CN108853010A - How the smooth cyclodextrin inclusion compound of appropriate pyrrole, compound combined formulation and its preparation method and application - Google Patents
How the smooth cyclodextrin inclusion compound of appropriate pyrrole, compound combined formulation and its preparation method and application Download PDFInfo
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
- A61K31/496—Non-condensed piperazines containing further heterocyclic rings, e.g. rifampin, thiothixene or sparfloxacin
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/47—Quinolines; Isoquinolines
- A61K31/473—Quinolines; Isoquinolines ortho- or peri-condensed with carbocyclic ring systems, e.g. acridines, phenanthridines
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
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Abstract
The invention belongs to field of medicaments, and in particular to it is a kind of how the smooth cyclodextrin inclusion compound of appropriate pyrrole, compound combined formulation and preparation method thereof.The present invention provides it is a kind of how appropriate pyrrole it is smooth or derivatives thereof formed with cyclodextrin or derivatives thereof how the smooth cyclodextrin inclusion compound of appropriate pyrrole.The method of the present invention by will how appropriate pyrrole it is smooth or derivatives thereof included with cyclodextrin or derivatives thereof to obtain how the smooth cyclodextrin inclusion compound of appropriate pyrrole, significantly improve how appropriate pyrrole is smooth and its water solubility and stability of derivative.Simultaneously the invention further relates to how smooth or derivatives thereof the cyclodextrin inclusion compound of appropriate pyrrole combine with palonosetron to be formed how appropriate pyrrole it is smooth/palonosetron compound combined formulation.
Description
Technical field
The present invention relates to field of medicaments, and in particular to it is a kind of how the smooth cyclodextrin inclusion compound of appropriate pyrrole, compound combined formulation and its
Preparation method.
Background technique
Chemotherapy is the common method of current treatment malignant tumour, but most chemotherapeutics can cause different degrees of nausea,
It vomits (CINV), such as cis-platinum, incidence of vomiting is up to 90%.Frequent and violent vomiting may interfere with food intake, cause to lose
Water and rock-soil coupling, acid-base imbalance, dystrophia, or even the complication such as esophagus and cardia mucous membrane lacerated wound occur not only can shadow
It rings the quality of life of patient, reduce the compliance of patient, and make oncotherapy effect undesirable.In addition to this, nausea is vomitted
Common one of side effect when being tumor radiotherapy is spat, most of is because caused by gastrointestinal dysfunction caused by radiotherapy.Therefore
Prevent or alleviate the important research content that CINV phenomenon is oncotherapy by drug.
How appropriate pyrrole smooth (netuppitant) is a kind of new drug, as a kind of nk 1 receptor retarding agent, can effectively be given protection against cancer in advance
The nausea and vomiting that disease chemotherapy acute stage and period of delay (in starting chemotherapy 25~120 hours) generate.How the smooth chinesization of appropriate pyrrole
Scientific name claims：2- [3,5- bis- (trifluoromethyl) phenyl]-N, 2- dimethyl-N-[(shout -1- 4- (2- aminomethyl phenyl) -6- by 4- methyl piperazine
Base) pyridin-3-yl] propionamide；English language Chemical name：2-[3,5-bis(trifluoromethyl)phenyl]-N,2-
dimethy-N-l[4-(2-methylphenyl)-6-(4-methyIpiperaz in-l-yl)pyridin-3-yI]
propanamide；Molecular weight：578.60；Molecular formula：C30H32F6N4O, CAS registration number：290297-26-6.
Palonosetron (palonosetron) is a kind of inhibition nausea and vomiting medicine, is belonged to novel highly selective, high affine
Property 5-HT3 receptor antagonist, it can block the excitement of the presynaptic 5-HT receptor of vomiting reflex maincenter peripheral neurons, and directly
The effect got excited through vagus nerve successor back zone that 5-HT receptor agonism in central nervous system generates is influenced, is blocked in enteron aisle
Vagus nerve ending prevents signal from being transferred to 5-HT receptor trigger region, reduces the incidence of nausea and vomiting.Clinically for controlling
It treats as in, severe causes acute, retardance nausea and vomiting caused by spitting property chemotherapeutics.Because it is with curative effect height, toxic side effect
Small, long half time (about 40h), the features such as dosage is small and be concerned.In July, 2003, palonosetron is because of its long-term effect
With it is highly selective become the 1st be approved by the fda in the United States for moderate cause vomitting property chemotherapeutics caused by retardance Nausea and vomiting
Prophylactic agent.It is also the 4th 5-HT3 receptor antagonist for being approved for treating acute CINV, while also going through to use
In the prevention of postoperative nauseaand vomiting (PONV).
Cyclodextrin is a series of cyclic oligosaccharides that amylose generates under cyclodextrin glycosyltransferase effect
General name, usually contains 6~12 D- glucopyranose units, the cylindrical shape that molecular structure tapers slightly, and one end is big, one end
It is small, make entire molecule in internal drainage, the structure of external hydrophilicity.This special molecular structure, making can be with envelope in its hydrophobic cavity
Some inorganic, organic molecules combine and form stable inclusion compound, to change the solubility of guest molecule, volatility and chemically
The physicochemical properties such as energy have protection, stablize, the characteristic of solubilized guest molecule and selectivity oriented molecule.And this inclusion compound
Structure is highly stable, not the influence vulnerable to external conditions such as enzyme, pH, heat.As modifying agent, stabilizer, adsorbent, excipient
Deng being all widely used in food, environmental protection, medicine and other fields.
Summary of the invention
For how the defect of the smooth poorly water-soluble of appropriate pyrrole, the method for the present invention will how appropriate pyrrole be smooth with cyclodextrin encapsulated, ultimately forms
How appropriate pyrrole smooth cyclodextrin inclusion compound.The method of the present invention improve how the smooth water solubility of appropriate pyrrole, enhance how the smooth curative effect of appropriate pyrrole,
To broadening how the smooth use scope of appropriate pyrrole.The how appropriate smooth cyclodextrin inclusion compound of pyrrole has water-soluble good, character stabilization, freeze-drying
It easily redissolves, easily absorb, bioavilability is high, the advantages that being injected intravenously.Meanwhile the present invention also provides one kind by how appropriate pyrrole is smooth
Cyclodextrin inclusion compound and palonosetron or derivatives thereof combine the compound combined formulation formed, are used for combination therapy CINV symptom,
Have the advantages that significant in efficacy.
First problem to be solved by this invention be to provide it is a kind of how the preparation method of the smooth cyclodextrin inclusion compound of appropriate pyrrole.It should
Preparation method includes the following steps：Will how appropriate pyrrole is smooth or derivatives thereof is dissolved into organic solvent, cyclodextrin or derivatives thereof is molten
Solution remixes uniformly into aqueous solution, then stirs to solution and clarifies, and removal organic solvent is up to how appropriate pyrrole is smooth cyclodextrin encapsulated
Object aqueous solution, re-dry go to remove water up to how the smooth cyclodextrin inclusion compound of appropriate pyrrole.
Preferably, above-mentioned how in the preparation method of the smooth cyclodextrin inclusion compound of appropriate pyrrole, how appropriate pyrrole is smooth or derivatives thereof is pasted with ring
Essence or derivatives thereof mass ratio is 0.001~0.087.Further preferably 0.087.
Preferably, above-mentioned how in the preparation method of the smooth cyclodextrin inclusion compound of appropriate pyrrole, described how how appropriate the smooth derivative of appropriate pyrrole is
The smooth phosphate of pyrrole.
Preferably, above-mentioned how in the preparation method of the smooth cyclodextrin inclusion compound of appropriate pyrrole, described cyclodextrin or derivatives thereof is selected from
Any one in beta-cyclodextrin or derivatives thereof, gamma-cyclodextrin or derivatives thereof.
Preferably, above-mentioned how in the preparation method of the smooth cyclodextrin inclusion compound of appropriate pyrrole, the beta-cyclodextrin derivative is hydroxypropyl
Group-beta-cyclodextrin；The gamma-cyclodextrin derivative is hydropropyl-y-cyclodextrin.
Preferably, above-mentioned how in the preparation method of the smooth cyclodextrin inclusion compound of appropriate pyrrole, the organic solvent be methanol, ethyl alcohol or
At least one of acetone.Preferable organic solvent is acetone.The aqueous solution is in pure water, physiological saline or glucose solution
It is at least one.Preferably pure water.
The present invention provides by it is above-mentioned how the preparation method of the smooth cyclodextrin inclusion compound of appropriate pyrrole be prepared how the smooth ring of appropriate pyrrole
Cyclodextrin inclusion compound aqueous solution.
The present invention provides by it is above-mentioned how the preparation method of the smooth cyclodextrin inclusion compound of appropriate pyrrole be prepared how the smooth ring of appropriate pyrrole
Cyclodextrin inclusion compound.
The present invention also provides by it is above-mentioned how the smooth cyclodextrin inclusion compound aqueous solution of appropriate pyrrole and palonosetron or derivatives thereof water
Solution be uniformly mixed obtain how the smooth cyclodextrin inclusion compound of appropriate pyrrole and palonosetron or derivatives thereof compound combined formulation solution.Again
The smooth cyclodextrin inclusion compound of the how appropriate pyrrole and palonosetron or derivatives thereof compound combined formulation solution are drying to obtain how appropriate pyrrole is smooth
Cyclodextrin inclusion compound and palonosetron or derivatives thereof compound combined formulation.The compound combined formulation can be prepared into powder-injection, piece
Agent, capsule or injection.
Preferably, in above-mentioned compound combined formulation aqueous solution or compound combined formulation, the palonosetron derivative is to appoint
It anticipates a kind of palonosetron salt compounds, such as palonosetron hydrochloride, phosphoric acid palonosetron.It is preferred that palonosetron hydrochloride.
The present invention also provides it is above-mentioned how the smooth cyclodextrin inclusion compound aqueous solution of appropriate pyrrole or how the smooth cyclodextrin inclusion compound of appropriate pyrrole, on
It states compound combined formulation solution or compound combined formulation and alleviates the vomiting caused by chemotherapy, radiotherapy and operation, nausea in preparation
(CINV) purposes in the drug of symptom.
The present invention also provides it is above-mentioned how the smooth cyclodextrin inclusion compound aqueous solution of appropriate pyrrole or how the smooth cyclodextrin inclusion compound of appropriate pyrrole, on
It states compound combined formulation solution or compound combined formulation and is preparing the purposes in nk 1 receptor retarding agent.
The method of the present invention by drug include in a manner of using cyclodextrin will how appropriate pyrrole it is smooth inclusion get up be made into how the smooth ring of appropriate pyrrole
Cyclodextrin inclusion compound, hence it is evident that improve how the smooth water solubility of appropriate pyrrole, improve the curative effect of drug.It is prepared using most preferably proportion
How the smooth phosphate cyclodextrin inclusion compound of appropriate pyrrole makes how the smooth solubility maximum in aqueous solution of appropriate pyrrole can reach 8mg/mL, show
Work improve how the smooth water solubility of appropriate pyrrole.Will how the smooth cyclodextrin inclusion compound of appropriate pyrrole and palonosetron combine to be formed how the smooth ring paste of appropriate pyrrole
Inclusion compounds and palonosetron compound combined formulation enhance how appropriate pyrrole is smooth and two drugs of palonosetron are being alleviated vomiting, disliked
The drug synergism of heart symptom improves curative effect.In addition, it is of the present invention how the smooth cyclodextrin inclusion compound of appropriate pyrrole and how appropriate pyrrole is smooth
Cyclodextrin inclusion compound and palonosetron compound combined formulation, overcome limitation of the drug in dosage form, drug can be made into
Any desired preparation, such as injection realization intravenous injection.
Detailed description of the invention
Fig. 1 is that how appropriate pyrrole is smooth and its chemical structural formula of derivative；Wherein, 1 for how the smooth bulk pharmaceutical chemicals of appropriate pyrrole, 2 for how appropriate pyrrole
Smooth phosphate；
Fig. 2 be how the X diffraction analysis spectrogram of the smooth cyclodextrin inclusion compound of appropriate pyrrole；Wherein, A is beta-cyclodextrin, B be how appropriate pyrrole
It is smooth, C be how the XRD spectra of the smooth cyclodextrin inclusion compound of appropriate pyrrole；
Fig. 3 be how the X diffraction analysis spectrogram of the smooth phosphate cyclodextrin inclusion compound of appropriate pyrrole；Wherein, A is beta-cyclodextrin, and how B is
The appropriate smooth phosphate of pyrrole, C be how the XRD spectra of the smooth phosphate cyclodextrin inclusion compound of appropriate pyrrole；
Fig. 4 be how the infrared spectrogram of the smooth cyclodextrin inclusion compound of appropriate pyrrole；Wherein, A is beta-cyclodextrin, and B is how appropriate pyrrole is smooth, C
For how appropriate pyrrole is smooth and the physical mixture of cyclodextrin, D be how the infrared spectrogram of the smooth cyclodextrin inclusion compound of appropriate pyrrole；
Fig. 5 be how the infrared spectrogram of the smooth phosphate cyclodextrin inclusion compound of appropriate pyrrole；Wherein A be beta-cyclodextrin, B be how appropriate pyrrole
Smooth phosphate, C be how the physical mixture of appropriate pyrrole smooth phosphate and cyclodextrin, D be how the smooth phosphate cyclodextrin inclusion compound of appropriate pyrrole
Infrared spectrogram.
Specific embodiment
Due to how the smooth poorly water-soluble of appropriate pyrrole, be difficult how appropriate pyrrole is smooth and palonosetron combination is prepared into compound pharmaceutical solutions.
It has been investigated that will how appropriate pyrrole it is smooth with it is cyclodextrin encapsulated formed how the smooth cyclodextrin inclusion compound of appropriate pyrrole, both solved how the smooth water of appropriate pyrrole
The problem of dissolubility difference improve simultaneously how the smooth bioavilability of appropriate pyrrole, improve drug effect.
How the preparation method of the smooth cyclodextrin inclusion compound of appropriate pyrrole, prepared in the following manner：Will how appropriate pyrrole be smooth or it spreads out
Biological dissolution in organic solvent, in aqueous solution by cyclodextrin or derivatives thereof dissolution, clarify after mixing by stirring to solution, removes
Go organic solvent obtain how the smooth cyclodextrin inclusion compound aqueous solution of appropriate pyrrole, re-dry water removal after obtain how appropriate pyrrole is smooth cyclodextrin encapsulated
Object.
Preferably, it is described how the smooth derivative of appropriate pyrrole be how the smooth phosphate of appropriate pyrrole.
Preferably, the cyclodextrine derivatives are in beta-cyclodextrin or derivatives thereof or gamma-cyclodextrin or derivatives thereof
Any one.Further, cyclodextrine derivatives are hydroxypropyl-β-cyclodextrin or hydropropyl-y-cyclodextrin.
Preferably, the organic solvent is at least one of methanol, ethyl alcohol or acetone；Preferable organic solvent is acetone.
The aqueous solution is at least one of pure water, physiological saline or glucose solution；Preferably pure water.
Inventor has found through overtesting, when how smooth or derivatives thereof the mass ratio with cyclodextrin or derivatives thereof of appropriate pyrrole exists
In the range of 0.001~0.087, how smooth can be included completely by cyclodextrin of appropriate pyrrole forms transparent inclusion complex in solution.Beyond this
Proportional region, then inclusion not exclusively, there is some drugs precipitating.How the smooth cyclodextrin inclusion compound of appropriate pyrrole is water-soluble obtained by the method for the present invention
Well, character is stable and freeze-drying can redissolve.
The present invention also provides by it is above-mentioned how the smooth cyclodextrin inclusion compound of appropriate pyrrole and palonosetron or derivatives thereof combination formed
Compound combined formulation.
The present invention also provides by it is above-mentioned how the compound combined formulation that the smooth cyclodextrin inclusion compound of appropriate pyrrole and palonosetron are formed
Any pharmaceutical formulation of preparation, such as powder-injection, tablet, capsule or injection.
The present invention also provides it is above-mentioned how the smooth cyclodextrin inclusion compound of appropriate pyrrole and how the smooth cyclodextrin inclusion compound of appropriate pyrrole and pa Lip river
It takes charge of fine jade compound combined formulation and is being used for antiemetic, alleviate the purposes of the drug of nausea.
The present invention also provides it is above-mentioned how the smooth inclusion compound of appropriate pyrrole and how the smooth cyclodextrin inclusion compound of appropriate pyrrole and palonosetron it is multiple
Square combination preparation is preparing the purposes in nk 1 receptor retarding agent.
For further illustrate the present invention, below with reference to embodiment to it is provided by the invention how the smooth cyclodextrin inclusion compound of appropriate pyrrole and
How the compound combined formulation of the smooth cyclodextrin inclusion compound of appropriate pyrrole and palonosetron is described in detail.
The preparation of the how appropriate smooth cyclodextrin inclusion compound of pyrrole of embodiment 1
Smooth be dissolved in 2mL dehydrated alcohol of the how appropriate pyrrole of 3mg is obtained into solution A, 97mg beta-cyclodextrin is dissolved in pure water and obtains B
Solution mixes A, B solution, is slowly stirred 10min until solution is clarified, and revolving removes dehydrated alcohol, and inclusion complex in solution is done
It is dry obtain how the smooth cyclodextrin inclusion compound of appropriate pyrrole.
The preparation of the smooth phosphate cyclodextrin inclusion compound of the how appropriate pyrrole of embodiment 2
The how appropriate smooth phosphate of pyrrole of 8mg is dissolved in 2mL acetone and obtains solution A, 92mg beta-cyclodextrin is dissolved in pure water and is obtained
To B solution, A, B solution are mixed, are slowly stirred 10min until solution is clarified, revolving removes acetone, and inclusion complex in solution is dry
Obtain how the smooth phosphate cyclodextrin inclusion compound of appropriate pyrrole.
3 couples of present invention of embodiment be prepared how the smooth cyclodextrin inclusion compound of appropriate pyrrole carries out XRD detection
Using X ' Pert PRO x-ray powder polycrystalline diffractometer, test condition is Cu/K α radiation wavelength 0.1540nm, electricity
Pressure and electric current are 45kV and 40Ma respectively, and 2 θ scanning ranges are 5 ゜ -80 ゜, 0.02 ゜ min-1 of step-length, 4 ゜ min-1 of scanning speed.
A is the XRD spectra of beta-cyclodextrin in Fig. 2, B is how the smooth XRD spectra of appropriate pyrrole, C are how appropriate pyrrole is smooth cyclodextrin encapsulated
The XRD spectra of object.As shown in Figure 2, the XRD diffraction maximum of inclusion compound with how the smooth diffraction maximum of appropriate pyrrole has very big difference.In inclusion compound
In, how the smooth most of diffraction maximum (17.77 ゜, 20.84 ゜, 22.47 ゜) of appropriate pyrrole disappears, and the position of some diffraction maximums is moved,
And the intensity of most of diffraction maximums obviously weakens, this is because how the masked knot of the smooth cavity for having crept into beta-cyclodextrin of appropriate pyrrole
Fruit illustrates that the clathration of beta-cyclodextrin to how the smooth crystal structure of appropriate pyrrole has an impact, leads to amorphization, so in inclusion compound
There is new diffraction maximum.The change of peak shape may determine that how appropriate pyrrole is smooth and form inclusion compound by cyclodextrin encapsulated from Fig. 2.
How the smooth phosphate cyclodextrin inclusion compound of appropriate pyrrole carries out XRD detection to 4 pairs of present invention gained of embodiment
X ' Pert PRO x-ray powder polycrystalline diffractometer, test condition are used using x-ray powder polycrystalline difraction spectrum
For：The source Cu/K α,The ゜~80 of 2 θ=5 ゜.
In Fig. 3 A be the XRD spectra of beta-cyclodextrin, B be how the XRD spectra of the smooth phosphate of appropriate pyrrole, C be how the smooth phosphoric acid of appropriate pyrrole
The XRD spectra of ester cyclodextrin inclusion compound.From the figure 3, it may be seen that the XRD diffraction maximum of inclusion compound with how the XRD diffraction of the smooth phosphate of appropriate pyrrole
There is very big difference at peak.In inclusion compound, how the smooth phosphonate moiety diffraction maximum of appropriate pyrrole (15.65 ゜, 22.24 ゜, 29.44 ゜, 40.44 ゜)
It disappears, the position of part diffraction maximum is moved, and the intensity of most of diffraction maximums obviously weakens, this is because how appropriate pyrrole is smooth
Phosphoric acid ester molecule crept into cyclodextrin cavity it is masked as a result, illustrate the clathration of beta-cyclodextrin to how the smooth crystalline substance of appropriate pyrrole
Body structure has an impact, and leads to amorphization, new peak shape occurs.It can thus be appreciated that how the smooth phosphate of appropriate pyrrole is by cyclodextrin encapsulated formation
How appropriate pyrrole smooth phosphate inclusion compound.
How the smooth cyclodextrin inclusion compound of appropriate pyrrole carries out infrared detection to 5 pairs of present invention gained of embodiment
Using Fourier transformation infrared spectrometer (Spectrum One type Nicolet), instrumental resolution 0.5cm-1,
Scanning optical spectrum region is 400cm-1-4000cm-1.
A is the infrared spectrogram of beta-cyclodextrin in Fig. 4, B be how the smooth infrared spectrogram of appropriate pyrrole, C is that how appropriate pyrrole is smooth and ring
The physical mixture infrared spectrogram of dextrin, D be how the infrared spectrogram of the smooth cyclodextrin inclusion compound of appropriate pyrrole.From fig. 4, it can be seen that
It is 3406cm in wave number in the infrared spectrogram of beta-cyclodextrin-1There are the stretching vibration of-OH, wave number 561cm in place-1、2926cm-1
Place is C-H stretching vibration, 1080cm-1Place is the characteristic absorption peaks such as C-C stretching vibration.How can in the smooth infrared spectrogram of appropriate pyrrole
To see, wave number 3457cm-1、2931cm-1There is the stretching vibration of N-H, 1646cm in place-1、1500cm-1Place is the flexible of phenyl ring
Vibration, 1276cm-1There are the characteristic absorption peaks such as the stretching vibration of C-F.The infrared spectrum of physical mixture is that how appropriate pyrrole is smooth and β-
The simple superposition of cyclodextrin, and in inclusion compound, how appropriate pyrrole is smooth in 1646cm-1、1500cm-1The vibration absorption peak for locating phenyl ring disappears,
3457cm-1The vibration absorption peak for locating N-H disappears, and it is small that the vibration of each eigen vibration absorption peak of beta-cyclodextrin has occurred
Mobile, showing how appropriate pyrrole is smooth has interaction with beta-cyclodextrin.Thus can speculate how β-has been crept into the smooth phenyl ring part of appropriate pyrrole
The cavity of cyclodextrin and form inclusion compound.
How the smooth phosphate cyclodextrin inclusion compound of appropriate pyrrole carries out infrared detection to 6 pairs of present invention gained of embodiment
Using Fourier transformation infrared spectrometer (Spectrum One type Nicolet), instrumental resolution 0.5cm-1,
Scanning optical spectrum region is 400cm-1-4000cm-1.
In Fig. 5 A be beta-cyclodextrin infrared spectrogram, B be how the infrared spectrogram of the smooth phosphate of appropriate pyrrole, C be how appropriate pyrrole
The physical mixture infrared spectrogram of smooth phosphate and cyclodextrin, D be how the infrared light of the smooth phosphate cyclodextrin inclusion compound of appropriate pyrrole
Spectrogram.From fig. 5, it can be seen that being 3406cm in wave number in the infrared spectrogram of beta-cyclodextrin-1There are the stretching vibration of-OH, wave in place
Number is 561cm-1、2926cm-1Place is C-H stretching vibration, 1080cm-1Place is the characteristic absorption peaks such as C-C stretching vibration.How appropriate
It can see in the infrared spectrogram of the smooth phosphate of pyrrole, wave number 3471cm-1、2997cm-1There is the stretching vibration of N-H in place,
1643cm-1Place is the stretching vibration of phenyl ring, 1281cm-1There are the characteristic absorption peaks such as the stretching vibration of C-F.Physical mixed it is red
Outer spectrogram be how the simple superposition of appropriate pyrrole smooth phosphate and beta-cyclodextrin, all have in figure how the spy of appropriate pyrrole smooth phosphate and cyclodextrin
Levy absorption peak.And in inclusion compound, how the smooth phosphate of appropriate pyrrole is in 1643cm-1Locate phenyl ring vibration absorption peak disappear, show how appropriate pyrrole
Smooth phosphate and beta-cyclodextrin have strong interaction.Thus can speculate how the phenyl ring part of the smooth phosphate of appropriate pyrrole is crept into
The cavity of beta-cyclodextrin and form inclusion compound.
The preparation of embodiment 7 how appropriate pyrrole smooth cyclodextrin inclusion compound and palonosetron compound combined formulation
To how the smooth cyclodextrin inclusion compound of appropriate pyrrole (1000mg) aqueous solution is mixed with palonosetron hydrochloride (0.05mg) aqueous solution,
Be dried to obtain how the smooth cyclodextrin inclusion compound of appropriate pyrrole and palonosetron compound combined formulation.The how appropriate smooth cyclodextrin inclusion compound of pyrrole of gained with
Transparent clear, character are stable in aqueous solution for palonosetron compound combined formulation, are lyophilized and easily redissolve.
The preparation of the how appropriate pyrrole of embodiment 8 smooth phosphate cyclodextrin inclusion compound and palonosetron compound combined formulation
Will how smooth phosphate cyclodextrin inclusion compound (375mg) aqueous solution of appropriate pyrrole and palonosetron hydrochloride (0.05mg) aqueous solution
Mixing, be dried to obtain how the smooth phosphate cyclodextrin inclusion compound of appropriate pyrrole and palonosetron compound combined formulation.The how appropriate smooth phosphorus of pyrrole of gained
Transparent clear, character are stable in aqueous solution for acid esters cyclodextrin inclusion compound and palonosetron compound combined formulation, are lyophilized and easily redissolve.
Claims (11)
1. how the preparation method of the smooth cyclodextrin inclusion compound of appropriate pyrrole, it is characterised in that：Include the following steps：Will how appropriate pyrrole be smooth or it spreads out
Into organic solvent, cyclodextrin or derivatives thereof is dissolved into aqueous solution biological dissolution, is remixed uniformly, is then stirred to solution
Clarification, removal organic solvent up to how the smooth cyclodextrin inclusion compound aqueous solution of appropriate pyrrole, re-dry go to remove water up to how the smooth ring paste of appropriate pyrrole
Inclusion compounds.
2. it is according to claim 1 how the preparation method of the smooth cyclodextrin inclusion compound of appropriate pyrrole, it is characterised in that：How appropriate pyrrole it is smooth or
Its derivative and cyclodextrin or derivatives thereof mass ratio are 0.001~0.087；Preferably 0.087.
3. it is according to claim 1 or 2 how the preparation method of the smooth cyclodextrin inclusion compound of appropriate pyrrole, it is characterised in that：It is described how
The appropriate smooth derivative of pyrrole be how the smooth phosphate of appropriate pyrrole.
4. it is according to claim 1 or 2 how the preparation method of the smooth cyclodextrin inclusion compound of appropriate pyrrole, it is characterised in that：The ring
Any one of dextrin or derivatives thereof in beta-cyclodextrin or derivatives thereof, gamma-cyclodextrin or derivatives thereof.
5. it is according to claim 4 how the preparation method of the smooth cyclodextrin inclusion compound of appropriate pyrrole, it is characterised in that：The β-ring paste
Smart derivative is hydroxypropyl-β-cyclodextrin；The gamma-cyclodextrin derivative is hydropropyl-y-cyclodextrin.
6. it is according to claim 1 how the preparation method of the smooth cyclodextrin inclusion compound of appropriate pyrrole, it is characterised in that：It is described organic molten
Agent is at least one of methanol, ethyl alcohol or acetone；The aqueous solution be pure water, physiological saline or glucose solution at least
It is a kind of；Preferable organic solvent is acetone, and preferred aqueous solutions are pure water.
7. by claim 1~6 it is described in any item how the preparation method of the smooth cyclodextrin inclusion compound of appropriate pyrrole be prepared it is how appropriate
The smooth cyclodextrin inclusion compound aqueous solution of pyrrole or how the smooth cyclodextrin inclusion compound of appropriate pyrrole.
8. how the aqueous solution of the smooth cyclodextrin inclusion compound aqueous solution of appropriate pyrrole and palonosetron or derivatives thereof mixes as described in claim 7
The compound combined formulation for closing the compound combined formulation solution uniformly obtained or obtaining the compound combined formulation solution after dry.
9. compound combined formulation solution according to claim 8 or compound combined formulation, it is characterised in that：The Pa Luosi
Fine jade derivative is any one palonosetron salt compounds；It is preferred that palonosetron hydrochloride.
10. it is as claimed in claim 7 how the smooth cyclodextrin inclusion compound aqueous solution of appropriate pyrrole or how the smooth cyclodextrin inclusion compound of appropriate pyrrole, right are wanted
Compound combined formulation solution or compound combined formulation described in asking 8 or 9 are alleviated in preparation to be vomitted as caused by chemotherapy, radiotherapy and operation
It spits, the purposes in the drug of nausea.
11. it is as claimed in claim 7 how the smooth cyclodextrin inclusion compound aqueous solution of appropriate pyrrole or how the smooth cyclodextrin inclusion compound of appropriate pyrrole, right are wanted
Compound combined formulation solution or compound combined formulation described in asking 8 or 9 are preparing the purposes in nk 1 receptor retarding agent.
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Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1379047A (en) * | 2002-05-10 | 2002-11-13 | 刘云清 | Match of organic medicine and beta-cyclodextrin derivative and its preparing process |
| WO2014206090A1 (en) * | 2013-06-27 | 2014-12-31 | 海南卫康制药(潜山)有限公司 | Aprepitant composition for injection |
| CN104856998A (en) * | 2009-11-18 | 2015-08-26 | 赫尔辛医疗股份公司 | Compositions for treating centrally mediated nausea and vomiting |
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| CN1379047A (en) * | 2002-05-10 | 2002-11-13 | 刘云清 | Match of organic medicine and beta-cyclodextrin derivative and its preparing process |
| CN104856998A (en) * | 2009-11-18 | 2015-08-26 | 赫尔辛医疗股份公司 | Compositions for treating centrally mediated nausea and vomiting |
| WO2014206090A1 (en) * | 2013-06-27 | 2014-12-31 | 海南卫康制药(潜山)有限公司 | Aprepitant composition for injection |
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