotide intravenous injection group, vapreotide gavage group, Lanreotide intravenous injection group, Lanreotide gavage group.
Second step: before administration, all Rat Fast can't help water 12h.The intravenous injection group of three peptide species carries out tail vein injection with the dosage of 0.1mg/kg to rat, gets blood at 2,5,10,20,40,60,90,120,240 minutes in heparinization EP pipe; Gavage group respectively with 15,30, dosage gavage three peptide species of 60mg/kg at aqueous solution, blood is got in heparinization EP pipe at 2,5,10,20,40,60,90,120,240,360,480 minutes, centrifugal 5 minutes of rat blood 2000g, gets blood plasma to be measured.
3rd step: get rat plasma 100 μ L, adds 500 μ L containing interior target acetonitrile precipitation albumen, vortex mixed, centrifugal 10 minutes of 30000g, get supernatant 500 μ L, add the anti-concentration contracting of 400 μ L dichloromethane, vortex mixed, the centrifugal 10min of 6000g, gets supernatant sample introduction, and LC-MS/MS measures blood drug level.
4th step: take time as abscissa, blood drug level is vertical coordinate, draws blood concentration-time curve in the rat body after the intravenous injection of three kinds of somatostatin analogue polypeptide and oral administration gavage, calculates relevant pharmacokinetic parameters with WinNonlin6.3.The blood concentration-time curve of three peptide species is shown in Fig. 3, Fig. 4, Fig. 5, and relevant pharmacokinetic parameters is in table 1, table 2, table 3.Result shows, all has absorption to a certain degree after three kinds of somatostatin analogue polypeptide, three dosage gavages in rat body.
The pharmacokinetic parameters of the intravenous injection of table 1 octreotide and gavage
The pharmacokinetic parameters of the intravenous injection of table 2 vapreotide and gavage
The pharmacokinetic parameters of the intravenous injection of table 3 Lanreotide and gavage
5th step: the absolute bioavailability calculating three kinds of somatostatin analogue polypeptide.According to formula F=AUC
i.gd
i.v/ AUC
i.vd
i.g, calculate oral absolute bioavailability.As calculated, the absolute bioavailability of octreotide three dosage is 0.36%, 0.48%, 0.43%; The absolute bioavailability of vapreotide three dosage is 0.18%, 0.24%, 0.29%; The absolute bioavailability of Lanreotide three dosage is 0.18%, 0.21%, 0.25%.
Claims (4)
1. the oral administration route of somatostatin analogue polypeptide octreotide, Lanreotide, vapreotide, wherein
Octreotide structure is:
Lanreotide structure is:
For general peptide structure be:
.
2. three peptide species medicines as claimed in claim 1, is characterized in that: in simulated gastric fluid, all can keep stable be not degraded.
3. three peptide species medicines as claimed in claim 1, is characterized in that: can be degraded gradually in simulated intestinal fluid, and it is octreotide > vapreotide > Lanreotide that its stability is closed.
4. three peptide species medicines as claimed in claim 1, it is characterized in that: after oral administration gavage, three peptide species all can measure medicine in vivo, and can be used for representing blood drug level through time process; In addition, each medicine distributes higher in target tissue.
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Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN108440664A (en) * | 2018-03-27 | 2018-08-24 | 上海欣科医药有限公司 | A kind of SMS 201-995 and its preparation method and application for cancer detection |
| CN111068041A (en) * | 2020-01-19 | 2020-04-28 | 中国药科大学 | Application of octreotide in preparation of medicine for treating ulcerative colitis |
| CN112138141A (en) * | 2019-06-10 | 2020-12-29 | 苏州兰鼎生物制药有限公司 | Oral pharmaceutical composition of somatostatin or analogue thereof |
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| CN1334742A (en) * | 1998-07-30 | 2002-02-06 | 研究及应用科学协会股份有限公司 | Method of using lanreotide as somatostatin analogue |
| US20020164365A1 (en) * | 1995-04-13 | 2002-11-07 | Shalaby Shalaby W. | Multifaceted compositions for post-surgical adhesion prevention |
| CN104667258A (en) * | 2015-03-20 | 2015-06-03 | 陈卓杰 | Octreotide acetate tablet and preparation method thereof |
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2015
- 2015-09-02 CN CN201510559263.0A patent/CN105168115A/en active Pending
Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US20020164365A1 (en) * | 1995-04-13 | 2002-11-07 | Shalaby Shalaby W. | Multifaceted compositions for post-surgical adhesion prevention |
| CN1334742A (en) * | 1998-07-30 | 2002-02-06 | 研究及应用科学协会股份有限公司 | Method of using lanreotide as somatostatin analogue |
| CN104667258A (en) * | 2015-03-20 | 2015-06-03 | 陈卓杰 | Octreotide acetate tablet and preparation method thereof |
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| Title |
|---|
| FENG CHEN ET AL: ""Mechanisms of action of long-acting analogs of somatostatin"", 《REGULATORY PEPTIDES》 * |
| R Z CAI ET AL: ""Synthesis of biological activity of highly potent octapeptide analogs of somatostatin"", 《PROC. NATL. ACAD. SCI》 * |
| 孙定人: "《国家临床新药集》", 28 February 2001 * |
| 王德心: "《活性多肽与药物开发》", 30 June 2008 * |
| 由品英: "《常用进口药物手册》", 31 October 1995 * |
Cited By (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN108440664A (en) * | 2018-03-27 | 2018-08-24 | 上海欣科医药有限公司 | A kind of SMS 201-995 and its preparation method and application for cancer detection |
| CN112138141A (en) * | 2019-06-10 | 2020-12-29 | 苏州兰鼎生物制药有限公司 | Oral pharmaceutical composition of somatostatin or analogue thereof |
| CN112138141B (en) * | 2019-06-10 | 2024-04-09 | 苏州兰鼎生物制药有限公司 | Oral pharmaceutical composition of somatostatin or analogue thereof |
| CN111068041A (en) * | 2020-01-19 | 2020-04-28 | 中国药科大学 | Application of octreotide in preparation of medicine for treating ulcerative colitis |
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Application publication date: 20151223 |