CN104225579B - Nasal cavity administrated preparation containing recombinant human somatropin and preparation method thereof - Google Patents
Nasal cavity administrated preparation containing recombinant human somatropin and preparation method thereof Download PDFInfo
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- CN104225579B CN104225579B CN201310240170.2A CN201310240170A CN104225579B CN 104225579 B CN104225579 B CN 104225579B CN 201310240170 A CN201310240170 A CN 201310240170A CN 104225579 B CN104225579 B CN 104225579B
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- 102000002265 Human Growth Hormone Human genes 0.000 title claims abstract description 49
- 108010000521 Human Growth Hormone Proteins 0.000 title claims abstract description 49
- 239000000854 Human Growth Hormone Substances 0.000 title claims abstract description 49
- 210000003928 nasal cavity Anatomy 0.000 title claims abstract description 38
- 229960004532 somatropin Drugs 0.000 title claims abstract description 38
- 238000002360 preparation method Methods 0.000 title claims abstract description 34
- 239000000227 bioadhesive Substances 0.000 claims abstract description 9
- 239000000463 material Substances 0.000 claims abstract description 9
- 239000003655 absorption accelerator Substances 0.000 claims abstract description 8
- 239000000843 powder Substances 0.000 claims description 8
- 229920001661 Chitosan Polymers 0.000 claims description 6
- 210000001331 nose Anatomy 0.000 claims description 6
- 239000003381 stabilizer Substances 0.000 claims description 6
- 239000003223 protective agent Substances 0.000 claims description 5
- DHMQDGOQFOQNFH-UHFFFAOYSA-N Glycine Chemical compound NCC(O)=O DHMQDGOQFOQNFH-UHFFFAOYSA-N 0.000 claims description 4
- 229930006000 Sucrose Natural products 0.000 claims description 4
- 239000000337 buffer salt Substances 0.000 claims description 4
- 229930182470 glycoside Natural products 0.000 claims description 4
- 239000005720 sucrose Substances 0.000 claims description 4
- RVGRUAULSDPKGF-UHFFFAOYSA-N Poloxamer Chemical compound C1CO1.CC1CO1 RVGRUAULSDPKGF-UHFFFAOYSA-N 0.000 claims description 3
- 230000006196 deacetylation Effects 0.000 claims description 3
- 238000003381 deacetylation reaction Methods 0.000 claims description 3
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- BHZOKUMUHVTPBX-UHFFFAOYSA-M sodium acetic acid acetate Chemical compound [Na+].CC(O)=O.CC([O-])=O BHZOKUMUHVTPBX-UHFFFAOYSA-M 0.000 claims description 3
- HDTRYLNUVZCQOY-UHFFFAOYSA-N α-D-glucopyranosyl-α-D-glucopyranoside Natural products OC1C(O)C(O)C(CO)OC1OC1C(O)C(O)C(O)C(CO)O1 HDTRYLNUVZCQOY-UHFFFAOYSA-N 0.000 claims description 2
- NIXOWILDQLNWCW-UHFFFAOYSA-N Acrylic acid Chemical compound OC(=O)C=C NIXOWILDQLNWCW-UHFFFAOYSA-N 0.000 claims description 2
- GUBGYTABKSRVRQ-XLOQQCSPSA-N Alpha-Lactose Chemical compound O[C@@H]1[C@@H](O)[C@@H](O)[C@@H](CO)O[C@H]1O[C@@H]1[C@@H](CO)O[C@H](O)[C@H](O)[C@H]1O GUBGYTABKSRVRQ-XLOQQCSPSA-N 0.000 claims description 2
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- 239000004471 Glycine Substances 0.000 claims description 2
- KDXKERNSBIXSRK-YFKPBYRVSA-N L-lysine Chemical compound NCCCC[C@H](N)C(O)=O KDXKERNSBIXSRK-YFKPBYRVSA-N 0.000 claims description 2
- GUBGYTABKSRVRQ-QKKXKWKRSA-N Lactose Natural products OC[C@H]1O[C@@H](O[C@H]2[C@H](O)[C@@H](O)C(O)O[C@@H]2CO)[C@H](O)[C@@H](O)[C@H]1O GUBGYTABKSRVRQ-QKKXKWKRSA-N 0.000 claims description 2
- KDXKERNSBIXSRK-UHFFFAOYSA-N Lysine Natural products NCCCCC(N)C(O)=O KDXKERNSBIXSRK-UHFFFAOYSA-N 0.000 claims description 2
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- CZMRCDWAGMRECN-UGDNZRGBSA-N Sucrose Chemical compound O[C@H]1[C@H](O)[C@@H](CO)O[C@@]1(CO)O[C@@H]1[C@H](O)[C@@H](O)[C@H](O)[C@@H](CO)O1 CZMRCDWAGMRECN-UGDNZRGBSA-N 0.000 claims description 2
- HDTRYLNUVZCQOY-WSWWMNSNSA-N Trehalose Natural products O[C@@H]1[C@@H](O)[C@@H](O)[C@@H](CO)O[C@@H]1O[C@@H]1[C@H](O)[C@@H](O)[C@@H](O)[C@@H](CO)O1 HDTRYLNUVZCQOY-WSWWMNSNSA-N 0.000 claims description 2
- ZOIORXHNWRGPMV-UHFFFAOYSA-N acetic acid;zinc Chemical compound [Zn].CC(O)=O.CC(O)=O ZOIORXHNWRGPMV-UHFFFAOYSA-N 0.000 claims description 2
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- HDTRYLNUVZCQOY-LIZSDCNHSA-N alpha,alpha-trehalose Chemical compound O[C@@H]1[C@@H](O)[C@H](O)[C@@H](CO)O[C@@H]1O[C@@H]1[C@H](O)[C@@H](O)[C@H](O)[C@@H](CO)O1 HDTRYLNUVZCQOY-LIZSDCNHSA-N 0.000 claims description 2
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- 125000003438 dodecyl group Chemical group [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])* 0.000 claims description 2
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- 239000008101 lactose Substances 0.000 claims description 2
- TWNIBLMWSKIRAT-VFUOTHLCSA-N levoglucosan Chemical compound O[C@@H]1[C@@H](O)[C@H](O)[C@H]2CO[C@@H]1O2 TWNIBLMWSKIRAT-VFUOTHLCSA-N 0.000 claims description 2
- 239000007787 solid Substances 0.000 claims description 2
- XPFJYKARVSSRHE-UHFFFAOYSA-K trisodium;2-hydroxypropane-1,2,3-tricarboxylate;2-hydroxypropane-1,2,3-tricarboxylic acid Chemical compound [Na+].[Na+].[Na+].OC(=O)CC(O)(C(O)=O)CC(O)=O.[O-]C(=O)CC(O)(CC([O-])=O)C([O-])=O XPFJYKARVSSRHE-UHFFFAOYSA-K 0.000 claims description 2
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- 241001289435 Astragalus brachycalyx Species 0.000 claims 1
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- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims 1
- 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 claims 1
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- 229910052708 sodium Inorganic materials 0.000 claims 1
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- DFIWJEVKLWMZBI-UHFFFAOYSA-M sodium;dihydrogen phosphate;phosphoric acid Chemical compound [Na+].OP(O)(O)=O.OP(O)([O-])=O DFIWJEVKLWMZBI-UHFFFAOYSA-M 0.000 claims 1
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- QFAADIRHLBXJJS-ZAZJUGBXSA-N amastatin Chemical compound CC(C)C[C@@H](N)[C@H](O)C(=O)N[C@@H](C(C)C)C(=O)N[C@@H](C(C)C)C(=O)N[C@H](C(O)=O)CC(O)=O QFAADIRHLBXJJS-ZAZJUGBXSA-N 0.000 description 2
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- ASWBNKHCZGQVJV-UHFFFAOYSA-N (3-hexadecanoyloxy-2-hydroxypropyl) 2-(trimethylazaniumyl)ethyl phosphate Chemical compound CCCCCCCCCCCCCCCC(=O)OCC(O)COP([O-])(=O)OCC[N+](C)(C)C ASWBNKHCZGQVJV-UHFFFAOYSA-N 0.000 description 1
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- Medicinal Preparation (AREA)
- Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
Abstract
The invention discloses a kind of nasal cavity administrated preparation containing recombinant human somatropin and preparation method thereof, the described nasal cavity administrated preparation containing recombinant human somatropin, by weight percentage, contain: mucosal absorption accelerator 0.1～30%, bioadhesive material 0.1～50%, recombinant human somatropin 1～30%.It is an advantage of the current invention that: simple and easy to do, be suitable for industrialized production.Preparation process does not use organic solvent, destroys less to the activity of recombinant human somatropin, and the medicine carrying microgranule of the present invention can dramatically increase the nasal cavity holdup time, and the per nasal increasing human growth hormone absorbs, and improves bioavailability.
Description
Technical field
The present invention relates to field of medicaments, specially one is used for treating endogenous growth hormone deficiency disease, chronic kidney hypofunction, spy
Receive children growth caused by syndrome slowly and the disease such as severe burn, nasal cavity administrated preparation containing recombinant human somatropin and
Its preparation method.
Background technology
Recombinant human somatropin (rhGH), since within 1985, coming out, has thoroughly solved corpse source property people GH source rare and latent
Infect in gastral cavity virus and cause the sick problem of Creutzfeldt-Jakob, provide for growth hormone deficiency (GHD) patient and control
Treatment approach.It has the effect equal with human endogenous's growth hormone, and the body weight of Hypophysectomy rat can be made to increase, and promotes tibia
And cartilage-derived growth.Also have simultaneously and promote whole body protein synthesis, correct the post-traumatic negative nitrogen balance states such as operation, immune stimulatory
Globulin synthesizes, and stimulates lymphoid tissue, macrophage and the propagation of lymphocyte, strengthens anti-infection ability；Stimulate burn wound
Face and otch collagenocyte, macrophage division growth, the effect of accelerating wound healing.
RhGH has passed through the clinical verification of more than 20 year in the application of human body up to now, and its effectiveness and safety obtain
The generally accreditation of doctor and patient.The application crowd of rhGH is also gradually expanding simultaneously, and FDA has had been approved by child GHD, slow
Property renal insufficiency, HIV be correlated with wasting syndrome, adult's GHD, Turner syndrome, small for gestational age infant (SGA), special send out
Property Short stature (ISS), short bowel syndrome, more than 10 rhGH indications such as Prader-Willi syndrome.
For a long time, rule uses rhGH to be the basis that rhGH treatment reaches optimum curative effect.Official listing in global range at present
The rhGH used needs drug administration by injection every day, child GHD to be up to 3 months to 3 years the course for the treatment of, makes patient not only bear because of injection band
The misery come, must undertake the financial burden that the many lives thus brought are inconvenient and extra, reduce patient compliance, impact
The long-term efficacy of rhGH treatment.Certain children's hospital's endocrine clinic portion data shows, after needing injection every day because of consulting rhGH
And about the 5～10% of abandoning cure.The external research delivered shows, accepts the child patient of rhGH injection for curing, 23%
Monthly can no marking at least 3 times, in the treatment phase of 2 years, the infant of 13% can cause actually used dosage to reduce because of no marking
More than 50%.Another adds up display, injection compliance only 36～49%, and 70% patient feels bad, and 30% considers to stop treatment
(Frost & Sullivan)。
Both at home and abroad some pharmacy corporations and research and development institution are devoted to the exploitation of rhGH durative action preparation, by slow controlled-release technology or
Chemical modification method improves the Pharmacokinetic Characteristics of rhGH, increases patient compliance.But the application surface of rhGH durative action preparation
Face some potential problems, as whether the blood GH concentration change after injection different from physiologic secretion pattern can affect GH durative action preparation
Curative effect？Whether the GH concentration of continual high levels can cause safety issue？How slow releasing preparation injection site local response solves
Certainly？First PLGA sustained-release micro-spheres Nutropin through FDA approvalBecause the reasons such as unsatisfactory curative effect and local side reaction
Stop selling.
Developing non-injection fugitive GH drug-supplying system is to meet treatment to require and relative safer administering mode have length
The advantage that effect injection delivery systems is incomparable.Such as mucosa deliveries such as per nasal, lung, eye, oral cavity, rectum, wherein nasal-cavity administration grinds
Study carefully more.
Up to now, the nasal-cavity administration about recombinant human somatropin is studied and is shown, although nasal cavity has bigger absorption
Area and abundant blood supply, but protein-based macromolecular drug is still difficult through bronchia mucosal.(1) albumen penetrates mucosa ability
Difference, albumen is too big due to molecular weight, and the ability therefore penetrating bronchia mucosal is relatively low;(2) Nasal mucociliary has quick removing machine
System, shortens the medicine holdup time at nasal absorption position, affects the bioavailability of medicine;(3) nasal cavity there may be
The Degradation of enzyme.
Absorb problem for solving the per nasal of recombinant human somatropin, have a lot by adding various absorption enhancement in the formulation
Agent improves the research of human growth hormone's bioavailability, but great majority not can exceed that hypodermic 30%, also implies that
Drug effect does not reaches the effect of drug administration by injection.Such as Pharm Res, 1990,7 (7): 772 report growth hormone give through rat nasal cavity,
When employing LYSOLECITHIN SUNLECITHIN A is accelerator, relative bioavailability is 25.8%, when being accelerator with hydrochloric acid amastatin
Relative bioavailability is 28.9%.The research of Eur.J.Pharm.Sci.26 (2005) 9-15 shows, sheep nasal cavity grows
Hormone and the powder mixture of chitosan, with subcutaneous injection ratio, bioavailability about 15%.
In sum, although having been carried out multiple trial to improve the absorption of human growth hormone's nose administration, but the most still
Fail to reach the effect suitable with subcutaneous injection, it is still desirable to improve the biological utilisation of human growth hormone's nose administration further
Degree.
Summary of the invention
It is an object of the invention to provide a kind of nasal cavity administrated preparation containing recombinant human somatropin and preparation method thereof,
With the defect overcoming prior art to exist, meet the needs of clinical practice.
The described nasal cavity administrated preparation containing recombinant human somatropin, by weight percentage, contains:
Mucosal absorption accelerator 0.1～30%
Bioadhesive material 0.1～50%
Recombinant human somatropin 1～30%
Preferably, by weight percentage, contain:
Mucosal absorption accelerator 2～23%
Bioadhesive material 1～7%
Recombinant human somatropin 6～12%
Described mucosal absorption accelerator selected from cyclodextrin or derivatives thereof, alkyl polyglucoside class surfactant, cholic acid salt,
More than one in amastatin, phospholipid or derivatives thereof；
Preferably mucosal absorption accelerator is alkyl polyglucoside class surfactant, more preferably eight/ten/12/14
Alkylmaltosides, sucrose glycosides or glucoside；
Bioadhesive material is selected from chitosan, gellan gum, amination gelatin, cellulose or derivatives thereof, carbomer or saturating
Bright matter acid etc. in more than one；
Preferably bioadhesive material is chitosan, molecular weight 50,000～1,000,000, and deacetylation > 85%.
The molecular weight of described recombinant human somatropin is～22,000Da, can be to have 191 amino acid residues and sky
So human growth hormone's structure and on all four albumen of aminoacid sequence, it is also possible to be that N-end increases the 192 of a methionine
The albumen of individual amino acid residue composition.Described recombinant human somatropin can also be molecular weight be 20KD, 176 aminoacid are residual
Base, the recombinant human somatropin of disappearance 32～46 15 amino acid residues of Native human growth hormone.
Preferably, the described nasal cavity administrated preparation containing recombinant human somatropin, also include protective agent, described protective agent
More than one in lactose, sucrose, trehalose, mannitol or glucosan etc., the work of growth hormone in dry run
Property protection；
It is further preferred that the described nasal cavity administrated preparation containing recombinant human somatropin, also include stabilizer, described
Stabilizer is selected from more than one in glycine, lysine, zinc acetate or poloxamer etc., for improving stablizing of growth hormone
Property；
Preferably, the described nasal cavity administrated preparation containing recombinant human somatropin, also include the buffer salt of pH=5～8,
The buffer of described pH=5～8 is selected from Acetic acid-sodium acetate, citric acid-sodium citrate or sodium dihydrogen phosphate-disodium hydrogen phosphate etc.；
Particularly preferred, the described nasal cavity administrated preparation containing recombinant human somatropin, including following percentage by weight
Component:
Particularly preferred, the described nasal cavity administrated preparation containing recombinant human somatropin, including following percentage by weight
Component:
The preparation method of the present invention, comprises the steps:
(1) bioadhesive material is dissolved in pH buffer, is subsequently adding recombinant human somatropin；
(2) in above-mentioned solution, add mucosal absorption accelerator, protective agent and stabilizer, use this area routine
Method, is dried, it is thus achieved that the described nasal cavity administrated preparation containing recombinant human somatropin；
Described drying means is conventional, including the method such as lyophilization or spray drying；
(3) dried solid is crossed 100 mesh sieves, obtain 30-150 μm powder, be according to dosage sub-packed in powder nose inhalant device
In.
The nasal cavity administrated preparation containing recombinant human somatropin of the present invention, can pass through nasal-cavity administration, and dosage is generally
0.1-0.15IU/kg/ days, specifically can determine by doctor according to the state of an illness of patient, age；
It is an advantage of the current invention that: simple and easy to do, be suitable for industrialized production.Preparation process does not use organic solvent, counterweight
The activity of group human growth hormone is destroyed less, and the medicine carrying microgranule of the present invention can dramatically increase the nasal cavity holdup time, increases people's growth
The per nasal of hormone absorbs, and improves bioavailability.
Accompanying drawing explanation
Fig. 1 is rat nasal cavity and subcutaneous injection gives the Drug-time curve after rhGH.
Wherein: in represents nasal-cavity administration, sc represents subcutaneous injection；
Fig. 2 is rabbit nasal cavity and subcutaneous injection gives the Drug-time curve after rhGH.
Wherein: in represents embodiment 2 nasal-cavity administration, and sc represents subcutaneous injection.
Detailed description of the invention
Embodiment 1
Prescription: (percentage by weight)
Bioadhesive material chitosan (deacetylation is more than 85%) is dissolved in Acetic acid-sodium acetate solution, it is thus achieved that solution
A。
Recombinant human somatropin is added in solution A；
Adding mannitol, Lauryl.beta.-maltoside, poloxamer F68, mix homogeneously, lyophilization, 100 mesh sieve
To 30-150 μm powder, it is sub-packed in nose dust cloud device, to obtain final product.
Recombinant human somatropin is the complete with Native human growth hormone's structure and aminoacid sequence of 191 amino acid residues
The most consistent albumen.
Embodiment 2
Prescription: (percentage by weight)
Recombinant human somatropin increases the albumen of 192 amino acid residue compositions of a methionine for N-end.
Preparation method is with embodiment 1.
Embodiment 3
Prescription: (percentage by weight)
Recombinant human somatropin is molecular weight 20KD, 176 amino acid residues, disappearance Native human growth hormone 32～46
The recombinant human somatropin of 15 amino acid residues.
Preparation method is with embodiment 1.
Embodiment 4
Prescription: (percentage by weight)
Recombinant human somatropin increases the albumen of 192 amino acid residue compositions of a methionine for N-end.
Preparing solution with example 1 method, be uniformly spray-dried after mixing, 100 mesh sieve and obtain 30-150 μm powder.To contain
The dry powder having 0.2～3mg recombinant human somatropin is sub-packed in nose dust cloud device, to obtain final product.
Embodiment 5
After the anesthesia of about 300g rat pentobarbital sodium, nasal cavity gives the rhGH powder spray of embodiment 1 and (contains respectively
And cervical region subcutaneous injection 1.5mg rhGH solution (n=2) rhGH1.5mg).0,10 it is quiet that, 30,45,60,90,120,180min adopts neck
Arteries and veins blood, low-temperature centrifugation separation serum, hGH ELISA kit measures blood drug level.Result is shown in accompanying drawing 1.
Fig. 1 is visible, and rat nasal cavity gives the rhGH powder spray of embodiment 1, and 30min is up to absorption peak, peak concentration and skin
Hemostasis is administered close.It is administered latter 3 hours nasal-cavity administration bioavailability up to hypodermic more than 50%.
Embodiment 6
2.5kg new zealand white rabbit nasal cavity respectively gives the rhGH powder spray (containing rhGH2.5mg) of embodiment 2,2.5mg
RhGH solution, cervical region subcutaneous injection 2.5mg rhGH solution (n=2).0,10,30,45,60,90,120min ear edge vein exploitating blood,
Low-temperature centrifugation separation serum, hGH ELISA kit measures blood drug level.Result is shown in accompanying drawing 2.
Fig. 2 is visible, and rabbit nasal cavity gives the rhGH powder spray of embodiment 2, and 30min is up to absorption peak, and peak concentration is slightly below
Same dose subcutaneous administrations, is administered latter 2 hours nasal-cavity administration bioavailability up to hypodermic more than 50%.And rabbit
Nasal cavity gives rhGH solution almost without absorption.Confirm the present invention powder spray can dramatically increase human growth hormone through snuffing
Receive, improve bioavailability.
Claims (3)
1. contain the nasal cavity administrated preparation of recombinant human somatropin, it is characterised in that by weight percentage, contain:
The percentage ratio sum of component is 100%
Described mucosal absorption accelerator is selected from Lauryl.beta.-maltoside, eight/ten alkyl-glucose glycoside, 12/tetradecane
Base-glucose glycoside or ten alkyl sucrose glycosides；
Described bioadhesive material selected from chitosan, gellan gum, amination gelatin, cellulose or derivatives thereof, carbomer or
More than one in hyaluronic acid, chitosan, molecular weight 50,000～1,000,000, deacetylation > 85%；
The molecular weight of described recombinant human somatropin is～22,000Da.
Nasal cavity administrated preparation containing recombinant human somatropin the most according to claim 1, it is characterised in that also include protecting
Protect agent, stabilizer or pH=5～8 buffer salt in more than one, described protective agent be selected from lactose, sucrose, trehalose, manna
More than one in alcohol or glucosan；
Described stabilizer is selected from more than one in glycine, lysine, zinc acetate or poloxamer；
The buffer salt of described pH=5～8 is selected from Acetic acid-sodium acetate, citric acid-sodium citrate or sodium dihydrogen phosphate-phosphoric acid hydrogen two
Sodium.
3. according to the preparation method of the nasal cavity administrated preparation containing recombinant human somatropin described in any one of claim 1～2,
It is characterized in that, comprise the steps:
(1) bioadhesive material is dissolved in the buffer of buffer salt preparation, is subsequently adding recombinant human somatropin；
(2) in above-mentioned solution, add mucosal absorption accelerator, protective agent and stabilizer, use lyophilization or spray dried
Dry, it is thus achieved that the described nasal cavity administrated preparation containing recombinant human somatropin；
(3) dried solid is crossed 100 mesh sieves, obtain 30-150 μm powder, be according to dosage sub-packed in powder nose inhalant device.
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