CN103784941A - Nasal gel composite and preparation method thereof - Google Patents
Nasal gel composite and preparation method thereof Download PDFInfo
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- CN103784941A CN103784941A CN201310730052.XA CN201310730052A CN103784941A CN 103784941 A CN103784941 A CN 103784941A CN 201310730052 A CN201310730052 A CN 201310730052A CN 103784941 A CN103784941 A CN 103784941A
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Abstract
The invention belongs to the field of chemicals, and relates to a Ziconotide-nasal gel composite and a preparation method thereof. The preparation is composed of Ziconotide, a gel matrix and pharmaceutical acceptable other auxiliary materials including an absorption enhancer, an osmotic pressure regulator, a moisturizing agent, an antioxidant, a preservative and a pH regulator. The preparation is mainly used for treating intolerable or invalid serious chronic pains such as generalized pain and the like. The preparation is simple in preparation process, convenient to take, rapid in onset, high in bioavailability, and beneficial to being accepted by patients.
Description
Technical field
The present invention relates to technical field of pharmaceutical chemistry, specifically ziconotide gel for nose.
Background technology
Ziconotide comprises 25 aminoacid, is first for the clinical N-type voltage-sensitive type calcium ion channel blocker with neuronal specificity, goes on the market first in 2005 in the U.S..And obtain European Union license.Its indication mainly contains: for being applicable to intrathecal injection and can not tolerating or invalid severe chronic pain patients other treatment (as whole body analgesic, auxiliary treatment or intrathecal morphine).Administering mode is to instil in sheath at present, though rapid-action, but the untoward reaction such as intrathecal drug delivery easily causes two numbnesss of lower limbs and pain, headache, dizziness, feels sick, vomiting, heating, tic, especially the most common with two numbnesss of lower limbs and pain, and independently administration, expense is higher, is unfavorable for that patient accepts, and medication limitation is larger.
In addition, drug administration by injection needs professional to complete, and be unwell to autonomous administration, and the use of gel for nose has overcome this limitation, convenient drug administration.Comprehensive above 2 points, administering mode of the present invention is conducive to expand the clinical practice of ziconotide.
Nasal mucosa has good permeability, the abundant blood vessel that distributing on it, and blood flow is high, effectively avoids the first pass effect of liver thereby the medicine of suction can directly enter body circulation.Nasal-cavity administration also has brain targeting, is not only applicable to local application, but also is one of effective way of being administered systemically of whole body.Nasal-cavity administration can only pass through the biomacromolecule of injection system administration at present for those, as polypeptide, protein, nucleic acid etc. have more advantage.The key of preparing protein and peptide class drug nasal preparation is to overcome the scavenging action of nasal cavity cilium, and selects which kind of dosage form so that medicine reasonably distributes at nasal cavity.The method that promotes protein and peptide class medicine nasal mucosa to absorb comprises: apply absorption enhancer, peptide medicament is carried out chemical modification or makes prodrug, and use macromolecular carrier to promote the absorption of medicine.
Summary of the invention
The object of the invention is to prepare a kind of gel for nose take ziconotide as active component, there is convenient drug administration, increased local organization drug level, improved targeting, the advantages such as bioavailability height.
The present invention has prepared a kind of gel for nose containing ziconotide medicine, and it comprises ziconotide, gel-type vehicle, and pharmaceutically acceptable adjuvant absorption enhancer, osmotic pressure regulator, wetting agent, antiseptic, pH adjusting agent; Wherein ziconotide content is 0.1%-20%, and gel-type vehicle is 0.01%-15%, and absorption enhancer is 0.1-5.0%, osmotic pressure regulator is 0.1-5.0%, wetting agent is 1-15.0%, and antiseptic is 0.01-2.0%, and it is 5.0-8.0 that pH adjusting agent regulates pH scope.
The present invention has prepared a kind of gel for nose containing ziconotide medicine, wherein said gel-type vehicle is selected from carbomer, cellulose family substrate, and wherein cellulose family substrate comprises methylcellulose, sodium carboxymethyl cellulose, hydroxypropyl cellulose one or more mixture wherein; Its absorption enhancer is selected from sodium deoxycholate, Tween 80, disodiumedetate, 2-hydroxypropyl-β-cyclodextrin, sodium lauryl sulphate one or more mixture wherein; Its osmotic pressure regulator is selected from sodium chloride, potassium chloride, mannitol, glucose, sodium chloride one or more mixture wherein; Its wetting agent is selected from water, glycerol, propylene glycol, ethanol one or more mixture wherein; Its antiseptic is selected from chlorobutanol, benzoic acid, sorbic acid, methyl parahydroxybenzoate, benzalkonium chloride, benzyl alcohol one or more mixture wherein; Its pH adjusting agent is selected from sodium hydroxide, potassium hydroxide, triethanolamine, ethylenediamine, sodium bicarbonate one or more mixture wherein.
In addition, the present invention also provides the method for preparation containing the nasal mist of ziconotide medicine.When gel-type vehicle is carbomer, its preparation technology is as follows: take carbomer, add water, stir, make it fully swelling, with pH adjusting agent adjusting, pH obtains gel, and then ziconotide is water-soluble, adds other adjuvants to mix, stir evenly, obtain ziconotide solution, this solution is joined in the swelling thing of carbomer, obtain ziconotide gel for nose; When gel-type vehicle is cellulose family substrate, its preparation technology is as follows: take cellulose family substrate, add water, stir, make it fully swelling, then add ziconotide and other adjuvants to mix, stir evenly, obtain ziconotide gel for nose.
The specific embodiment:
Below in conjunction with embodiment, embodiment of the present invention are described in detail, but it will be understood to those of skill in the art that the following example is only for the present invention is described, and should not be considered as limiting scope of the present invention.
Embodiment 1
Ziconotide nasal gel agent prescription is: 1.0% ziconotide, and 0.5% carbomer, 0.5% disodiumedetate, 1.0% sodium chloride, 10% glycerol, 0.30% chlorobutanol, it is 6.5 that sodium hydroxide regulates pH.
Its preparation process is as follows: take recipe quantity carbomer, add water, stir, make it fully swelling, then add recipe quantity ziconotide, and recipe quantity disodiumedetate, sodium chloride, glycerol, chlorobutanol mix, add water and stir evenly, with sodium hydroxide regulate pH be 6.5 gel, stir 30min, obtain ziconotide gel for nose.
Make instillation in ziconotide gel for nose and ziconotide sheath by the present embodiment, by zoopery, its pharmacokinetics and bioavailability are investigated.
By 10 grow up, healthy beasle dog is divided into two groups, 5 every group immediately.Give respectively above-mentioned two groups of beasle dogs by instillation in the gel for nose of above-mentioned ziconotide and ziconotide sheath, measure main pharmacokinetic parameter, comprise medicine removing half-life (t1/2), clearance rate (CL), apparent volume of distribution (Vd), its meansigma methods result is as shown in table 1:
Table 1 ziconotide nasal mist and injection pharmacokinetic parameter
| Parameter | Instillation in ziconotide sheath | Ziconotide gel for nose |
| t1/2/h | 4.6±0.9 | 7.2±0.6 |
| CL /ml /min | 0.38±0.56 | 0.24±0.3 |
| Vd /ml | 155±263 | 164±152 |
Can find out by table 1, instillation comparison in ziconotide gel for nose prepared by the present invention and ziconotide sheath, pharmacokinetics index is more excellent, and recording its absolute bioavailability is 92.8%, and said preparation is easy to use, no pain, patient's acceptance level is high, can substitute instillation in ziconotide sheath completely.
Meanwhile, the present invention also adopts in body toad palate modelling, and ziconotide gel for nose prepared by the present embodiment is investigated the impact of nose fibre swing time, take normal saline as matched group, has assessed its stimulation to nasal membrane.Result shows, ziconotide gel for nose is take normal saline as contrast, on the nasal mucosa fibre swing time without impact.
Moreover the present invention also utilizes rat experiment, ziconotide gel for nose nasal mucosa form impact is investigated, take normal saline as matched group, result shows, ziconotide gel for nose is non-stimulated to nasal mucosa morphogenetic stimulus rank.
Embodiment 2
Ziconotide nasal gel agent prescription is: 5.0% ziconotide, and 1.5% carbomer, 1.2%2-hydroxypropyl-β-cyclodextrin, 2.0% potassium chloride, 8.0% ethanol, 0.50% benzalkonium chloride, it is 7.0 that sodium bicarbonate regulates pH.
Its preparation process is as follows: take recipe quantity carbomer, add water, stir, make it fully swelling, then add recipe quantity 2-hydroxypropyl-β-cyclodextrin, potassium chloride, ethanol, benzalkonium chloride to mix, add water and stir evenly, with sodium bicarbonate regulate pH be 7.0 gel, stir 30min, obtain ziconotide gel for nose.
Make instillation in ziconotide gel for nose and ziconotide sheath by the present embodiment, by zoopery, its pharmacokinetics and bioavailability are investigated.
By 10 grow up, healthy beasle dog is divided into two groups, 5 every group immediately.Give respectively above-mentioned two groups of beasle dogs by instillation in the gel for nose of above-mentioned ziconotide and ziconotide sheath, measure main pharmacokinetic parameter, comprise medicine removing half-life (t1/2), clearance rate (CL), apparent volume of distribution (Vd), its meansigma methods result is as shown in table 2:
Table 2 ziconotide nasal mist and injection pharmacokinetic parameter
| Parameter | Instillation in ziconotide sheath | Ziconotide gel for nose |
| t1/2/h | 4.6±0.9 | 6.8±0.9 |
| CL /ml /min | 0.38±0.56 | 0.29±0.5 |
| Vd /ml | 155±263 | 176±184 |
Can find out by table 2, instillation comparison in ziconotide gel for nose prepared by the present invention and ziconotide sheath, pharmacokinetics index is more excellent, and recording its absolute bioavailability is 94.6%, and said preparation is easy to use, no pain, patient's acceptance level is high, can substitute instillation in ziconotide sheath completely.
Meanwhile, the present invention also adopts in body toad palate modelling, and ziconotide gel for nose prepared by the present embodiment is investigated the impact of nose fibre swing time, take normal saline as matched group, has assessed its stimulation to nasal membrane.Result shows, ziconotide gel for nose is take normal saline as contrast, on the nasal mucosa fibre swing time without impact.
Moreover the present invention also utilizes rat experiment, ziconotide gel for nose nasal mucosa form impact is investigated, take normal saline as matched group, result shows, ziconotide gel for nose is non-stimulated to nasal mucosa morphogenetic stimulus rank.
Embodiment 3
Ziconotide nasal gel agent prescription is: 10.0% ziconotide, and 1.5% carbomer, 2.0% Tween 80,2.0% mannitol, 10% propylene glycol, 0.5% benzoic acid, it is 6.8 that triethanolamine regulates pH.
Its preparation process is as follows: take recipe quantity carbomer, add water, stir, make it fully swelling, then add recipe quantity Tween 80, mannitol, propylene glycol, benzoic acid to mix, add water and stir evenly, with triethanolamine regulate pH be 6.8 gel, stir 30min, obtain ziconotide gel for nose.
Make instillation in ziconotide gel for nose and ziconotide sheath by the present embodiment, by zoopery, its pharmacokinetics and bioavailability are investigated.
By 10 grow up, healthy beasle dog is divided into two groups, 5 every group immediately.Give respectively above-mentioned two groups of beasle dogs by instillation in the gel for nose of above-mentioned ziconotide and ziconotide sheath, measure main pharmacokinetic parameter, comprise medicine removing half-life (t1/2), clearance rate (CL), apparent volume of distribution (Vd), its meansigma methods result is as shown in table 3:
Table 3 ziconotide nasal mist and injection pharmacokinetic parameter
| Parameter | Instillation in ziconotide sheath | Ziconotide gel for nose |
| t1/2/h | 4.6±0.9 | 5.3±0.9 |
| CL /ml /min | 0.38±0.56 | 0.33±0.7 |
| Vd /ml | 155±263 | 162±131 |
Can find out by table 3, instillation comparison in ziconotide gel for nose prepared by the present invention and ziconotide sheath, pharmacokinetics index is more excellent, and recording its absolute bioavailability is 88.2%, and said preparation is easy to use, no pain, patient's acceptance level is high, can substitute instillation in ziconotide sheath completely.
Meanwhile, the present invention also adopts in body toad palate modelling, and ziconotide gel for nose prepared by the present embodiment is investigated the impact of nose fibre swing time, take normal saline as matched group, has assessed its stimulation to nasal membrane.Result shows, ziconotide gel for nose is take normal saline as contrast, on the nasal mucosa fibre swing time without impact.
Moreover the present invention also utilizes rat experiment, ziconotide gel for nose nasal mucosa form impact is investigated, take normal saline as matched group, result shows, ziconotide gel for nose is non-stimulated to nasal mucosa morphogenetic stimulus rank.
Embodiment 4
Ziconotide nasal gel agent prescription is: 15.0% ziconotide, and 1.5% carbomer, 3.0% sodium deoxycholate, 2.5% mannitol, 15% ethanol, 0.5% methyl parahydroxybenzoate, it is 6.5 that potassium hydroxide regulates pH.
Its preparation process is as follows: take recipe quantity carbomer, add water, stir, make it fully swelling, then add recipe quantity sodium deoxycholate, mannitol, ethanol, methyl parahydroxybenzoate to mix, add water and stir evenly, with potassium hydroxide regulate pH be 6.5 gel, stir 30min, obtain ziconotide gel for nose.
Make instillation in ziconotide gel for nose and ziconotide sheath by the present embodiment, by zoopery, its pharmacokinetics and bioavailability are investigated.
By 10 grow up, healthy beasle dog is divided into two groups, 5 every group immediately.Give respectively above-mentioned two groups of beasle dogs by instillation in the gel for nose of above-mentioned ziconotide and ziconotide sheath, measure main pharmacokinetic parameter, comprise medicine removing half-life (t1/2), clearance rate (CL), apparent volume of distribution (Vd), its meansigma methods result is as shown in table 4:
Table 4 ziconotide nasal mist and injection pharmacokinetic parameter
| Parameter | Instillation in ziconotide sheath | Ziconotide gel for nose |
| t1/2/h | 4.6±0.9 | 7.1±0.4 |
| CL /ml /min | 0.38±0.56 | 0.19±0.5 |
| Vd /ml | 155±263 | 187±161 |
Can find out by table 4, instillation comparison in ziconotide gel for nose prepared by the present invention and ziconotide sheath, pharmacokinetics index is more excellent, and recording its absolute bioavailability is 86.9%, and said preparation is easy to use, no pain, patient's acceptance level is high, can substitute instillation in ziconotide sheath completely.
Meanwhile, the present invention also adopts in body toad palate modelling, and ziconotide gel for nose prepared by the present embodiment is investigated the impact of nose fibre swing time, take normal saline as matched group, has assessed its stimulation to nasal membrane.Result shows, ziconotide gel for nose is take normal saline as contrast, on the nasal mucosa fibre swing time without impact.
Moreover the present invention also utilizes rat experiment, ziconotide gel for nose nasal mucosa form impact is investigated, take normal saline as matched group, result shows, ziconotide gel for nose is non-stimulated to nasal mucosa morphogenetic stimulus rank.
Embodiment 5
Ziconotide nasal gel agent prescription is: 15.0% ziconotide, 5.0% methylcellulose, 3.0% sodium lauryl sulphate, 3.5% glucose, 10% glycerol, 5% propylene glycol, 0.5% benzyl alcohol.
Its preparation process is as follows: take recipe quantity methylcellulose, add water, stir, make it fully swelling, then add ziconotide and sodium lauryl sulphate, glucose, glycerol, propylene glycol, benzyl alcohol, mix, stir evenly, obtain ziconotide gel for nose.
Make instillation in ziconotide gel for nose and ziconotide sheath by the present embodiment, by zoopery, its pharmacokinetics and bioavailability are investigated.
By 10 grow up, healthy beasle dog is divided into two groups, 5 every group immediately.Give respectively above-mentioned two groups of beasle dogs by instillation in the gel for nose of above-mentioned ziconotide and ziconotide sheath, measure main pharmacokinetic parameter, comprise medicine removing half-life (t1/2), clearance rate (CL), apparent volume of distribution (Vd), its meansigma methods result is as shown in table 5:
Table 5 ziconotide nasal mist and injection pharmacokinetic parameter
| Parameter | Instillation in ziconotide sheath | Ziconotide gel for nose |
| t1/2/h | 4.6±0.9 | 5.5±0.7 |
| CL /ml /min | 0.38±0.56 | 0.29±0.8 |
| Vd /ml | 155±263 | 167±130 |
Can find out by table 5, instillation comparison in ziconotide gel for nose prepared by the present invention and ziconotide sheath, pharmacokinetics index is more excellent, and recording its absolute bioavailability is 88.3%, and said preparation is easy to use, no pain, patient's acceptance level is high, can substitute instillation in ziconotide sheath completely.
Meanwhile, the present invention also adopts in body toad palate modelling, and ziconotide gel for nose prepared by the present embodiment is investigated the impact of nose fibre swing time, take normal saline as matched group, has assessed its stimulation to nasal membrane.Result shows, ziconotide gel for nose is take normal saline as contrast, on the nasal mucosa fibre swing time without impact.
Moreover the present invention also utilizes rat experiment, ziconotide gel for nose nasal mucosa form impact is investigated, take normal saline as matched group, result shows, ziconotide gel for nose is non-stimulated to nasal mucosa morphogenetic stimulus rank.
Embodiment 6
Ziconotide nasal gel agent prescription is: 5.0% ziconotide, 10% Carboxymethyl cellulose sodium, 0.5% sodium lauryl sulphate, 1.0% sodium deoxycholate, 1.5% sodium chloride, 5.0% glycerol, 2.0% ethanol, 0.5% potassium sulfite, 0.5% chlorobutanol.
Its preparation process is as follows: take recipe quantity Carboxymethyl cellulose sodium, add water, stir, make it fully swelling, then add ziconotide and sodium lauryl sulphate, sodium deoxycholate, sodium chloride, glycerol, ethanol, potassium sulfite, chlorobutanol, mix, stir evenly, obtain ziconotide gel for nose.
Make instillation in ziconotide gel for nose and ziconotide sheath by the present embodiment, by zoopery, its pharmacokinetics and bioavailability are investigated.
By 10 grow up, healthy beasle dog is divided into two groups, 5 every group immediately.Give respectively above-mentioned two groups of beasle dogs by instillation in the gel for nose of above-mentioned ziconotide and ziconotide sheath, measure main pharmacokinetic parameter, comprise medicine removing half-life (t1/2), clearance rate (CL), apparent volume of distribution (Vd), its meansigma methods result is as shown in table 6:
Table 6 ziconotide nasal mist and injection pharmacokinetic parameter
| Parameter | Instillation in ziconotide sheath | Ziconotide gel for nose |
| t1/2/h | 4.6±0.9 | 6.6±0.5 |
| CL /ml /min | 0.38±0.56 | 0.34±0.4 |
| Vd /ml | 155±263 | 169±113 |
Can find out by table 6, instillation comparison in ziconotide gel for nose prepared by the present invention and ziconotide sheath, pharmacokinetics index is more excellent, and recording its absolute bioavailability is 91.7%, and said preparation is easy to use, no pain, patient's acceptance level is high, can substitute instillation in ziconotide sheath completely.
Meanwhile, the present invention also adopts in body toad palate modelling, and ziconotide gel for nose prepared by the present embodiment is investigated the impact of nose fibre swing time, take normal saline as matched group, has assessed its stimulation to nasal membrane.Result shows, ziconotide gel for nose is take normal saline as contrast, on the nasal mucosa fibre swing time without impact.
Moreover the present invention also utilizes rat experiment, ziconotide gel for nose nasal mucosa form impact is investigated, take normal saline as matched group, result shows, ziconotide gel for nose is non-stimulated to nasal mucosa morphogenetic stimulus rank.
Embodiment 7
Ziconotide nasal gel agent prescription is: 30% ziconotide, 10% hydroxypropyl cellulose, 0.5% sodium lauryl sulphate, 1.0% Tween 80,1.5% sodium chloride, 1.5% mannitol, 5.0% propylene glycol, 2.0% ethanol, 0.5% benzoic acid.
Its preparation process is as follows: take recipe quantity hydroxypropyl cellulose, add water, stir, make it fully swelling, then add ziconotide and sodium lauryl sulphate, Tween 80, sodium chloride, mannitol, propylene glycol, ethanol, benzoic acid, mix, stir evenly, obtain ziconotide gel for nose.
Make instillation in ziconotide gel for nose and ziconotide sheath by the present embodiment, by zoopery, its pharmacokinetics and bioavailability are investigated.
By 10 grow up, healthy beasle dog is divided into two groups, 5 every group immediately.Give respectively above-mentioned two groups of beasle dogs by instillation in the gel for nose of above-mentioned ziconotide and ziconotide sheath, measure main pharmacokinetic parameter, comprise medicine removing half-life (t1/2), clearance rate (CL), apparent volume of distribution (Vd), its meansigma methods result is as shown in table 7:
Table 7 ziconotide nasal mist and injection pharmacokinetic parameter
| Parameter | Instillation in ziconotide sheath | Ziconotide gel for nose |
| t1/2/h | 4.6±0.9 | 5.2±0.3 |
| CL /ml /min | 0.38±0.56 | 0.25±0.5 |
| Vd /ml | 155±263 | 166±128 |
Can find out by table 7, instillation comparison in ziconotide gel for nose prepared by the present invention and ziconotide sheath, pharmacokinetics index is more excellent, and recording its absolute bioavailability is 85.4%, and said preparation is easy to use, no pain, patient's acceptance level is high, can substitute instillation in ziconotide sheath completely.
Meanwhile, the present invention also adopts in body toad palate modelling, and ziconotide gel for nose prepared by the present embodiment is investigated the impact of nose fibre swing time, take normal saline as matched group, has assessed its stimulation to nasal membrane.Result shows, ziconotide gel for nose is take normal saline as contrast, on the nasal mucosa fibre swing time without impact.
Moreover the present invention also utilizes rat experiment, ziconotide gel for nose nasal mucosa form impact is investigated, take normal saline as matched group, result shows, ziconotide gel for nose is non-stimulated to nasal mucosa morphogenetic stimulus rank.
Embodiment 8
Ziconotide nasal gel agent prescription is: 20% ziconotide, 10% hydroxypropyl cellulose, 5% methylcellulose, 0.5% sodium deoxycholate, 2.5% sodium chloride, 5.0% propylene glycol, 2.0% ethanol, 0.5% benzoic acid.
Its preparation process is as follows: take recipe quantity hydroxypropyl cellulose, methylcellulose, add water, stir, make it fully swelling, then add ziconotide and sodium deoxycholate, sodium chloride, propylene glycol, ethanol, benzoic acid, mix, stir evenly, obtain ziconotide gel for nose.
Make instillation in ziconotide gel for nose and ziconotide sheath by the present embodiment, by zoopery, its pharmacokinetics and bioavailability are investigated.
By 10 grow up, healthy beasle dog is divided into two groups, 5 every group immediately.Give respectively above-mentioned two groups of beasle dogs by instillation in the gel for nose of above-mentioned ziconotide and ziconotide sheath, measure main pharmacokinetic parameter, comprise medicine removing half-life (t1/2), clearance rate (CL), apparent volume of distribution (Vd), its meansigma methods result is as shown in table 8:
Table 8 ziconotide nasal mist and injection pharmacokinetic parameter
| Parameter | Instillation in ziconotide sheath | Ziconotide gel for nose |
| t1/2/h | 4.6±0.9 | 6.8±0.8 |
| CL /ml /min | 0.38±0.56 | 0.25±0.7 |
| Vd /ml | 155±263 | 172±116 |
Can find out by table 8, instillation comparison in ziconotide gel for nose prepared by the present invention and ziconotide sheath, pharmacokinetics index is more excellent, and recording its absolute bioavailability is 95.2%, and said preparation is easy to use, no pain, patient's acceptance level is high, can substitute instillation in ziconotide sheath completely.
Meanwhile, the present invention also adopts in body toad palate modelling, and ziconotide gel for nose prepared by the present embodiment is investigated the impact of nose fibre swing time, take normal saline as matched group, has assessed its stimulation to nasal membrane.Result shows, ziconotide gel for nose is take normal saline as contrast, on the nasal mucosa fibre swing time without impact.
Moreover the present invention also utilizes rat experiment, ziconotide gel for nose nasal mucosa form impact is investigated, take normal saline as matched group, result shows, ziconotide gel for nose is non-stimulated to nasal mucosa morphogenetic stimulus rank.
Embodiment 9
Ziconotide nasal gel agent prescription is: 10% ziconotide, 10% Carboxymethyl cellulose sodium, 5% hydroxypropyl cellulose, 0.5% sodium deoxycholate, 2.5% sodium chloride, 5.0% propylene glycol, 2.0% ethanol, 0.5% benzoic acid.
Its preparation process is as follows: take recipe quantity hydroxypropyl cellulose, Carboxymethyl cellulose sodium, add water, stir, make it fully swelling, then add ziconotide and sodium deoxycholate, sodium chloride, propylene glycol, ethanol, benzoic acid, mix, stir evenly, obtain ziconotide gel for nose.
Make instillation in ziconotide gel for nose and ziconotide sheath by the present embodiment, by zoopery, its pharmacokinetics and bioavailability are investigated.
By 10 grow up, healthy beasle dog is divided into two groups, 5 every group immediately.Give respectively above-mentioned two groups of beasle dogs by instillation in the gel for nose of above-mentioned ziconotide and ziconotide sheath, measure main pharmacokinetic parameter, comprise medicine removing half-life (t1/2), clearance rate (CL), apparent volume of distribution (Vd), its meansigma methods result is as shown in table 9:
Table 9 ziconotide nasal mist and injection pharmacokinetic parameter
| Parameter | Instillation in ziconotide sheath | Ziconotide gel for nose |
| t1/2/h | 4.6±0.9 | 7.1±0.3 |
| CL /ml /min | 0.38±0.56 | 0.12±0.7 |
| Vd /ml | 155±263 | 192±124 |
Can find out by table 9, instillation comparison in ziconotide gel for nose prepared by the present invention and ziconotide sheath, pharmacokinetics index is more excellent, and recording its absolute bioavailability is 94.7%, and said preparation is easy to use, no pain, patient's acceptance level is high, can substitute instillation in ziconotide sheath completely.
Meanwhile, the present invention also adopts in body toad palate modelling, and ziconotide gel for nose prepared by the present embodiment is investigated the impact of nose fibre swing time, take normal saline as matched group, has assessed its stimulation to nasal membrane.Result shows, ziconotide gel for nose is take normal saline as contrast, on the nasal mucosa fibre swing time without impact.
Moreover the present invention also utilizes rat experiment, ziconotide gel for nose nasal mucosa form impact is investigated, take normal saline as matched group, result shows, ziconotide gel for nose is non-stimulated to nasal mucosa morphogenetic stimulus rank.
Above content is in conjunction with concrete preferred implementation further description made for the present invention, can not assert that specific embodiment of the invention is confined to these explanations.For general technical staff of the technical field of the invention, without departing from the inventive concept of the premise, make concrete change or change and all belong to protection scope of the present invention.
Claims (10)
1. a ziconotide gel for nose, is characterized in that: comprise ziconotide, gel-type vehicle, and pharmaceutically acceptable adjuvant absorption enhancer, osmotic pressure regulator, wetting agent, antiseptic, pH adjusting agent, water; Wherein ziconotide content is 0.1%-20%, and gel-type vehicle is 0.01%-15%, and absorption enhancer is 0.1-5.0%, osmotic pressure regulator is 0.1-5.0%, wetting agent is 1-15.0%, and antiseptic is 0.01-2.0%, and it is 5.0-8.0 that pH adjusting agent regulates pH scope.
2. ziconotide gel for nose according to claim 1, wherein said gel-type vehicle is selected from carbomer, cellulose family substrate, and wherein cellulose family substrate comprises methylcellulose, sodium carboxymethyl cellulose, hydroxypropyl cellulose one or more mixture wherein.
3. ziconotide gel for nose according to claim 1, its absorption enhancer is selected from sodium deoxycholate, Tween 80, disodiumedetate, 2-hydroxypropyl-β-cyclodextrin, sodium lauryl sulphate one or more mixture wherein.
4. ziconotide gel for nose according to claim 1, its osmotic pressure regulator is selected from sodium chloride, potassium chloride, mannitol, glucose one or more mixture wherein.
5. ziconotide gel for nose according to claim 1, its wetting agent is selected from glycerol, propylene glycol, ethanol one or more mixture wherein.
6. ziconotide gel for nose according to claim 1, its antiseptic is selected from chlorobutanol, benzoic acid, sorbic acid, methyl parahydroxybenzoate, benzalkonium chloride, benzyl alcohol one or more mixture wherein.
7. ziconotide gel for nose according to claim 1, its pH adjusting agent is selected from sodium hydroxide, potassium hydroxide, triethanolamine, ethylenediamine, sodium bicarbonate one or more mixture wherein.
8. ziconotide gel for nose according to claim 1, when gel-type vehicle is carbomer, its preparation technology is as follows: take carbomer, add water, stir, make it fully swelling, then add ziconotide and other adjuvants to mix, add water and stir evenly, with pH adjusting agent adjusting, pH obtains gel, stir 30min, obtain ziconotide gel for nose.
9. ziconotide gel for nose according to claim 1, when gel-type vehicle is cellulose family substrate, its preparation technology is as follows: take cellulose family substrate, add water, stir, make it fully swelling, then add ziconotide and other adjuvants to mix, stir evenly, obtain ziconotide gel for nose.
10. ziconotide gel for nose according to claim 1, is characterized in that described gel preparation passes through nasal-cavity administration with spraying or collunarium form.
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| WO2017114379A1 (en) * | 2015-12-29 | 2017-07-06 | 深圳翰宇药业股份有限公司 | Nasal gel composition for treating multiple sclerosis |
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| CN100522245C (en) * | 2002-05-23 | 2009-08-05 | Umd公司 | Compositions for transmucosal drug delivery and cryoprotection |
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| CN106924175B (en) * | 2015-12-29 | 2020-07-03 | 深圳翰宇药业股份有限公司 | Pharmaceutical composition for treating multiple sclerosis |
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