CN112451476A - Tomoxetine hydrochloride oral liquid and preparation method thereof - Google Patents
Tomoxetine hydrochloride oral liquid and preparation method thereof Download PDFInfo
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- CN112451476A CN112451476A CN201910845663.6A CN201910845663A CN112451476A CN 112451476 A CN112451476 A CN 112451476A CN 201910845663 A CN201910845663 A CN 201910845663A CN 112451476 A CN112451476 A CN 112451476A
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- tomoxetine hydrochloride
- cyclodextrin
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/0087—Galenical forms not covered by A61K9/02 - A61K9/7023
- A61K9/0095—Drinks; Beverages; Syrups; Compositions for reconstitution thereof, e.g. powders or tablets to be dispersed in a glass of water; Veterinary drenches
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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
- A61K31/13—Amines
- A61K31/135—Amines having aromatic rings, e.g. ketamine, nortriptyline
- A61K31/138—Aryloxyalkylamines, e.g. propranolol, tamoxifen, phenoxybenzamine
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/50—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates
- A61K47/69—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the conjugate being characterised by physical or galenical forms, e.g. emulsion, particle, inclusion complex, stent or kit
- A61K47/6949—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the conjugate being characterised by physical or galenical forms, e.g. emulsion, particle, inclusion complex, stent or kit inclusion complexes, e.g. clathrates, cavitates or fullerenes
- A61K47/6951—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the conjugate being characterised by physical or galenical forms, e.g. emulsion, particle, inclusion complex, stent or kit inclusion complexes, e.g. clathrates, cavitates or fullerenes using cyclodextrin
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/14—Drugs for disorders of the nervous system for treating abnormal movements, e.g. chorea, dyskinesia
Abstract
The invention discloses a tomoxetine hydrochloride oral liquid for treating attention deficit hyperactivity disorder and a preparation method thereof. The preparation comprises atomoxetine hydrochloride, hydroxypropyl-beta-cyclodextrin, pH regulator, antiseptic, essence, 50% ethanol and water. The preparation method comprises the following steps: putting water into a tank 1, stirring, adding cyclodextrin, and dissolving to obtain a solution 1. The 50 percent ethanol is put into a tank 2, stirred and added with the tomoxetine hydrochloride to be dissolved to obtain a solution 2. And uniformly mixing the solution 2 and the solution 1, transferring the mixture into a grinding tank, grinding, adding cyclodextrin, and drying in an oven after 1 hour to obtain the intermediate 1. Placing water in a preparation tank, adding the converted intermediate 1, sodium dihydrogen phosphate, phosphoric acid and sodium benzoate, stirring, dissolving, adding essence, uniformly measuring the pH value, and controlling the pH value to be 3.7-4.3 to obtain the tomoxetine hydrochloride concentration oral solution of 4.6 mg/ml. The oral aqueous solution of the invention greatly improves the stability of the tomoxetine hydrochloride and brings greater social value.
Description
Technical Field
The invention belongs to the technical field of medicines and preparation methods thereof, and relates to a tomoxetine hydrochloride oral liquid and a preparation method thereof.
Background
Attention Deficit Hyperactivity Disorder (ADHD), encompassing Attention Deficit Disorder (ADD), is a common class of mental disorders in childhood manifested by inattention and short periods of Attention, hyperactivity and impulsivity disproportionate to age and development level, often accompanied by learning difficulties, conduct Disorder and maladaptation, with symptoms typically occurring around the age of twelve years and lasting for more than six months and occurring in at least two contexts (e.g., school, family, leisure activity, etc.).
The main recommended drugs currently recommended for the treatment of attention deficit hyperactivity disorder include central stimulants: methylphenidate long-acting formulations, methylphenidate short-acting formulations, dexmethylphenidate; the central stimulant is only used by patients over 6 years old, is not suitable for use at night due to the central stimulant effect, has side effects of appetite reduction, insomnia, headache, dysphoria, irritability and the like due to drug side effects, cannot determine whether growth and development are influenced or not, can induce or aggravate the twitch symptoms of the patients, and is not recommended to be used by the patients suffering from the co-morbid twitch disorder.
Selective norepinephrine reuptake inhibitors: a representative drug, tomoxetine hydrochloride. Tomoxetine hydrochloride has similar therapeutic effect to methylphenidate, but has few adverse reactions and good tolerance, and is classified as a first-line therapeutic drug of ADHD, and the chemical name of the tomoxetine hydrochloride is (-) -N-methyl-3-phenyl-3- (o-tolyloxy) propylamine or a pharmaceutically acceptable salt thereof. Tomoxetine hydrochloride is a very potent selective norepinephrine reuptake inhibitor, and it has essentially no other central nervous system activity at concentrations or doses effective to inhibit norepinephrine reuptake, so tomoxetine hydrochloride is a very safe drug, and due to its high safety, its use for ADHD (including adults and children) is a better treatment for this disease, and in addition, it has a very low onset dose, so it can be administered safely and effectively once daily.
The solubility of hydroxypropyl-beta-cyclodextrin in water is good, more than 100 g of hydroxypropyl-beta-cyclodextrin can be dissolved in 100ml of water, the conventional beta-cyclodextrin is adopted in the patent CN106727291 for inclusion, the solubility of beta-cyclodextrin in water is known to be low and is only 1.85% at room temperature, the solubility is increased along with the increase of temperature, the beta-cyclodextrin can be completely dissolved only by setting a certain temperature in the preparation process, but the precipitation risk is increased along with the decrease of temperature, so that certain risk is brought to the stability of the solution.
The original research company of the oral liquid of tomoxetine hydrochloride is a gift, and it can be known that the medicine marketed in europe contains 33 mg of sorbitol per ml, the embodiment in patent CN105705135 relates to the addition of xylitol with a high concentration of up to 30%, the high content of sugar alcohol can improve the taste of the medicine to some extent, and increase the compliance of the patient, but eating a large amount of sorbitol can cause gastrointestinal problems, such as gastrointestinal pain, flatulence and diarrhea with different degrees, sorbitol can also aggravate irritable bowel syndrome and fructose malabsorption, human cells can be synthesized even if the diet is deficient in sorbitol, for the diabetic, excessive synthesis of sorbitol can damage cells, and some domestic and foreign articles report that the existence of sugar alcohol substances can affect the bioavailability of the medicine, and the addition of cyclodextrin can cause the medicine to be included, the method not only can avoid the influence of a plurality of factors such as light, heat, humidity and the like on the medicine in the storage process, but also can prevent the volatilization, sublimation, oxidation and visible light decomposition of the medicine, thereby playing the role of increasing the stability of the medicine without influencing the bioavailability of the medicine, more importantly playing the role of covering the bad taste of the medicine, improving the compliance of the medicine taking of a patient to the maximum extent and having better social value.
Disclosure of Invention
The invention mainly utilizes the inclusion technology and combines with a proper amount of flavoring agent to solve the bitter taste problem of the atomoxetine hydrochloride, and ADHD is the most common neurodevelopmental disorder and is also one of the chronic mental health problems with the highest morbidity of school-age children, and is a mental disorder affecting life-long; as a pediatric medicament, if the taste is easily accepted by children, the medicament compliance can be greatly improved, and the medicament can be better distinguished in similar competitive products, so that the bad odor is improved, and the taste of the oral medicament is controlled within an acceptable degree range, which is particularly important.
The invention provides a tomoxetine hydrochloride oral solution, which comprises tomoxetine hydrochloride, hydroxypropyl-beta-cyclodextrin, a pH regulator, a preservative, essence and water in a formula, wherein the pH value of the tomoxetine hydrochloride oral solution is 3.0-5.0.
The invention provides a pharmaceutical composition, which comprises 0.1-25mg/ml of tomoxetine hydrochloride, 0.5-150mg/ml of hydroxypropyl-beta-cyclodextrin, 0.01-2mg/ml of preservative, 0.05-2mg/ml of essence, 0.01-30mg/ml of pH regulator and the balance of water.
The invention provides a tomoxetine hydrochloride oral preparation composition, which comprises tomoxetine hydrochloride, 36mg/ml hydroxypropyl-beta-cyclodextrin, 0.2mg/ml preservative, 0.5mg/ml essence, 25mg/ml pH regulator and the balance of water.
The invention provides a tomoxetine hydrochloride oral solution, which is prepared from tomoxetine hydrochloride, hydroxypropyl-beta-cyclodextrin, sodium dihydrogen phosphate, phosphoric acid, sodium benzoate, strawberry essence and water, wherein the pH value of the solution is 3.7-4.3.
Compared with the prior art, the invention has the beneficial effects that:
the invention adopts the inclusion technology and uses the hydroxypropyl-beta-cyclodextrin to perform the inclusion on the medicament, thereby playing the role of covering the bad taste of the medicament, simultaneously improving the medicament stability and better improving the medicament compliance of patients.
Detailed Description
The invention is further illustrated by the following examples, which are not intended to limit the scope of the invention.
Example 1
In the formulation of the tomoxetine hydrochloride oral liquid provided in this embodiment, every 200L of the solution is prepared from the following raw material drugs and auxiliary materials by weight, as shown in table 1
Table 1 formula of tomoxetine hydrochloride oral liquid formulation in example 1
Purified water (11.04 kg) was added to the formulation tank 1, stirring was started (stirring speed 500 rpm), and then hydroxypropyl- β -cyclodextrin (3.59 kg) was added thereto, and stirred until the hydroxypropyl- β -cyclodextrin was dissolved, as solution 1.
50% aqueous ethanol (11.13 kg) was added to formulation tank 2, stirring was started (stirring speed 500 rpm), and tomoxetine hydrochloride (0.92kg) was subsequently added thereto, stirring until tomoxetine hydrochloride dissolved, as solution 2.
And mixing the solution 2 and the solution 1, starting stirring (stirring speed is 500 rpm), uniformly mixing, transferring into a grinding tank, starting grinding (speed is 700 rpm), adding hydroxypropyl-beta-cyclodextrin (3.59 kg), grinding for 1 hour, then putting into an oven at 60 ℃ for drying, wherein the dried product is used as an intermediate 1, and the calculated yield is 92.05%.
Detecting the drug content of the intermediate 1, and calculating the addition amount of the intermediate 1 according to the drug content. Adding purified water (167 kg) into a preparation tank, weighing the converted intermediate 1, sodium dihydrogen phosphate dihydrate (5kg), phosphoric acid (0.1 kg) and sodium benzoate (0.04kg) into the preparation tank, starting stirring (stirring speed 500 rpm) until the intermediate is completely dissolved, adding strawberry essence (1 kg), continuously stirring until the intermediate is uniformly dispersed, carrying out pH value inspection in the final process, controlling the pH value range to be 3.7-4.3, and correcting by using sodium hydroxide/phosphoric acid solution when the intermediate is deviated, thereby finally obtaining the oral solution with the concentration of the tomoxetine hydrochloride of 4.6 mg/ml.
Example 2
In the formulation of the tomoxetine hydrochloride oral liquid provided in this embodiment, every 200L of the solution is prepared from the following raw material drugs and auxiliary materials by weight, as shown in table 2
Table 2 formula of tomoxetine hydrochloride oral liquid formulation in example 2
Purified water (11.04 kg) was added to the formulation tank 1, stirring was started (stirring speed 500 rpm), and then hydroxypropyl- β -cyclodextrin (3.59 kg) was added thereto, and stirred until the hydroxypropyl- β -cyclodextrin was dissolved, as solution 1.
50% aqueous ethanol (11.13 kg) was added to formulation tank 2, stirring was started (stirring speed 500 rpm), and tomoxetine hydrochloride (0.92kg) was subsequently added thereto, stirring until tomoxetine hydrochloride dissolved, as solution 2.
And mixing the solution 2 with the solution 1, starting stirring (the stirring speed is 500 rpm), uniformly mixing, putting into a 60 ℃ oven for drying, taking the dried product as an intermediate 1, and calculating the yield to be 91.84%.
Detecting the drug content of the intermediate 1, calculating the adding amount of the intermediate 1 according to the drug content, adding purified water (176 kg) into a preparation tank, weighing the converted intermediate 1, adding sodium dihydrogen phosphate dihydrate (5kg), phosphoric acid (0.1 kg) and sodium benzoate (0.04kg) into the preparation tank, starting stirring (stirring speed 500 rpm) until the intermediate 1 is completely dissolved, adding strawberry essence (1 kg), continuously stirring until the intermediate is uniformly dispersed, performing pH value inspection in the final process, controlling the range of the determined pH value to be 3.7-4.3, and correcting by using a sodium hydroxide/phosphoric acid solution when the intermediate is deviated, so as to finally obtain an oral solution with the concentration of 4.6mg/ml of tomoxetine hydrochloride.
Comparative example 1
In the formulation of the oral liquid without inclusion of tomoxetine hydrochloride provided in this example, the addition of sugar alcohol substances was increased, and each 200L of the solution was prepared from the following raw material drugs and adjuvants by weight, as shown in table 3
Table 3 formula of tomoxetine hydrochloride oral liquid formulation in comparative example 1
Purified water (128 kg) was added to the formulation tank and stirring was initiated (stirring speed 500 rpm) followed by the addition of tomoxetine hydrochloride (0.92kg) and stirring until the tomoxetine hydrochloride dissolved. To this, sodium dihydrogen phosphate dihydrate (5kg) and phosphoric acid (0.1 kg) were added and stirring was continued until completely dissolved, and then sodium benzoate (0.04kg) was added and stirred until the sodium benzoate was dissolved as solution 1.
Sorbitol (6.4 kg), xylitol (60 kg) and sucralose (2 kg) were added to solution 1 with constant stirring until the solid dissolved, and the rate of dissolution was increased by the necessary heating in this step, but the temperature was not higher than 60 ℃, and this solution was regarded as solution 2.
Pouring the strawberry essence into the solution 2, continuously stirring until the strawberry essence is uniformly dispersed, carrying out pH value check in the final process, controlling the pH value range to be 3.7-4.3, and correcting by using a sodium hydroxide/phosphoric acid solution when the pH value range deviates, finally obtaining an oral solution with the concentration of 4.6mg/ml of tomoxetine hydrochloride, and taking the solution as a solution 3.
Filtering the solution 3 with a 4.5-micron cylinder filter (PP material), filling the solution into a material barrel for later use, and finally subpackaging.
Comparative example 2
Referring to the prescription of example 2 in patent CN106727291, the tomoxetine hydrochloride oral liquid is prepared by using the following raw material medicines and auxiliary materials in weight per 200L of solution, as shown in Table 4
Table 4 formula table of tomoxetine hydrochloride oral liquid formulation in comparative example 2
90% purified water was added to a suitable manufacturing vessel maintained at a temperature of about 40 ℃ and then β -cyclodextrin (4 kg), tomoxetine hydrochloride (0.92kg) was added, stirred until tomoxetine hydrochloride dissolved, tartaric acid (0.06kg), sorbitol (21kg) was added and stirred until dissolved as solution 1.
To another manufacturing vessel, sucralose powder (0.4kg), sodium hydroxy phenylpropionate (0.02 kg), sodium hydroxy benzoate (0.04kg) was added with the remaining 10% of the prescribed water and stirred until the solids dissolved as solution 2.
Adding the solution 2 into the solution 1, and adjusting to neutral with sodium citrate in the final process to obtain the final product
The taste test results were tasted by highly experienced and highly trained tasters and the results were rated according to the rating scale shown in table 5 below, and the rating results are shown in table 6.
TABLE 5 taste rating Table
TABLE 6 taste evaluation chart of tomoxetine hydrochloride solution
| Examples and flavors | Example 1 | Example 2 | Comparative example 1 | Comparative example 2 |
| Bitter taste | 1.5 | 2.9 | 6.5 | 5.5 |
The analysis results in table 6 show that not only the sugar alcohol is not used in the presence of hydroxypropyl- β -cyclodextrin, but also there is a slight bitterness in taste as compared with examples 2 and 3 in which a large amount of sugar alcohol is added.
Investigation of influence factors
The influence factor investigation of the example 1 and the comparative example 1 is carried out, the components are respectively packaged in transparent ampoules, sealed by melting, marked, respectively placed under the conditions of illumination, high temperature of 40 ℃ and high temperature of 60 ℃ and sampled for 0 day, 10 days and 30 days to detect the related substances and contents, and the detection method and the detection result are respectively as follows:
the content detection method comprises the following steps:
buffer solution: 1L of 2.9g/L phosphoric acid solution is prepared, 5M potassium hydroxide is added to adjust the pH value to 2.5, and 5.9g of sodium octane sulfonate monohydrate is added to dissolve.
Mobile phase: n-propanol-buffer (27: 73) (Note: n-propanol 26-29)
System applicability solution: taking a proper amount of a mandelic acid reference substance, an impurity A reference substance and a proper amount of a tomoxetine hydrochloride reference substance, and adding a mobile phase to dilute into a solution containing 0.1mg/ml of mandelic acid, 0.15mg/ml of impurity A and 0.25mg/ml of tomoxetine hydrochloride.
Control solution: taking a proper amount of the tomoxetine hydrochloride reference substance, and adding a mobile phase to dilute to 0.25 mg/ml.
Test solution: a proper amount of sample is taken and diluted to 0.25mg/ml by adding mobile phase. (ultrasonic aid-dissolving)
Detection wavelength: 215nm
A chromatographic column: 150 x 4.6, 3.5 um; l7
Column temperature: 40 deg.C
Flow rate: 1.0ml/min
Sample introduction amount: 10ul of
Operating time: 1.3 times the retention time
The related substance method comprises the following steps:
mobile phase and chromatographic conditions of same content
System applicability solution: taking a proper amount of mandelic acid reference substance, impurity A reference substance and tomoxetine hydrochloride reference substance, and adding mobile phase to dilute into mandelic acid 0.1mg/ml, impurity A0.15mg/ml and tomoxetine hydrochloride 0.25 mg/ml.
Control solution: taking a proper amount of the tomoxetine hydrochloride reference substance, and adding a mobile phase to dilute to 0.0025 mg/ml.
A chromatographic column: 250 x 4.6,5 um; l40
Flow rate: 1.0ml/min
Wavelength: 273nm
Sample introduction amount: 10ul of
Operating time: 1.3 times the retention time
The results are as follows:
TABLE 7 results of the influencing factors of the tomoxetine hydrochloride solution
The results show that not only the taste is greatly improved in the presence of hydroxypropyl-beta-cyclodextrin, but also a good effect is shown in improving the stability of the drug.
Claims (6)
1. The tomoxetine hydrochloride oral solution is characterized in that the prescription contains tomoxetine hydrochloride and hydroxypropyl-beta-cyclodextrin.
2. The tomoxetine hydrochloride oral solution is characterized in that the formula contains tomoxetine hydrochloride, hydroxypropyl-beta-cyclodextrin, a pH regulator, a preservative, essence and water, and the pH value of the tomoxetine hydrochloride oral solution is 3.0-5.0.
3. A pharmaceutical composition as claimed in claim 1, which comprises 0.1-25mg/ml tomoxetine hydrochloride, 0.5-150mg/ml hydroxypropyl- β -cyclodextrin, 0.01-2mg/ml preservative, 1-20mg/ml flavoring agent, 0.05-2mg/ml flavor, 0.01-30mg/ml pH modifier, and the balance water.
4. Tomoxetine hydrochloride oral dosage composition according to any one of claims 1 to 2 comprising tomoxetine hydrochloride comprising 4.6mg/ml tomoxetine hydrochloride, 36mg/ml hydroxypropyl- β -cyclodextrin, 0.2mg/ml preservative, 0.5mg/ml flavor, 25mg/ml pH adjusting agent, the balance water.
5. The tomoxetine hydrochloride oral solution of claims 1 to 3 wherein the materials are separately tomoxetine hydrochloride, hydroxypropyl- β -cyclodextrin, sodium dihydrogen phosphate, phosphoric acid, sodium benzoate, strawberry flavor and water combination, wherein the pH of the solution is 3.7-4.3.
6. The tomoxetine hydrochloride oral solution is characterized by comprising the following preparation processes: adding purified water into the preparation tank 1, starting stirring, then adding hydroxypropyl-beta-cyclodextrin into the purified water, and stirring until the hydroxypropyl-beta-cyclodextrin is dissolved to obtain a solution 1; adding 50% ethanol water solution into the preparation tank 2, starting stirring, then adding tomoxetine hydrochloride into the ethanol water solution, and stirring until the tomoxetine hydrochloride is dissolved to obtain a solution 2; mixing the solution 2 and the solution 1, starting stirring, uniformly mixing, transferring into a grinding tank, starting grinding, adding hydroxypropyl-beta-cyclodextrin, grinding for 1 hour, putting into a 60 ℃ drying oven for drying, taking the dried product as an intermediate 1, and calculating the yield to be 92.05%; detecting the drug content of the intermediate 1, and calculating the addition amount of the intermediate 1 according to the drug content; adding purified water into a preparation tank, putting the weighed and converted intermediate 1, sodium dihydrogen phosphate dihydrate, phosphoric acid and sodium benzoate into the preparation tank, starting stirring until the intermediate is completely dissolved, adding strawberry essence, continuously stirring until the intermediate is uniformly dispersed, checking the pH value in the final process, controlling the range of the determined pH value to be 3.7-4.3, and correcting by using a sodium hydroxide/phosphoric acid solution when the pH value deviates to obtain the oral solution with the concentration of 4.6mg/ml tomoxetine hydrochloride.
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| CN201910845663.6A CN112451476A (en) | 2019-09-09 | 2019-09-09 | Tomoxetine hydrochloride oral liquid and preparation method thereof |
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| CN201910845663.6A CN112451476A (en) | 2019-09-09 | 2019-09-09 | Tomoxetine hydrochloride oral liquid and preparation method thereof |
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Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN115317445A (en) * | 2022-08-31 | 2022-11-11 | 广西维威制药有限公司 | Tomoxetine hydrochloride oral solution and production process thereof |
| CN115721634A (en) * | 2022-12-02 | 2023-03-03 | 海南卓科制药有限公司 | Tomoxetine hydrochloride composition, preparation method thereof and application thereof in oral solution |
Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN105705135A (en) * | 2013-11-08 | 2016-06-22 | 伊莱利利公司 | Atomoxetine solution |
| CN106727291A (en) * | 2016-12-06 | 2017-05-31 | 山东达因海洋生物制药股份有限公司 | A kind of tomoxetine hydrochloride oral administration solution and preparation method thereof |
-
2019
- 2019-09-09 CN CN201910845663.6A patent/CN112451476A/en active Pending
Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN105705135A (en) * | 2013-11-08 | 2016-06-22 | 伊莱利利公司 | Atomoxetine solution |
| CN106727291A (en) * | 2016-12-06 | 2017-05-31 | 山东达因海洋生物制药股份有限公司 | A kind of tomoxetine hydrochloride oral administration solution and preparation method thereof |
Non-Patent Citations (2)
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| YANGJIE WEI,ET AL: "Masking the Bitter Taste of Injectable Lidocaine HCL Formulation for Dental Procedures", 《AAPS PHARMSCITECH》 * |
| 何燕等: "国内外口服制剂掩味技术的研究进展", 《中国新药杂志》 * |
Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN115317445A (en) * | 2022-08-31 | 2022-11-11 | 广西维威制药有限公司 | Tomoxetine hydrochloride oral solution and production process thereof |
| CN115721634A (en) * | 2022-12-02 | 2023-03-03 | 海南卓科制药有限公司 | Tomoxetine hydrochloride composition, preparation method thereof and application thereof in oral solution |
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