CN115475141A

CN115475141A - Desloratadine oral solution and preparation method thereof

Info

Publication number: CN115475141A
Application number: CN202211261637.7A
Authority: CN
Inventors: 林纬奇; 黄进明; 刘丛盛; 于娟; 陈志亮; 林锦霞; 杨丽美; 高龙辉; 姚伟; 唐行涛; 蒲静
Original assignee: Zhangzhou Pientzehuang Pharmaceutical Co Ltd
Current assignee: Zhangzhou Pientzehuang Pharmaceutical Co Ltd
Priority date: 2022-10-14
Filing date: 2022-10-14
Publication date: 2022-12-16

Abstract

The invention provides a desloratadine oral solution preparation and a preparation method thereof, which can obviously reduce the strong bitter taste of desloratadine, obviously improve the stability of the product by controlling the quality of auxiliary materials, reduce the increase of related substances and improve the stability of the product in the storage process. The pharmaceutical composition is particularly useful for administration to adolescents and infants undergoing treatment with loratadine for allergic rhinitis, urticaria.

Description

Desloratadine oral solution and preparation method thereof

1. Field of the invention

The invention relates to the technical field of pharmaceutical preparations, in particular to a desloratadine oral solution with good taste and stable quality and a preparation method thereof.

2. Background of the invention

Desloratadine, its chemical name: 8-chloro-6, 11-dihydro-11- (4-cyclohexylidene) -5H-benzene- [5,6] -cyclohepta [1,2-b ] pyridine.

The chemical structural formula is as follows:

desloratadine is an active metabolite of loratadine, was first developed successfully by american research pharmaceutical company, sepracor, and was globally licensed and developed by a desloratadine-related patent filed on Sepracor in mr 12 months of pioneering and youth (Schering Plough,2009, incorporated with morshadong). Desloratadine was first approved in europe for the relief of allergic rhinitis symptoms at 1/15/2001, with a supplementary indication at 8/6/2001 for chronic idiopathic urticaria.

The desloratadine is alkalescent, slightly soluble in water, bitter in taste and peculiar in smell. The currently available desloratadine preparations are tablets, capsules, dry suspensions, syrups and the like, and can achieve the purpose of treatment. The bitter taste of the drug itself presents serious compliance problems with administration, especially to infant patients, especially in liquid formulations which are convenient to take. The current marketed products of desloratadine do not completely solve the bitter taste compliance problem, despite the existence of many methods to suppress the bitter taste of drugs.

The use of flavoring agents, including sweeteners, fragrances, mucilages, to improve the taste of drugs is one of the most widely used methods for taste masking, especially in pediatric formulations such as liquid formulations. However, for desloratadine which is highly bitter and water soluble, the formulations on the market and the prior art do not ideally solve the bitter taste problem of desloratadine, and even solve the bitter taste problem, other aspects such as stability are caused.

In addition, desloratadine is a primary amine compound, is sensitive to oxygen and is easily oxidized. In order to improve the stability of the desloratadine oral liquid, aeris which is a product on the market of Merck Sharp & Dohme B.V. of original research company is added with a metal ion complexing agent such as disodium edetate, and other auxiliary materials comprise sorbitol, sucralose, propylene glycol, hydroxypropyl methylcellulose, anhydrous citric acid, sodium citrate, bubble gum essence, desloratadine and purified water. However, the research of the patent CN113081958A shows that the oral liquid still can generate obvious impurities by interaction with auxiliary materials under the condition of long-term storage.

The invention patent CN104095807A develops the product into syrup, adds sucrose as sweetener, and tries to solve the problem of bitter taste. However, when used for treating allergic rhinitis for a long time by infants and teenagers, sucrose has a high possibility of causing damage to teeth, and is not recommended in many countries in Europe. Meanwhile, BHA and BHT are added into a desloratadine preparation to be used as antioxidants to solve the stability problem, however, BHA and BHT have certain toxicity and can induce tumors of experimental animals, and in 1987, the International agency for research on cancer (IARC) lists BHA and BHT as 2B carcinogens (possible human carcinogens) and 3 carcinogens (suspected human carcinogens), respectively. Therefore, the addition of BHA and BHT as antioxidants to solve the stability problem is not the optimal solution, and safer methods need to be researched.

In the invention patent CN110638750A, when a liquid preparation of the product is prepared, the active site of desloratadine is subjected to space-occupying protection by high-activity organic polycarboxylic acid salt, so that related substances of the preparation are reduced, and the stability of the product is improved.

The invention patents US6100274A, CN1246794A, WO2006/020534A3 and the like adopt various methods such as coating/ion exchange and the like to prepare tablets to improve the stability, but are not applicable to liquid preparations. In order to solve the problem of oxidation, the liquid preparation usually adopts a method of adding an antioxidant or introducing inert gas in the production process and the preservation process, but the addition of the antioxidant may cause a safety problem, and the introduction of the inert gas increases the production and manufacturing cost, and is not suitable for being repeatedly used after being opened and packaged for many times.

Therefore, how to completely solve the bitter taste compliance problem of desloratadine and improve the stability, especially the oxygen stability, of the desloratadine oral liquid is a difficult problem to be solved urgently for those skilled in the art, and is also a hot problem for those skilled in the art to study.

3. Summary of the invention

The invention solves the technical problems of bitter compliance and stability of desloratadine, provides a desloratadine oral solution preparation and a preparation method thereof, and obviously improves the stability of desloratadine on the premise of satisfying good taste. The pharmaceutical composition is particularly useful for administration to adolescents and infants undergoing treatment with loratadine for allergic rhinitis, urticaria.

The invention discloses a desloratadine oral liquid preparation, which has the following specific technical scheme:

a desloratadine oral solution preparation comprises the following components: desloratadine active ingredient, solubilizer, flavoring agent, pH buffering agent, stabilizing agent and purified water.

Wherein the content of the first and second substances,

the pH buffer is citric acid and sodium citrate buffer salt, or disodium hydrogen phosphate and sodium dihydrogen phosphate buffer salt, preferably citric acid and sodium citrate buffer salt;

the stabilizer is edetate disodium or edetate calcium sodium, preferably edetate disodium;

the correctant comprises sweetener, mucilage, and aromatic;

the sweetener is selected from natural sweetener or synthetic sweetener, and the natural sweetener is one or more selected from sucrose or simple syrup, sorbitol, xylitol, mel, stevioside, etc.; the synthesized sweetener is one or more selected from saccharin sodium, acesulfame potassium, sucralose and aspartame. Preferred are acesulfame potassium, sucralose and aspartame, with xylitol and sucralose being most preferred.

The flavoring agent is selected from banana essence, pineapple essence, orange essence, lemon essence, chocolate essence, etc. The aromatic is usually composed of dozens of spices, and different manufacturers have different types of essences, so that the masking effect on the bitter taste of the desloratadine is great. As a preferable technical scheme, the strawberry essence comprises 99702-C (Shenzhen Li Co.), SN314878 (IFF Co.), BNY1014 (VIRGINIADARE Co.), BNY1015, BNY1016 (VIRGINIADARE Co.), XF81 (VIRGINIADARE Co.), BNY1018 with caramel flavor. The research shows that the strawberry essence-SN 314878 (IFF company) has the best effect of masking the bitter taste of the loratadine.

The mucilage is selected from one or more of starch, sodium carboxymethylcellulose, sodium alginate, agar, gelatin, acacia, tragacanth, etc. Preferably, hypromellose and sodium carboxymethylcellulose are selected, further preferably, hypromellose LV E3, hypromellose LV E5, hypromellose LV E6, hypromellose LV E15, hypromellose LV E50, hypromellose LV K100, sodium carboxymethylcellulose SHX-5 and sodium carboxymethylcellulose SHX-10 are selected, and most preferably, hypromellose LV E15 is selected.

The solubilizer is one or more of propylene glycol, glycerol and ethanol, preferably propylene glycol.

Of these, propylene glycol has a peroxide number of 5 or less, preferably a peroxide number of 3 or less, and more preferably a peroxide number of 1 or less.

The pH value of the solution is 5.0-6.0.

The desloratadine oral solution has a total impurity content of less than or equal to 0.1 percent after being placed for 6 months under the conditions of 40 ℃ and 75 percent RH.

After the desloratadine oral solution is placed at a high temperature of 80 ℃ for 48 hours, the total impurity content is less than or equal to 0.1 percent.

The proportion of desloratadine active ingredients and propylene glycol in the formula is 1; the ratio of desloratadine to strawberry essence is 1; the ratio of desloratadine to hypromellose is 1.

The invention also discloses a preparation method of the desloratadine oral liquid preparation, which comprises the following steps:

(1) firstly adding 60-80% of purified water in preparation and filling, and sequentially adding a pH buffering agent, a stabilizing agent, a half of solubilizer and desloratadine, stirring and dissolving to obtain a solution I;

(2) adding the remaining solubilizer into the mucilage, and uniformly stirring to obtain a solution II;

(3) adding the solution II into the solution I, and uniformly stirring;

(4) adding aromatic, adding purified water to full volume, and stirring.

(5) Removing insoluble impurities by clarifying filter, and packaging to obtain final oral liquid preparation.

The pharmaceutical composition in the form of oral aqueous solution of desloratadine obviously reduces the strong bitter taste of desloratadine, obviously improves the stability of the product by controlling the quality of auxiliary materials, reduces the increase of related substances and improves the stability of the product in the storage process. The pharmaceutical composition is particularly useful for administration to adolescents and infants undergoing treatment with loratadine for allergic rhinitis, urticaria.

4. Description of the drawings

FIG. 1 is a liquid phase diagram of the substances of example 6.

FIG. 2 is a liquid phase diagram of the substances of example 7, which is a stability test conducted at 0 month.

FIG. 3 is a liquid phase detection chart of the substances involved in the acceleration test of example 7 for 6 months.

5. Detailed description of the preferred embodiments

In order to make the objects, technical solutions and advantages of the present invention more apparent, the present invention is described in further detail below with reference to specific embodiments. It should be understood that the detailed description and specific examples, while indicating the invention, are intended for purposes of illustration only and are not intended to limit the scope of the invention.

Oral solution of pratadine chloride as control example

Trade names of outsourcing: aerius, manufacturer: merck Sharp & Dohme Limited desloratadine oral solution.

EXAMPLE 1 Desloratadine oral solution

The types and the dosages of other raw and auxiliary materials except the aromatic essence are fixed, essence samples with different models are respectively prepared, and the preparation methods are basically consistent and are respectively the prescriptions 1-6.

TABLE 1 Desloratadine oral solution prescription composition

Wherein, the strawberry essence 99702-C is from Shenzhen Li company, the strawberry essence-SN 314878 is from IFF company, the strawberry essence BNY1014 is from VIRGINIADARE company, the strawberry essence BNY1016 is from VIRGINIADARE company, the bubble gum essence XF81 is from VIRGINIADARE company, and the caramel essence BNY1018 is from VIRGINIADARE company.

The formulas 1 to 6 all adopt the following preparation processes:

(1) firstly adding 60-80% of purified water in preparation and filling, and sequentially adding citric acid, sodium citrate, xylitol, sucralose, edetate disodium, half of propylene glycol and desloratadine, stirring and dissolving to obtain a solution I;

(2) adding the rest propylene glycol into hydroxypropyl methylcellulose E15, and stirring uniformly to obtain solution II;

(3) adding the solution II into the solution I, and uniformly stirring;

(4) adding the above aromatic agents, adding purified water to 3000ml, and stirring.

EXAMPLE 2 Desloratadine oral solution taste test

Samples were prepared using the above recipes 1 to 6, and compared with the taste (sweet taste, bitter taste) of a control example (trade name: aerus, manufacturer: merck Sharp & Dohme Limited), the basic taste was the taste initially perceived by the mouth, and the remaining taste was the taste remaining after oral administration, and it was important for taste evaluation. The scoring criteria are shown in Table 2, and the results of 5 taster tasters on the scoring of taste are shown in Table 3.

TABLE 2 Scoring basis

Flavor grade

0 to 1

1.1 to 3

3.1 to 6

6 to 9

9 to 12.5

＞12.5

Description of the invention

Very slight; hardly distinguishable

Slight, it is a little

Mild to moderate

Medium grade

Moderate to high

Height of

TABLE 3 taste comparison of recipes 1-6 with the control

The taste comparison results of the formulas 1-6 and the comparison example in the table 3 show that the flavors of different specifications have obvious difference, although the formulas 1-4 are all strawberry flavor, the strawberry flavor usually consists of a fresh flavor, a sweet flavor, an acid flavor, a fruit flavor, a flower flavor and a characteristic flavor, each flavor consists of a plurality of flavors, and the composition types and the proportions of the flavors influence the flavors, so that the different flavors can also cause different tastes.

The difference between the sweet taste (basic taste) and the sweet taste (aftertaste) of the formulas 1 to 6 and the comparative examples is not large, so that the satisfactory effect can be achieved, and the reasonable use of the sweetener is shown. However, the bitterness (basic taste) and the aftertaste (aftertaste) are greatly different, and the difference between different prescriptions is large. The bitter taste is the taste possessed by desloratadine itself.

According to the formulas 1-6, different types of essences of different manufacturers are found to have great influence on covering bitter taste of the desloratadine, wherein the strawberry essence SN314878 of the formula 2 has the best taste-modifying effect, the covering bitter taste is most obvious, and the essence is most easily accepted when being added into a desloratadine liquid preparation. And the taste of the prescription 2 is better than that of the control example.

EXAMPLE 3 Desloratadine oral solution

To investigate the possibility of further reducing bitterness, the kind and amount of mucilage were further screened on the basis of the strawberry essence model number SN314878 of prescription 2 and the supplier IFF company, and the influence of the mucilage on the taste of the product was screened. The prescriptions of other raw and auxiliary materials except the mucilage are kept consistent, and mucilage samples with different types and models are respectively prepared, wherein the prescriptions are respectively 7-12.

TABLE 4 Desloratadine oral solution prescription composition

The prescription is 7-12, and the prescription mucilage respectively adopts hydroxypropyl methylcellulose LV E5, hydroxypropyl methylcellulose LV E6, hydroxypropyl methylcellulose LV E15, hydroxypropyl methylcellulose LV E50, sodium carboxymethylcellulose SHX-5 and sodium carboxymethylcellulose SHX-5.

The same preparation process is adopted in the formulas 7 to 12, and the preparation process comprises the following steps:

(1) adding 60-80% of purified water, sequentially adding citric acid, sodium citrate, xylitol, sucralose, edetate disodium, half of propylene glycol and desloratadine, stirring and dissolving to obtain a solution I;

(2) adding different mucilage agents into the residual propylene glycol, and uniformly stirring to obtain a solution II;

(3) adding the solution II into the solution I, and uniformly stirring;

(4) adding strawberry essence SN314878, adding purified water to 3000ml, and stirring.

Example 4 taste test of Desloratadine oral solution

Samples were prepared according to recipes 7-12 and taste (sweetness, bitterness, flavor) was compared to the control (trade name: aerus, manufacturer: merck Sharp & Dohme Limited) and scored according to Table 2, and the results of 5 people scoring the taste are shown in Table 5.

TABLE 5 taste comparison of recipes 7-12 with the control

The mucilage has the properties of viscosity and moderation, and can interfere the taste sense of taste buds to achieve the aim of correcting the bitter taste of the desloratadine, and the mucilage with different types and specifications has different molecular structures, different lengths of molecular chains and different generated viscosities, and possibly has different effects on the desloratadine. The bitter taste of samples prepared by different mucilage agents is obviously different.

The formulas 7-12 and the comparative examples have different sweet taste (basic taste) and aftertaste, so that the satisfied effect can be achieved, and the mucilage has little influence on the sweet taste. However, the bitter taste (basic taste) and the bitter taste (aftertaste) have certain differences, and the difference between different products is large. The bitter taste is the taste of desloratadine itself.

According to the formulas 7-12, different types and specifications of mucilages are found to have great influence on the masking of the bitter taste of the desloratadine, wherein the tastes of the formulas 8 and 10-12 are close to those of the control example, and the bitter taste of the formula 7 is different from that of the control example.

Wherein, the hydroxypropyl methylcellulose LV E15 in the prescription 9 has the best taste-modifying effect, and the bitterness of the prescription 9 is the smallest after being taken, so that the hydroxypropyl methylcellulose LV E15 is most easily accepted by people.

According to the comparison between the prescriptions 1-12 and the comparison with the comparison example, the optimal flavoring agent combination adopted by the product is determined as follows: the sweetener is sucralose and xylitol, the aromatic is strawberry essence with model SN314878, and the mucilage is hypromellose with model LV E15.

EXAMPLE 5 Desloratadine oral solution

Desloratadine is a primary amine compound, is sensitive to oxygen and is easy to oxidize.

It is generally believed that the addition of propylene glycol increases the dielectric constant of the formulation and increases the stability of desloratadine, but we have found unexpectedly that certain impurities contained in propylene glycol sometimes destabilize desloratadine. We have further investigated that the component affecting the instability of desloratadine is a peroxide, the amount of peroxide is expressed by the peroxide number, and the stability of desloratadine is increased by controlling the peroxide number in propylene glycol to be less than or equal to 5, more preferably less than or equal to 3, and most preferably less than or equal to 1.

The purification method of propylene glycol (peroxide value is less than or equal to 1) can be obtained according to the following purification methods: taking a propylene glycol auxiliary material (from lake Nanerkang pharmaceutical Co., ltd.), adding anhydrous sodium sulfite with the weight 0.1% of that of the propylene glycol, heating to 60-90 ℃, stirring for 1 hour, carrying out precision filtration, and removing redundant or reacted anhydrous sodium sulfite products to obtain the purified propylene glycol. The peroxide number test method is carried out according to general rules of the four parts 0713 of the 2020 edition of Chinese pharmacopoeia.

The propylene glycol is purified by adopting the method, the purified propylene glycol is prepared, the peroxide value is detected to be less than or equal to 1 according to 0713 of the general rule of four parts in China pharmacopoeia 2020 edition, the purified propylene glycol is adopted to prepare a sample as a prescription 13, and the propylene glycol before purification is adopted to prepare a sample as a prescription 14. Other auxiliary materials are kept consistent, and the preparation method is kept consistent, as shown in the following table 6.

TABLE 6 Desloratadine oral solution prescription composition

Prescription	Prescription 13	Prescription 14
			Desloratadine	1.5g	1.5g
Propylene glycol (after purification)	300g	——
			Propylene glycol (before purification)	——	300g
Xylitol, its preparation method and application	300g	300g
			Citric acid	1.6g	1.6g
Citric acid sodium salt	3.8g	3.8g
			Edetate disodium	0.75g	0.75g
Hydroxypropyl methylcellulose LV E15	60g	60g
			Sucralose	12g	12g
Strawberry essence SN314878	3g	3g
			Purified water is added to	3000ml	3000ml

The formulas 13-14 all adopt the following preparation processes:

(1) firstly adding 60-80% of purified water in preparation and filling, sequentially adding citric acid, sodium citrate, xylitol, sucralose, edetate disodium and half of propylene glycol and desloratadine which are respectively before and after purification, stirring and dissolving to obtain a solution I;

(2) taking the rest propylene glycol before and after purification respectively, adding hydroxypropyl methylcellulose LV E15, and stirring uniformly to obtain solution II;

(3) adding the solution II into the solution I, and uniformly stirring;

Example 6 Desloratadine oral solution stability Studies

Formulas 13-14, respectively standing at 80 deg.C for 48 hr, examining the stability of the sample at high temperature, comparing with the sample without high temperature, detecting the related substances according to the prepared test solution of related substances, focusing on specific oxidation impurity peak A, peak B, and peak C, and finding the results in tables 7-8 and the chromatogram for related substances examination in FIG. 1.

The formula 14 sample prepared by using the propylene glycol before purification has large degradation impurities at the positions of the peak A, the peak B and the peak C, and the total impurities are 2.59 percent, while the formula 13 sample prepared by using the propylene glycol after purification is very stable, has no obvious degradation impurities at the corresponding positions of the peak A, the peak B and the peak C, and has 0.07 percent of total impurities, and almost has no change. Therefore, the propylene glycol peroxide has great influence on related substances of the desloratadine, and the peroxide value of the propylene glycol is controlled to be less than or equal to 1 most preferably.

Table 7 formulas 13 to 14 results of detection of impurities without leaving high temperature

Name of impurity	Relative retention time	Prescription 13 impurity (%)	Prescription 14 impurity (%)
				Peak A	0.68	N.D	0.06
Peak B	0.79	0.04	0.12
				Peak C	0.95	0.01	0.05
Total impurities	——	0.05	0.23

Table 8 shows the results of impurity detection under the conditions of 13-14 high temperature of 48h

Name of impurity	Relative retention time	Prescription 13 impurity (%)	Prescription 14 impurity (%)
				Peak A	0.68	N.D	0.64
Peak B	0.79	0.05	1.45
				Peak C	0.95	0.02	0.50
Total impurities	——	0.07	2.59

Example 7 comparative study of the stability of Desloratadine oral solution

3 batches of samples were prepared according to recipe 13, with sample batches of 1709401, 1709402, 1709403, respectively, and stability compared to the control, which was 6ETSC32004, 7ETSC31001, 7ETSC50002, respectively. Stability is carried out according to the four-part guiding principle 9001 of the Chinese pharmacopoeia 2015 edition, the guiding principle of the stability of the bulk drug and the pharmaceutical preparation is carried out by placing the bulk drug for 6 months under the conditions of 40 ℃ and 75% RH, key indexes are checked, the comparison result of the prescription 13 and the comparison example in 0 month is shown in table 9, and the liquid phase detection chart 2 of substances related to the stability in 0 month is shown. The results of the 6 month accelerated comparison are shown in Table 10, and the stability of the results is accelerated for 6 months, and the liquid phase detection of the relevant substances is shown in FIG. 3.

TABLE 9 quality comparison of prescription 13 with the control (0 month)

Note: N.D means not detected

TABLE 10 quality comparison of prescription 13 with the control (accelerated 6 months)

Note: N.D. not detected

The formula 13 and the comparison example are compared and investigated by accelerating the stability for 6 months, the stability of the formula 13 is obviously superior to that of the comparison example, and the purified propylene glycol can obviously reduce related substances of desloratadine and improve the stability of the preparation, thereby improving the safety of clinical use.

Claims

1. The desloratadine oral solution is characterized by comprising the following components: the composition comprises desloratadine active ingredients, propylene glycol, sucralose, xylitol, hydroxypropyl methylcellulose, strawberry essence, a pH buffering agent, a stabilizing agent and purified water.

2. The desloratadine oral solution of claim 1 wherein said propylene glycol has a peroxide number of 5 or less.

3. The desloratadine oral solution of claim 1 wherein the hypromellose is hypromellose LV E15.

4. The desloratadine oral solution of claim 1 wherein the strawberry flavor is strawberry flavor SN314878.

5. The desloratadine oral solution of claim 1 wherein the pH of the solution is in the range of 5.0-6.0.

6. The oral desloratadine solution of claim 1 wherein the total impurity content of the desloratadine oral solution is less than or equal to 0.1% after standing for 6 months at 40 ℃, 75% rh.

7. A preparation method of a desloratadine oral liquid preparation comprises the following steps:

(1) firstly adding 60-80% of purified water in preparation and filling, and sequentially adding a pH buffering agent, a stabilizing agent, xylitol, sucralose, a part of propylene glycol and desloratadine, stirring and dissolving to obtain a solution I;

(2) adding the rest propylene glycol into hydroxypropyl methylcellulose, and stirring uniformly to obtain a solution II;

(3) adding the solution II into the solution I, and uniformly stirring;

(4) adding strawberry essence, adding purified water to full volume, and stirring.

8. The method for preparing the desloratadine oral liquid preparation according to claim 7, wherein the peroxide value of the propylene glycol is less than or equal to 5.

9. The preparation method of the desloratadine oral liquid preparation according to claim 7, wherein the hypromellose is hypromellose LV E15.

10. The preparation method of the desloratadine oral liquid preparation according to claim 7, wherein the strawberry essence is strawberry essence SN314878.