High-stability doxycycline hydrochloride soluble powder and preparation method thereof

Abstract

The invention relates to high-stability doxycycline hydrochloride soluble powder which mainly comprises the following components in percentage by weight: 10-50% of doxycycline hydrochloride, 30-50% of a buffer system, 1-10% of an antioxidant / metal ion chelating system, 4-12% of an acidifying agent and the balance of a filling agent. Through the synergistic effect of a pH buffer system and an antioxidant / metal ion chelating system, the chemical stability of doxycycline in different water qualities (especially slightly alkaline and high-hardness water) is doubly guaranteed. Experiments prove that the effective content of the product in tap water with the pH value of 8.0 is reduced by less than 5% within 24 hours, while the effective content of a common preparation is reduced by more than 70%.

Description

Technical Field

[0001] This invention belongs to the field of doxycycline hydrochloride preparation technology, specifically relating to a highly stable doxycycline hydrochloride soluble powder and its preparation method. Background Technology

[0002] Doxycycline hydrochloride is a broad-spectrum, highly effective tetracycline antibiotic. Doxycycline reversibly binds to receptors on the 30S subunit of bacterial ribosomes, interfering with the formation of ribosome complexes between tRNA and mRNA, preventing peptide chain elongation and inhibiting protein synthesis, thereby rapidly suppressing bacterial growth and reproduction. Doxycycline is effective against both Gram-positive and Gram-negative bacteria. Cross-resistance exists between bacteria and oxytetracycline. It is rapidly absorbed orally, minimally affected by food, has high bioavailability, and strong tissue penetration, and is widely used in the treatment of bacterial diseases in livestock, poultry, and aquatic animals.

[0003] Clinically, doxycycline hydrochloride is often administered via drinking water in soluble powder form, which is convenient to use and maintains an effective blood concentration for a long time. The protein binding rate in pigs is 93%. However, doxycycline hydrochloride has poor stability in aqueous solution, and its degradation is affected by various factors. 1) pH value: Doxycycline is relatively stable under acidic conditions, but degrades more rapidly under neutral and alkaline conditions. The pH value of water sources varies greatly in different regions (from 6.0 to above 8.5), resulting in unstable efficacy.

[0004] 2) Metal ions: Commonly present metal ions in water, such as Ca²⁺, Mg²⁺, and Fe²⁺, can form complexes with doxycycline, catalyzing its oxidative degradation, leading to solution discoloration, decreased potency, and even toxic side effects.

[0005] 3) Light and oxygen: Doxycycline is sensitive to light and oxygen and can undergo photolysis and oxidation reactions.

[0006] Currently, commercially available doxycycline hydrochloride soluble powder often experiences a significant decrease in effective concentration within hours when exposed to alkaline or high-hardness water, severely impacting efficacy and potentially inducing bacterial resistance due to insufficient dosage. Therefore, developing a doxycycline hydrochloride soluble powder that can adapt to different water qualities and maintain long-term stability in water has become a pressing technical problem in this field.

[0007] Based on this, this application was developed. Summary of the Invention

[0008] The purpose of this invention is to overcome the shortcomings of existing technologies and provide a highly stable doxycycline hydrochloride soluble powder. Through the synergistic effect of a pH buffer system and an antioxidant / metal ion chelating system, it provides dual protection for the chemical stability of doxycycline in different water qualities (especially alkaline and high-hardness water). Experiments have shown that the effective content of this product decreases by less than 5% within 24 hours in tap water at pH 8.0, while the decrease rate of ordinary formulations can reach over 70%.

[0009] The present invention also provides a method for preparing the above-mentioned highly stable doxycycline hydrochloride soluble powder.

[0010] To achieve the above objectives, the present invention adopts the following technical solution: A highly stable doxycycline hydrochloride soluble powder, which is mainly composed of the following components by weight percentage: doxycycline hydrochloride 10%~50%, buffer system 30%~50%, antioxidant / metal ion chelating system 1%~10%, optional rapid acidifier 4%~12%, and the balance being filler.

[0011] Specifically, the buffer system can be one or more combinations of propylene glycol alginate, L-glutamic acid hydrochloride and sodium L-glutamic acid, L-aspartic acid and sodium L-aspartate, etc., and the amount used is sufficient to stabilize the pH value of the aqueous solution after drug dissolution in the range of 4.0-6.5.

[0012] Specifically, the metal ion chelating agent can be at least one of inositol phosphate and its pharmaceutically acceptable salts, oligomeric proanthocyanidins, alginate, etc.

[0013] Furthermore, the inositol phosphate ester (inositol hexaphosphate, phytic acid) can be a pharmaceutical salt, preferably sodium phytate; the oligomeric proanthocyanidins are derived from grape seed extract or pine bark extract. The alginate can be sodium alginate and / or potassium alginate, etc.

[0014] Specifically, the acidifying agent comprises one or more combinations of organic acids, coated or encapsulated delayed-release acids (such as microencapsulated fumaric acid, microencapsulated citric acid, etc.). Further, the organic acid may be at least one of fumaric acid, tartaric acid, etc. In the delayed-release acid, the microencapsulated coating material is selected from one or more of lipids, cellulose derivatives, acrylic resins, etc.; the lipid may be hydrogenated vegetable oil; the acrylic resin is enteric-coated acrylic resin.

[0015] Specifically, the filler can be at least one of sucrose, lactose, anhydrous glucose, etc.

[0016] The present invention also provides a method for preparing the above-mentioned highly stable doxycycline hydrochloride soluble powder, which includes the following steps: 1) Weigh each raw material according to the proportions; 2) Premix the materials in the buffer system to obtain mixture A; 3) Premix the acidifier and filler to obtain mixture B. 4) Add mixture A and the antioxidant / metal ion chelating system into the mixer; 5) Then add mixture B into the mixer; 6) Finally, add doxycycline hydrochloride to the mixer and mix thoroughly to obtain the final product.

[0017] The core technology of this invention lies in constructing a "three-in-one" synergistic stabilization system that simultaneously attacks the factors leading to doxycycline degradation from three different dimensions. This system consists of a "pH buffering dimension," an "antioxidant / integration dimension," and a "rapid-start dimension." 1) Key Technology Point 1: Precise pH Buffering Dimension - Constructing and Maintaining a Stable Microenvironment: Technical issue: The degradation rate of doxycycline is highly pH-dependent, accelerating dramatically under near-neutral and alkaline conditions. With conventional formulations, the pH is entirely determined by the external water quality, exhibiting no self-regulating ability.

[0018] 2) Key Technology Point Two: Catalysts for Dual Antioxidant and Metal Ion Integration-Severing Degradation: Technical issue: Dissolved oxygen and trace metal ions (such as Cu²⁺, Fe²⁺ / Fe³⁺, Ca²⁺, Mg²⁺, etc.) in water are highly efficient catalysts for the oxidative degradation of doxycycline.

[0019] 3) Key Technology Point Three: Rapid Acidification Start-up – Seizing the Degradation Opportunity: Technical issue: There is a brief "unstable window" between the time the drug is added to the water and before it completely dissolves and the pH buffer system is established. Within these few seconds to a minute, the drug molecules are exposed to the attack of poor water quality.

[0020] Compared with the prior art, the present invention has the following significant advantages and beneficial effects: 1) Excellent water stability: This invention provides dual protection for the chemical stability of doxycycline in different water qualities (especially alkaline and hard water) through the synergistic effect of a pH buffering system and an antioxidant / metal ion chelating system. Experiments have shown that the effective content of this product decreases by less than 5% within 24 hours in tap water with pH 8.0, while the decrease rate of ordinary formulations can reach more than 70%.

[0021] 2) Wide adaptability: The formula of this invention can automatically adjust the water to the stable pH range of the drug, overcome the problem of drug instability caused by regional water quality differences, and ensure the reliability and consistency of the therapeutic effect.

[0022] 3) High safety: This invention effectively reduces the complexes formed between metal ions and drugs by using an integrator, thereby reducing potential toxicity.

[0023] 4) Simple process and low cost: The excipients used in this invention are all conventional pharmaceutical excipients, which are widely available and inexpensive. The preparation process does not require special equipment and is easy to scale up for industrial production.

[0024] 5) High scalability: The basic framework of the formula of this invention can be easily supplemented with masking agents, synergists, etc., to develop a series of products with better palatability or synergistic therapeutic effects. Detailed Implementation

[0025] The technical solution of the present invention will be further described in detail below with reference to the embodiments, but the scope of protection of the present invention is not limited thereto.

[0026] In the following examples, all raw materials used are common commercially available products that can be purchased directly, or can be prepared using conventional techniques in the art.

[0027] Example 1 A highly stable doxycycline hydrochloride soluble powder, comprising the following components by weight percentage: Doxycycline hydrochloride: 20%, Buffer system: 40% (20% L-monosodium glutamate + 20% L-aspartic acid). (Note: Using a mixture of monosodium glutamate and aspartic acid can provide stable and mild buffering capacity.) Antioxidant / metal ion chelating system: 5% (sodium phytate: 5%) (Note: Sodium phytate is a powerful and economical metal ion chelating agent.) Rapid acidifier: 5% (organic acid, fumaric acid: 5%) (Note: This is used to quickly address slightly alkaline water quality and ensure that the pH quickly returns to a stable range.) Filler (anhydrous glucose): 30%, Total: 100%.

[0028] A method for preparing the above-mentioned highly stable doxycycline hydrochloride soluble powder includes the following steps: 1) Weigh each raw material according to the proportions; 2) Premix the materials in the buffer system to obtain mixture A; 3) Premix the acidifier and filler to obtain mixture B. 4) Add mixture A and the antioxidant / metal ion chelating system into the mixer; 5) Then add mixture B into the mixer; 6) Finally, add doxycycline hydrochloride to the mixer and mix thoroughly to obtain the final product.

[0029] Example 2 A highly stable doxycycline hydrochloride soluble powder, comprising the following components by weight percentage: Doxycycline hydrochloride: 20%, Buffer system: 35% (15% propylene glycol alginate + 20% L-glutamic acid hydrochloride). Antioxidant / metal ion chelating system: 8% (pine bark extract, oligomeric proanthocyanidins, purchased from Xi'an Aosai Biotechnology Co., Ltd.: oligomeric proanthocyanidins 95% : 8%) Rapid acidifier: 10% (tartaric acid: 5% + microencapsulated citric acid, purchased from Hubei Mairuike Biotechnology Co., Ltd.: microencapsulated citric acid 90%, coating material: hydrogenated vegetable oil: 5%) Filler (sucrose): 27%, Total: 100%.

[0030] The preparation method of the above-mentioned highly stable doxycycline hydrochloride soluble powder is as described in Example 1.

[0031] Example 3 A highly stable doxycycline hydrochloride soluble powder, comprising the following components by weight percentage: Doxycycline hydrochloride: 20%, Buffer system: 45% (L-aspartate sodium: 45%) Antioxidant / metal ion chelating system: 2% (sodium alginate: 2%) Rapid acidifier: 4% (fumaric acid: 4%) Filler (anhydrous glucose): 29%, Total: 100%.

[0032] The preparation method of the above-mentioned highly stable doxycycline hydrochloride soluble powder is as described in Example 1.

[0033] Example 4 A highly stable doxycycline hydrochloride soluble powder, comprising the following components by weight percentage: Doxycycline hydrochloride: 50%, Buffer system: 35% (15% L-glutamate hydrochloride + 20% L-aspartate sodium). Antioxidant / metal ion chelating system: 5% (sodium phytate 3% + grape seed extract, oligomeric proanthocyanidins 2%). Rapid acidifying agent: 8% (tartaric acid: 4% + microencapsulated fumaric acid, purchased from Hubei Mairuike Biotechnology Co., Ltd.: microencapsulated fumaric acid 85%, coating material: enteric acrylic resin: 4%) Filler (lactose): 2%, Total: 100%.

[0034] The preparation method of the above-mentioned highly stable doxycycline hydrochloride soluble powder is as described in Example 1.

[0035] Example 5 A highly stable doxycycline hydrochloride soluble powder, comprising the following components by weight percentage: Doxycycline hydrochloride: 50%, Buffer system: 32% (12% propylene glycol alginate + 20% L-aspartic acid). Antioxidant / metal ion chelating system: 3% (sodium phytate: 3%) Rapid acidifier: 13% (tartaric acid: 13%) Filler (sucrose): 2%, Total: 100%.

[0036] The preparation method of the above-mentioned highly stable doxycycline hydrochloride soluble powder is as described in Example 1.

[0037] Comparative Example 1 A soluble powder of doxycycline hydrochloride, comprising the following components by weight percentage: Doxycycline hydrochloride: 20%, Filler (anhydrous glucose): 80%.

[0038] The preparation method of the above-mentioned doxycycline hydrochloride soluble powder is as described in Example 1.

[0039] Comparative Example 2 A soluble powder of doxycycline hydrochloride, comprising the following components by weight percentage: Doxycycline hydrochloride: 50%, Filler (lactose): 50%.

[0040] The preparation method of the above-mentioned doxycycline hydrochloride soluble powder is as described in Example 1.

[0041] Stability test data of content in different water qualities 1. Water sample numbering and testing Table 1. Different water sample numbers and testing methods 2. Stability detection of sample content in different water qualities 2.1 Test Materials: Reagents and instruments: electronic balance, high performance liquid chromatography, acetonitrile, etc.

[0042] 2.2 Methods 2.2.1 Preparation of sample content detection solution: Take an appropriate amount of this product (approximately equivalent to 80 mg of doxycycline), accurately weigh it, place it in a 100 ml volumetric flask, add 0.01 mol / L hydrochloric acid solution to dissolve and dilute to the mark, shake well, accurately measure 5 ml, place it in a 50 ml volumetric flask, add 0.01 mol / L hydrochloric acid solution to dissolve and dilute to the mark, shake well, and set aside (1).

[0043] 2.2.2 Preparation of aqueous solution: The doxycycline hydrochloride soluble powder sample was dissolved in 8 different water samples according to the clinically commonly used concentration of 0.2 g / L water (i.e., 20 mg / 100 ml) to obtain aqueous solution (2).

[0044] 2.2.3 Stability test: The prepared sample content detection solution (1) and aqueous solution (2) were placed at room temperature (18-25℃). The preparation time of aqueous solution (2) was timed separately, and samples were taken at regular intervals (2, 4, 6, 12, 24h) to detect its content. At the same time, the sample content of solution (1) was detected.

[0045] 2.3 Results Table 2. Water Quality W1 (Standard purified water, pH=6.8) - Stability of sample content in mild environments Table 3. Water Quality W2 (Soft Acidic Water, pH=6.0) - Sample Content Stability in Friendly Environments Table 4. Water Quality W3 (Soft Neutral Water, pH=7.2) - Stability of Sample Content in Common High-Quality Water Sources Table 5 Water Quality W4 (Medium Hardness Neutral Water, pH=7.5) - Common Challenges in Water Sources (Sample Content) Table 6 Water Quality W5 (High Hardness, Slightly Alkaline Water, pH=8.0) - Sample Content Stability in Typical Challenging Environments Table 7. Stability of Sample Content in Water Quality W6 (High Hardness Alkaline Water, pH=8.5) - Highly Challenging Water Quality Table 8. Water Quality W7 (High Hardness, High Alkalinity Water, pH=9.0) - Sample Content Stability in Extreme Challenge Environments Table 9. Water Quality W8 (Containing high levels of metal ions, pH=7.8) - Sample Content in the Oxidation Catalysis Challenge The experimental data in Tables 2 to 9 above can be summarized as follows: 1. The effectiveness and synergistic effect of the formulation of the present invention: The effective content of all products in the embodiments decreased by less than 5% within 24 hours, and the stability within 24 hours was significantly better than that of comparative examples 1 and 2, which proves the necessity of the synergistic effect of the buffer system, acidifier and chelating system in the formulation of the present invention, and none of them can be omitted.

[0046] 2. Water quality adaptability: Example 2 (highly alkali resistant type) and Example 4 (high concentration highly effective type) are the most robust and reliable in all water qualities, especially harsh water qualities (high pH, ​​high metal ion), making them the first choice for those seeking high efficiency and versatility.

[0047] Example 1 (standard type) and Example 5 (high concentration economical alkali resistant type) performed well under non-extreme water quality conditions and had good cost performance.

[0048] Example 3 (Economical) and all comparative examples have stringent water quality requirements and are only applicable to known water-friendly environments, resulting in poor universality.

[0049] 3. Concentration and stability: Comparing Examples 1 and 4, and Examples 2 and 5, it can be seen that, with proper design of the excipient system, high-concentration (50%) products can also achieve excellent stability, even better than low-concentration products with poor design (such as Example 3).

Claims

1. A highly stable doxycycline hydrochloride soluble powder, characterized in that, It is mainly composed of the following components by weight percentage: doxycycline hydrochloride 10%~50%, buffer system 30%~50%, antioxidant / metal ion chelating system 1%~10%, acidifier 4%~12%, and the balance is filler.

2. The highly stable doxycycline hydrochloride soluble powder as described in claim 1, characterized in that, The buffer system is one or more combinations of propylene glycol alginate, L-glutamic acid hydrochloride and sodium L-glutamic acid, L-aspartic acid and sodium L-aspartate.

3. The highly stable doxycycline hydrochloride soluble powder as described in claim 1, characterized in that, The metal ion chelating agent is at least one of inositol phosphate and its pharmaceutically acceptable salts, oligomeric proanthocyanidins, and alginate.

4. The highly stable doxycycline hydrochloride soluble powder as described in claim 3, characterized in that, The pharmaceutically acceptable salt of the inositol phosphate is sodium phytate; the oligomeric proanthocyanidins are derived from grape seed extract or pine bark extract.

5. The highly stable doxycycline hydrochloride soluble powder as described in claim 3, characterized in that, The alginate is sodium alginate and / or potassium alginate.

6. The highly stable doxycycline hydrochloride soluble powder as described in claim 1, characterized in that, The acidifier comprises one or more combinations of organic acids, coated or encapsulated delayed-release acids.

7. The highly stable doxycycline hydrochloride soluble powder as described in claim 1, characterized in that, The filler is at least one of sucrose, lactose, and anhydrous glucose.

8. A method for preparing the highly stable doxycycline hydrochloride soluble powder according to any one of claims 1 to 7, characterized in that, Includes the following steps: 1) Weigh each raw material according to the proportions; 2) Premix the materials in the buffer system to obtain mixture A; 3) Premix the acidifier and filler to obtain mixture B. 4) Add mixture A and the antioxidant / metal ion chelating system into the mixer; 5) Then add mixture B into the mixer; 6) Finally, add doxycycline hydrochloride to the mixer and mix thoroughly to obtain the final product.

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