CN115778895B - Atomoxetine hydrochloride oral solution - Google Patents
Atomoxetine hydrochloride oral solution Download PDFInfo
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- CN115778895B CN115778895B CN202211514973.8A CN202211514973A CN115778895B CN 115778895 B CN115778895 B CN 115778895B CN 202211514973 A CN202211514973 A CN 202211514973A CN 115778895 B CN115778895 B CN 115778895B
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- oral solution
- tomoxetine hydrochloride
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- tomoxetine
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- 229940100688 oral solution Drugs 0.000 title claims abstract description 96
- LUCXVPAZUDVVBT-UNTBIKODSA-N atomoxetine hydrochloride Chemical compound Cl.O([C@H](CCNC)C=1C=CC=CC=1)C1=CC=CC=C1C LUCXVPAZUDVVBT-UNTBIKODSA-N 0.000 title claims description 131
- 229960002828 atomoxetine hydrochloride Drugs 0.000 title claims description 17
- 229960002430 atomoxetine Drugs 0.000 claims abstract description 119
- KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 claims abstract description 69
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 claims abstract description 46
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims abstract description 32
- FBPFZTCFMRRESA-KVTDHHQDSA-N D-Mannitol Chemical compound OC[C@@H](O)[C@@H](O)[C@H](O)[C@H](O)CO FBPFZTCFMRRESA-KVTDHHQDSA-N 0.000 claims abstract description 30
- 229930195725 Mannitol Natural products 0.000 claims abstract description 30
- 239000000594 mannitol Substances 0.000 claims abstract description 30
- 235000010355 mannitol Nutrition 0.000 claims abstract description 30
- ZGTMUACCHSMWAC-UHFFFAOYSA-L EDTA disodium salt (anhydrous) Chemical compound [Na+].[Na+].OC(=O)CN(CC([O-])=O)CCN(CC(O)=O)CC([O-])=O ZGTMUACCHSMWAC-UHFFFAOYSA-L 0.000 claims abstract description 25
- 239000005715 Fructose Substances 0.000 claims abstract description 23
- 229930091371 Fructose Natural products 0.000 claims abstract description 23
- RFSUNEUAIZKAJO-ARQDHWQXSA-N Fructose Chemical compound OC[C@H]1O[C@](O)(CO)[C@@H](O)[C@@H]1O RFSUNEUAIZKAJO-ARQDHWQXSA-N 0.000 claims abstract description 23
- 239000004376 Sucralose Substances 0.000 claims abstract description 23
- FEWJPZIEWOKRBE-UHFFFAOYSA-N Tartaric acid Natural products [H+].[H+].[O-]C(=O)C(O)C(O)C([O-])=O FEWJPZIEWOKRBE-UHFFFAOYSA-N 0.000 claims abstract description 23
- TVXBFESIOXBWNM-UHFFFAOYSA-N Xylitol Natural products OCCC(O)C(O)C(O)CCO TVXBFESIOXBWNM-UHFFFAOYSA-N 0.000 claims abstract description 23
- BNIILDVGGAEEIG-UHFFFAOYSA-L disodium hydrogen phosphate Chemical compound [Na+].[Na+].OP([O-])([O-])=O BNIILDVGGAEEIG-UHFFFAOYSA-L 0.000 claims abstract description 23
- HEBKCHPVOIAQTA-UHFFFAOYSA-N meso ribitol Natural products OCC(O)C(O)C(O)CO HEBKCHPVOIAQTA-UHFFFAOYSA-N 0.000 claims abstract description 23
- 239000011780 sodium chloride Substances 0.000 claims abstract description 23
- 235000019408 sucralose Nutrition 0.000 claims abstract description 23
- BAQAVOSOZGMPRM-QBMZZYIRSA-N sucralose Chemical compound O[C@@H]1[C@@H](O)[C@@H](Cl)[C@@H](CO)O[C@@H]1O[C@@]1(CCl)[C@@H](O)[C@H](O)[C@@H](CCl)O1 BAQAVOSOZGMPRM-QBMZZYIRSA-N 0.000 claims abstract description 23
- 235000002906 tartaric acid Nutrition 0.000 claims abstract description 23
- 239000011975 tartaric acid Substances 0.000 claims abstract description 23
- 239000000811 xylitol Substances 0.000 claims abstract description 23
- 235000010447 xylitol Nutrition 0.000 claims abstract description 23
- HEBKCHPVOIAQTA-SCDXWVJYSA-N xylitol Chemical compound OC[C@H](O)[C@@H](O)[C@H](O)CO HEBKCHPVOIAQTA-SCDXWVJYSA-N 0.000 claims abstract description 23
- 229960002675 xylitol Drugs 0.000 claims abstract description 23
- 229940068918 polyethylene glycol 400 Drugs 0.000 claims abstract description 20
- 238000000034 method Methods 0.000 claims abstract description 11
- FEWJPZIEWOKRBE-JCYAYHJZSA-N Dextrotartaric acid Chemical compound OC(=O)[C@H](O)[C@@H](O)C(O)=O FEWJPZIEWOKRBE-JCYAYHJZSA-N 0.000 claims abstract description 10
- 235000015165 citric acid Nutrition 0.000 claims abstract description 7
- 238000003756 stirring Methods 0.000 claims description 34
- 239000008213 purified water Substances 0.000 claims description 13
- 238000002156 mixing Methods 0.000 claims description 10
- 208000036864 Attention deficit/hyperactivity disease Diseases 0.000 claims description 9
- 208000015802 attention deficit-hyperactivity disease Diseases 0.000 claims description 9
- 238000009835 boiling Methods 0.000 claims description 8
- 238000001816 cooling Methods 0.000 claims description 8
- 238000002360 preparation method Methods 0.000 claims description 8
- 238000001914 filtration Methods 0.000 claims description 7
- 239000012528 membrane Substances 0.000 claims description 7
- 239000003814 drug Substances 0.000 claims description 4
- 238000004519 manufacturing process Methods 0.000 claims description 3
- 235000002639 sodium chloride Nutrition 0.000 claims description 3
- 235000019640 taste Nutrition 0.000 abstract description 13
- 238000005286 illumination Methods 0.000 abstract description 9
- 238000003860 storage Methods 0.000 abstract description 8
- VHGCDTVCOLNTBX-QGZVFWFLSA-N atomoxetine Chemical compound O([C@H](CCNC)C=1C=CC=CC=1)C1=CC=CC=C1C VHGCDTVCOLNTBX-QGZVFWFLSA-N 0.000 abstract 6
- 229920000139 polyethylene terephthalate Polymers 0.000 description 11
- 239000005020 polyethylene terephthalate Substances 0.000 description 11
- 238000011835 investigation Methods 0.000 description 9
- 235000019658 bitter taste Nutrition 0.000 description 8
- 239000000203 mixture Substances 0.000 description 8
- PEDCQBHIVMGVHV-UHFFFAOYSA-N Glycerine Chemical compound OCC(O)CO PEDCQBHIVMGVHV-UHFFFAOYSA-N 0.000 description 5
- 239000012535 impurity Substances 0.000 description 4
- 238000011156 evaluation Methods 0.000 description 3
- 230000006866 deterioration Effects 0.000 description 2
- 229940079593 drug Drugs 0.000 description 2
- 235000011187 glycerol Nutrition 0.000 description 2
- 238000004128 high performance liquid chromatography Methods 0.000 description 2
- 239000002245 particle Substances 0.000 description 2
- 239000002244 precipitate Substances 0.000 description 2
- 238000013112 stability test Methods 0.000 description 2
- 230000000694 effects Effects 0.000 description 1
- 238000002474 experimental method Methods 0.000 description 1
- 238000009472 formulation Methods 0.000 description 1
- 239000011521 glass Substances 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- 239000008194 pharmaceutical composition Substances 0.000 description 1
- 239000000825 pharmaceutical preparation Substances 0.000 description 1
- 229920003023 plastic Polymers 0.000 description 1
- -1 polyethylene terephthalate Polymers 0.000 description 1
- 238000004321 preservation Methods 0.000 description 1
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- Medicinal Preparation (AREA)
Abstract
The invention relates to a tomoxetine hydrochloride oral solution. Specifically, the invention provides a tomoxetine hydrochloride oral solution, which comprises tomoxetine hydrochloride, polyethylene glycol 400, sucralose, fructose, mannitol, xylitol, citric acid, tartaric acid, disodium hydrogen phosphate, sodium chloride, EDTA-2Na and water. The tomoxetine hydrochloride oral solution has excellent taste and illumination and high-temperature stability, so that the oral compliance of the tomoxetine hydrochloride oral solution and the stability in the transportation and storage processes are improved, and the application value of the tomoxetine hydrochloride oral solution is improved.
Description
Technical Field
The invention relates to the field of pharmaceutical preparations, in particular to a tomoxetine hydrochloride oral solution.
Background
Atomoxetine hydrochloride (CAS number 82248-59-7) is used primarily for the treatment of attention deficit/hyperactivity disorder (ADHD) in children and adolescents and has the following structure:
the tomoxetine hydrochloride oral solution has the advantages of quick response, convenient administration and the like, and is widely applied clinically. However, the existing tomoxetine hydrochloride oral solution has the problems of bitter taste and residual thereof, so that the taste of the tomoxetine hydrochloride oral solution is reduced, the oral compliance of the tomoxetine hydrochloride oral solution is reduced, especially the oral compliance of children is reduced, in addition, the tomoxetine hydrochloride oral solution also has the problems of poor illumination and high-temperature stability, so that the tomoxetine hydrochloride oral solution needs to be packaged in brown bottles for preservation, the storage and transportation cost is increased, and the brown bottles are packaged with the tomoxetine hydrochloride oral solution, so that the patient is difficult to simply, quickly and effectively observe the deterioration phenomena of the oral solution such as clarity, whether precipitate particles exist, mildewing, foreign matters and the like through the brown bottles when buying or using the tomoxetine hydrochloride oral solution, and the medication safety problem is easy to occur.
Accordingly, there is a need in the art to develop an oral solution of tomoxetine hydrochloride having excellent mouthfeel and stability.
Disclosure of Invention
The invention aims to provide a tomoxetine hydrochloride oral solution which has excellent taste and stability.
According to a first aspect of the invention, there is provided an oral solution of tomoxetine hydrochloride, which comprises tomoxetine hydrochloride, polyethylene glycol 400, sucralose, fructose, mannitol, xylitol, citric acid, tartaric acid, disodium hydrogen phosphate, sodium chloride, EDTA-2Na and water.
Preferably, the tomoxetine hydrochloride is 0.1 to 1.0 parts by weight, preferably 0.3 to 0.5 parts by weight, more preferably 0.4 parts by weight.
Preferably, the polyethylene glycol 400 is 1.0 to 5.0 parts by weight, preferably 2.0 to 4.0 parts by weight, more preferably 3.0 parts by weight.
Preferably, the sucralose is 0.08 to 0.16 parts by weight, preferably 0.10 to 0.14 parts by weight, more preferably 0.12 parts by weight.
Preferably, the fructose is 2.0 to 8.0 parts by weight, preferably 4.0 to 6.0 parts by weight, more preferably 5.0 parts by weight.
Preferably, the mannitol is 1 to 5 parts by weight, preferably 1.5 to 2.5 parts by weight, more preferably 2.0 parts by weight.
Preferably, the xylitol is present in an amount of 0.5 to 3.0 parts by weight, preferably 1.0 to 2.0 parts by weight, more preferably 1.5 parts by weight.
Preferably, the citric acid is 0.5-1.5 parts by weight, preferably 0.8-1.2 parts by weight, more preferably 1.0 part by weight.
Preferably, the tartaric acid is 0.1 to 1.0 parts by weight, preferably 0.3 to 0.7 parts by weight, more preferably 0.5 parts by weight.
Preferably, the disodium hydrogen phosphate is 0.05 to 0.5 parts by weight, preferably 0.1 to 0.3 parts by weight, more preferably 0.2 parts by weight.
Preferably, the sodium chloride is 0.5 to 2.0 parts by weight, preferably 1.0 to 1.4 parts by weight, more preferably 1.2 parts by weight.
Preferably, the EDTA-2Na is present in an amount of 0.02 to 0.10 parts by weight, preferably 0.05 to 0.07 parts by weight, more preferably 0.06 parts by weight.
Preferably, the water is 90-100 parts by weight, preferably 95-105 parts by weight, more preferably 100 parts by weight.
Preferably, the water is purified water.
Preferably, the tomoxetine hydrochloride oral solution comprises:
| Component (A) | Dosage of |
| Tomoxetine hydrochloride | 0.3 To 0.5 part by weight |
| Polyethylene glycol 400 | 2.0 To 5.0 parts by weight |
| Sucralose | 0.08-0.16 Part by weight |
| Fructose | 2.0 To 8.0 parts by weight |
| Mannitol (mannitol) | 0.5 To 5.0 parts by weight |
| Xylitol | 0.5 To 3.0 parts by weight |
| Citric acid | 0.5 To 1.5 parts by weight |
| Tartaric acid | 0.1 To 1.0 part by weight |
| Disodium hydrogen phosphate | 0.05 To 0.5 part by weight |
| Sodium chloride | 0.8-1.6 Parts by weight |
| EDTA-2Na | 0.02-0.10 Parts by weight; and |
| Adding water | 90-100 Parts by weight. |
Preferably, the tomoxetine hydrochloride oral solution comprises:
Preferably, the tomoxetine hydrochloride oral solution comprises:
| Component (A) | Dosage of |
| Tomoxetine hydrochloride | 0.4 Part by weight |
| Polyethylene glycol 400 | 3.0 Parts by weight |
| Sucralose | 0.12 Part by weight |
| Fructose | 5.0 Parts by weight |
| Mannitol (mannitol) | 2.0 Parts by weight |
| Xylitol | 1.5 Parts by weight |
| Citric acid | 1.0 Part by weight |
| Tartaric acid | 0.5 Part by weight |
| Disodium hydrogen phosphate | 0.2 Part by weight |
| Sodium chloride | 1.2 Parts by weight |
| EDTA-2Na | 0.06 Parts by weight; and |
| Adding water | 90-100 Parts by weight. |
Preferably, the tomoxetine hydrochloride oral solution comprises:
| Component (A) | Dosage of |
| Tomoxetine hydrochloride | 0.4g |
| Polyethylene glycol 400 | 3.0g |
| Sucralose | 0.12g |
| Fructose | 5.0g |
| Mannitol (mannitol) | 2.0g |
| Xylitol | 1.5g |
| Citric acid | 1.0g |
| Tartaric acid | 0.5g |
| Disodium hydrogen phosphate | 0.2g |
| Sodium chloride | 1.2g |
| EDTA-2Na | 0.06g |
| Adding water | To 100ml. |
In a second aspect of the present invention, there is provided a process for preparing an oral solution of tomoxetine hydrochloride as described in the first aspect of the present invention, the process comprising the steps of:
Mixing atomoxetine hydrochloride, polyethylene glycol 400, sucralose, fructose, mannitol, xylitol, citric acid, tartaric acid, disodium hydrogen phosphate, sodium chloride, EDTA-2Na and water to obtain the atomoxetine hydrochloride oral solution.
Preferably, the tomoxetine hydrochloride oral solution is prepared by the following method:
Adding water with the prescription amount of 75-85%, adding polyethylene glycol 400, stirring and dissolving at 35-45 ℃, adding citric acid, tartaric acid and disodium hydrogen phosphate, stirring and dissolving at 35-45 ℃, adding atomoxetine hydrochloride, stirring and dissolving at 35-45 ℃, adding sucralose, fructose, mannitol, xylitol, sodium chloride and EDTA-2Na, stirring and dissolving at 35-45 ℃, adding water to a fixed volume, stirring and mixing, and filtering by a microporous filter membrane with the size of 0.22 mu m to obtain the atomoxetine hydrochloride oral solution.
In a third aspect of the present invention, there is provided a tomoxetine hydrochloride kit comprising a tomoxetine hydrochloride oral solution and a transparent container according to the first aspect of the present invention;
The tomoxetine hydrochloride oral solution is packaged in the transparent container.
Preferably, the transparent container comprises a transparent plastic container or a transparent glass container.
Preferably, the transparent container comprises a transparent PET bottle.
In a fourth aspect of the present invention there is provided the use of tomoxetine hydrochloride oral solution according to the first aspect of the present invention for the manufacture of a medicament for attention deficit/hyperactivity disorder (ADHD).
Preferably, the attention deficit/hyperactivity disorder (ADHD) includes attention deficit/hyperactivity disorder (ADHD) in children and adolescents.
It is understood that within the scope of the present invention, the above-described technical features of the present invention and technical features specifically described below (e.g., in the examples) may be combined with each other to constitute new or preferred technical solutions.
Detailed Description
The invention develops a tomoxetine hydrochloride oral solution which comprises tomoxetine hydrochloride, polyethylene glycol 400, sucralose, fructose, mannitol, xylitol, citric acid, tartaric acid, disodium hydrogen phosphate, sodium chloride, EDTA-2Na and water. The tomoxetine hydrochloride oral solution has excellent taste and illumination and high-temperature stability, so that the oral compliance of the tomoxetine hydrochloride oral solution and the stability in the transportation and storage processes are improved, and the application value of the tomoxetine hydrochloride oral solution is improved.
Terminology
As used herein, the terms "comprising," "including," and "containing" are used interchangeably, and include not only closed-form definitions, but also semi-closed-form and open-form definitions. In other words, the term includes "consisting of … …", "consisting essentially of … …".
As used herein, the term "PET" refers to polyethylene terephthalate, english name Poly (ethylene Terephthalate).
As used herein, the term "EDTA-2Na" refers to disodium edetate.
As used herein, the term "parts by weight" may be any fixed weight in milligrams, grams, or kilograms (e.g., 1mg, 1g, or 1kg, etc.). For example, a composition comprising 1 part by weight of component a and 9 parts by weight of component b may be a composition comprising 1 gram of component a+9 gram of component b, or 10 grams of component a+90 gram of component b, etc. In the pharmaceutical composition, the percentage content of a certain component= (the parts by weight of the component/the sum of the parts by weight of all components) ×100%, and therefore, in the composition composed of 1 part by weight of component a and 9 parts by weight of component b, the content of component a is 10%, and the content of component b is 90%.
Atomoxetine hydrochloride oral solution and preparation method thereof
The tomoxetine hydrochloride oral solution provided by the invention has excellent taste and stability, and can improve the application value of tomoxetine hydrochloride oral solution.
The tomoxetine hydrochloride oral solution of the present invention may include (but is not limited to) tomoxetine hydrochloride, polyethylene glycol 400, sucralose, fructose, mannitol, xylitol, citric acid, tartaric acid, disodium hydrogen phosphate, sodium chloride, EDTA-2Na, and water.
In the tomoxetine hydrochloride oral solution, the components act together to ensure that the tomoxetine hydrochloride oral solution has excellent taste and stability, so that the application value of the tomoxetine hydrochloride oral solution can be improved.
In the tomoxetine hydrochloride oral solution of the present invention, the dosage of tomoxetine hydrochloride may be 0.1-1.0 weight parts, preferably 0.3-0.5 weight parts, and more preferably 0.4 weight parts.
In the tomoxetine hydrochloride oral solution of the present invention, the polyethylene glycol 400 may be used in an amount of 1.0 to 5.0 parts by weight, preferably 2.0 to 4.0 parts by weight, more preferably 3.0 parts by weight.
In the tomoxetine hydrochloride oral solution of the present invention, the amount of sucralose may be 0.08-0.16 parts by weight, preferably 0.10-0.14 parts by weight, more preferably 0.12 parts by weight.
In the tomoxetine hydrochloride oral solution of the present invention, the fructose may be used in an amount of 2.0 to 8.0 parts by weight, preferably 4.0 to 6.0 parts by weight, more preferably 5.0 parts by weight.
In the tomoxetine hydrochloride oral solution of the present invention, the amount of mannitol may be 1-5 parts by weight, preferably 1.5-2.5 parts by weight, more preferably 2.0 parts by weight.
In the tomoxetine hydrochloride oral solution of the present invention, the xylitol may be used in an amount of 0.5 to 3.0 parts by weight, preferably 1.0 to 2.0 parts by weight, more preferably 1.5 parts by weight.
In the tomoxetine hydrochloride oral solution of the present invention, the amount of citric acid may be 0.5-1.5 parts by weight, preferably 0.8-1.2 parts by weight, more preferably 1.0 part by weight.
In the tomoxetine hydrochloride oral solution of the present invention, the amount of tartaric acid may be 0.1 to 1.0 part by weight, preferably 0.3 to 0.7 part by weight, and more preferably 0.5 part by weight.
In the tomoxetine hydrochloride oral solution of the present invention, the amount of disodium hydrogen phosphate may be 0.05 to 0.5 part by weight, preferably 0.1 to 0.3 part by weight, and more preferably 0.2 part by weight.
In the tomoxetine hydrochloride oral solution of the present invention, the amount of sodium chloride may be 0.5-2.0 parts by weight, preferably 1.0-1.4 parts by weight, more preferably 1.2 parts by weight.
Preferably, the EDTA-2Na may be used in an amount of 0.02 to 0.10 parts by weight, preferably 0.05 to 0.07 parts by weight, more preferably 0.06 parts by weight.
In the tomoxetine hydrochloride oral solution of the present invention, the water may be used in an amount of 90-100 parts by weight, preferably 95-105 parts by weight, more preferably 100 parts by weight.
Representatively, the tomoxetine hydrochloride oral solution of the present invention comprises:
typically, the tomoxetine hydrochloride oral solution of the present invention comprises:
| Component (A) | Dosage of |
| Tomoxetine hydrochloride | 0.4g |
| Polyethylene glycol 400 | 3.0g |
| Sucralose | 0.12g |
| Fructose | 5.0g |
| Mannitol (mannitol) | 2.0g |
| Xylitol | 1.5g |
| Citric acid | 1.0g |
| Tartaric acid | 0.5g |
| Disodium hydrogen phosphate | 0.2g |
| Sodium chloride | 1.2g |
| EDTA-2Na | 0.06g |
| Adding water | To 100ml. |
The tomoxetine hydrochloride oral solution can be packaged in transparent containers (such as transparent PET bottles) for storage and transportation.
The tomoxetine hydrochloride oral solution can be prepared by a mixing method, for example, tomoxetine hydrochloride, polyethylene glycol 400, sucralose, fructose, mannitol, xylitol, citric acid, tartaric acid, disodium hydrogen phosphate, sodium chloride, EDTA-2Na and water are mixed to obtain the tomoxetine hydrochloride oral solution.
Representatively, the tomoxetine hydrochloride oral solution of the present invention is prepared by the following method:
Adding water with the prescription amount of 75-85%, adding polyethylene glycol 400, stirring and dissolving at 35-45 ℃, adding citric acid, tartaric acid and disodium hydrogen phosphate, stirring and dissolving at 35-45 ℃, adding atomoxetine hydrochloride, stirring and dissolving at 35-45 ℃, adding sucralose, fructose, mannitol, xylitol, sodium chloride and EDTA-2Na, stirring and dissolving at 35-45 ℃, adding water to a fixed volume, stirring and mixing, and filtering by a microporous filter membrane with the size of 0.22 mu m to obtain the atomoxetine hydrochloride oral solution.
The main excellent technical effects of the invention include:
The atomoxetine hydrochloride oral solution has excellent taste and illumination and high-temperature stability, so that the oral compliance and the stability in the transportation and storage processes of the atomoxetine hydrochloride oral solution are improved, and the application value of the atomoxetine hydrochloride oral solution is improved.
The invention will be further illustrated with reference to specific examples. It is to be understood that these examples are illustrative of the present invention and are not intended to limit the scope of the present invention. The experimental procedure, in which specific conditions are not noted in the examples below, is generally followed by conventional conditions.
Example 1 tomoxetine hydrochloride oral solution
The prescription composition of the tomoxetine hydrochloride oral solution of this example 1 is shown in table 1:
| Component (A) | Dosage of |
| Tomoxetine hydrochloride | 0.4g |
| Polyethylene glycol 400 | 3.0g |
| Sucralose | 0.12g |
| Fructose | 5.0g |
| Mannitol (mannitol) | 2.0g |
| Xylitol | 1.5g |
| Citric acid | 1.0g |
| Tartaric acid | 0.5g |
| Disodium hydrogen phosphate | 0.2g |
| Sodium chloride | 1.2g |
| EDTA-2Na | 0.06g |
| Adding purified water | To 100ml. |
Preparation method
Taking 80% of purified water with a prescription amount after boiling and cooling, adding polyethylene glycol 400 with a prescription amount, stirring and dissolving at 40 ℃, adding citric acid with a prescription amount, tartaric acid with a prescription amount and disodium hydrogen phosphate with a prescription amount, stirring and dissolving at 40 ℃, adding tomoxetine hydrochloride with a prescription amount, stirring and dissolving at 40 ℃, adding sucralose with a prescription amount, fructose with a prescription amount, mannitol with a prescription amount, xylitol with a prescription amount, sodium chloride with a prescription amount and EDTA-2Na with a prescription amount, stirring and dissolving at 40 ℃, adding purified water with a prescription amount after boiling and cooling to a dosage volume, stirring and mixing, filtering through a microporous filter membrane with a size of 0.22 mu m, and obtaining tomoxetine hydrochloride oral solution which is packaged in transparent PET bottles, wherein the specification of tomoxetine hydrochloride is 4mg/ml.
EXAMPLE 2 tomoxetine hydrochloride oral solution
The prescription composition of the tomoxetine hydrochloride oral solution of this example 2 is shown in table 2:
| Component (A) | Dosage of |
| Tomoxetine hydrochloride | 0.4g |
| Polyethylene glycol 400 | 3.0g |
| Sucralose | 0.12g |
| Fructose | 5.0g |
| Mannitol (mannitol) | 2.0g |
| Xylitol | 1.5g |
| Citric acid | 0.3g |
| Tartaric acid | 1.2g |
| Disodium hydrogen phosphate | 0.2g |
| Sodium chloride | 1.2g |
| EDTA-2Na | 0.06g |
| Adding purified water | To 100ml. |
Preparation method
Taking 80% of purified water with a prescription amount after boiling and cooling, adding polyethylene glycol 400 with a prescription amount, stirring and dissolving at 40 ℃, adding citric acid with a prescription amount, tartaric acid with a prescription amount and disodium hydrogen phosphate with a prescription amount, stirring and dissolving at 40 ℃, adding tomoxetine hydrochloride with a prescription amount, stirring and dissolving at 40 ℃, adding sucralose with a prescription amount, fructose with a prescription amount, mannitol with a prescription amount, xylitol with a prescription amount, sodium chloride with a prescription amount and EDTA-2Na with a prescription amount, stirring and dissolving at 40 ℃, adding purified water with a prescription amount after boiling and cooling to a dosage volume, stirring and mixing, filtering through a microporous filter membrane with a size of 0.22 mu m, and obtaining tomoxetine hydrochloride oral solution which is packaged in transparent PET bottles, wherein the specification of tomoxetine hydrochloride is 4mg/ml.
EXAMPLE 3 tomoxetine hydrochloride oral solution
The prescription composition of the tomoxetine hydrochloride oral solution of this example 3 is shown in Table 3:
| Component (A) | Dosage of |
| Tomoxetine hydrochloride | 0.4g |
| Glycerol | 3.0g |
| Sucralose | 0.12g |
| Fructose | 5.0g |
| Mannitol (mannitol) | 2.0g |
| Xylitol | 1.5g |
| Citric acid | 1.0g |
| Tartaric acid | 0.5g |
| Disodium hydrogen phosphate | 0.2g |
| Sodium chloride | 1.2g |
| EDTA-2Na | 0.06g |
| Adding purified water | To 100ml. |
Preparation method
Taking 80% of the prescription amount of purified water after boiling and cooling, adding the prescription amount of glycerin, stirring and dissolving at 40 ℃, adding the prescription amount of citric acid, the prescription amount of tartaric acid and the prescription amount of disodium hydrogen phosphate, stirring and dissolving at 40 ℃, adding the prescription amount of tomoxetine hydrochloride, stirring and dissolving at 40 ℃, adding the prescription amount of sucralose, the prescription amount of fructose, the prescription amount of mannitol, the prescription amount of xylitol, the prescription amount of sodium chloride and the prescription amount of EDTA-2Na, stirring and dissolving at 40 ℃, adding the boiled and cooled purified water to a dosage volume, stirring and mixing, filtering through a microporous filter membrane of 0.22 mu m to obtain tomoxetine hydrochloride oral solution, and subpackaging in transparent PET bottles, wherein the specification of tomoxetine hydrochloride is 4mg/ml.
EXAMPLE 4 tomoxetine hydrochloride oral solution
The prescription composition of the tomoxetine hydrochloride oral solution of this example 4 is shown in table 4:
Preparation method
Taking 80% of the purified water with the prescription amount after boiling and cooling, adding the citric acid with the prescription amount, the tartaric acid with the prescription amount and the disodium hydrogen phosphate with the prescription amount, stirring and dissolving at 40 ℃, adding the tomoxetine hydrochloride with the prescription amount, stirring and dissolving at 40 ℃, adding the sucralose with the prescription amount, the fructose with the prescription amount, the mannitol with the prescription amount, the xylitol with the prescription amount, the sodium chloride with the prescription amount and the EDTA-2Na with the prescription amount, stirring and dissolving at 40 ℃, adding the purified water with the boiling and cooling to the dosage volume, stirring and mixing, filtering through a microporous filter membrane with the size of 0.22 mu m to obtain an oral solution of tomoxetine hydrochloride, and subpackaging in transparent PET bottles, wherein the tomoxetine hydrochloride has the size of 4mg/ml.
Investigation of formulations
1. Taste investigation
Oral taking of tomoxetine hydrochloride oral solutions of examples 1-4 was performed by 20 subjects, and the evaluation indexes are the degree of bitter taste in mouth and residual bitter taste, and the scoring criteria for the degree of bitter taste in mouth and residual bitter taste are as follows: 0 minutes (none, pleasant mouthfeel); score 1 (slight, no impact on mouthfeel); 2 minutes (have, influence on mouthfeel); score 3 (more severe, acceptable); score 4 (severe, unacceptable). In evaluating the taste of the tomoxetine hydrochloride oral solution by a single blind method, the subject cannot make a possible taste judgment in advance for the tomoxetine hydrochloride oral solution to be tasted, and the taste evaluation results of the tomoxetine hydrochloride oral solution are shown in table 5.
Table 5 taste evaluation of tomoxetine hydrochloride oral solutions prepared in examples 1 to 4
| Experimental group | Degree of bitter taste in mouth | Residual bitter taste |
| Example 1 | 0.4 | 0.2 |
| Example 2 | 2.2 | 1.7 |
| Example 3 | 2.7 | 1.9 |
| Example 4 | 3.6 | 2.5 |
As can be seen from table 5, the tomoxetine hydrochloride oral solution prepared in this embodiment can reduce or improve the bitter taste of tomoxetine hydrochloride and the residual problem thereof, and improve the taste of tomoxetine hydrochloride oral solution, thereby improving the oral compliance of patients to tomoxetine hydrochloride oral solution.
2. Stability investigation
2.1 Investigation of the light stability
The tomoxetine hydrochloride oral solutions prepared in examples 1-4 and packaged in transparent PET bottles were placed under illumination conditions (4500 lx,25 ℃) for 0 days, 10 days and 30 days, illumination single factor investigation was performed according to the principle of stability test guidance of Chinese pharmacopoeia preparations, and the tomoxetine hydrochloride and the impurity A content and the total impurity content thereof at different investigation time points were measured by high performance liquid chromatography, so that the illumination stability of the tomoxetine hydrochloride oral solutions prepared in examples 1-4 was investigated, and the results are shown in Table 6.
Table 6 results of examination of stability of tomoxetine hydrochloride oral solutions prepared in examples 1-4 under light conditions (4500 lx,25 ℃ C.)
2.2 High temperature stability investigation
The tomoxetine hydrochloride oral solutions prepared in examples 1-4 and packaged in transparent PET bottles were placed at a high temperature of 60 ℃ for 0 day, 10 days and 30 days, high-temperature single factor investigation was performed according to the stability test guidelines of Chinese pharmacopoeia preparations, the tomoxetine hydrochloride and the impurity A content and the total impurity content thereof at different investigation time points were measured by high performance liquid chromatography, and the high-temperature stability of the tomoxetine hydrochloride oral solutions prepared in examples 1-4 was examined, and the results are shown in Table 7.
Table 7 results of examination of stability of tomoxetine hydrochloride oral solutions prepared in examples 1 to 4 at high temperature of 60 °c
As can be seen from tables 6 and 7, the tomoxetine hydrochloride oral solution prepared in example 1 has the most excellent illumination and high temperature stability under illumination conditions (4500 lx,25 ℃) and high temperature 60 ℃, can be packaged in a transparent container for storage and transportation, and when a patient purchases or uses the tomoxetine hydrochloride oral solution, the transparent container can be used for simply, quickly and effectively observing the properties of the tomoxetine hydrochloride oral solution, such as clarity, whether precipitate particles, mildewing, foreign matters and other deterioration phenomena exist, so that the medication safety is ensured, the quality requirements of the tomoxetine hydrochloride oral solution in the transportation and storage process can be ensured, the quality safety is ensured, and the storage and transportation cost is reduced.
While the invention has been described in terms of one embodiment, it should be noted that modifications could be made without departing from the principles of the invention, which would be apparent to those skilled in the art, would also be considered to be within the scope of the invention.
Claims (6)
1. An oral solution of tomoxetine hydrochloride, which is characterized in that,
The tomoxetine hydrochloride oral solution consists of the following components:
2. the tomoxetine hydrochloride oral solution of claim 1, wherein the tomoxetine hydrochloride oral solution consists of the following components:
3. A process for preparing an oral solution of tomoxetine hydrochloride as claimed in claim 1, comprising the steps of:
Mixing atomoxetine hydrochloride, polyethylene glycol 400, sucralose, fructose, mannitol, xylitol, citric acid, tartaric acid, disodium hydrogen phosphate, sodium chloride, EDTA-2Na and water to obtain the atomoxetine hydrochloride oral solution.
4. A method according to claim 3, wherein the tomoxetine hydrochloride oral solution is prepared by the following method:
Adding polyethylene glycol 400 into 75-85% of water with a prescription amount after boiling and cooling, stirring and dissolving at 35-45 ℃, adding citric acid, tartaric acid and disodium hydrogen phosphate, stirring and dissolving at 35-45 ℃, adding atomoxetine hydrochloride, stirring and dissolving at 35-45 ℃, adding sucralose, fructose, mannitol, xylitol, sodium chloride and EDTA-2Na, stirring and dissolving at 35-45 ℃, adding the boiled and cooled purified water to a fixed volume, stirring and mixing, and filtering through a 0.22 mu m microporous filter membrane to obtain the atomoxetine hydrochloride oral solution.
5. A tomoxetine hydrochloride kit, comprising the tomoxetine hydrochloride oral solution of claim 1 and a transparent container;
The tomoxetine hydrochloride oral solution is packaged in the transparent container.
6. Use of tomoxetine hydrochloride oral solution according to claim 1 for the preparation of a medicament for attention deficit/hyperactivity disorder.
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| CN111956607A (en) * | 2020-09-25 | 2020-11-20 | 健民药业集团股份有限公司 | Tomoxetine hydrochloride oral solution and preparation method thereof |
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| WO2015144255A1 (en) * | 2014-03-21 | 2015-10-01 | Lamda Laboratories S.A. | Oral solution comprising atomoxetine hydrochloride |
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