A preparation method of lincomycin hydrochloride soluble powder

Abstract

The present invention provides a method for preparing lincomycin hydrochloride soluble powder. The preparation comprises the following ingredients: 10% lincomycin hydrochloride (calculated as lincomycin), 2% sustained-release agent, 5% solidifying agent, 1% moisturizing agent, 0.1% taste masking agent, and anhydrous glucose as an auxiliary material. The preparation is prepared through the steps of liquid preparation, drying, crushing, and mixing. The preparation prepared by this method solves the problem of the peculiar smell of the drug and does not affect the feed intake of animals after feeding; it can be administered with drinking water, mixed with feed, or directly orally; it can effectively improve the bioavailability of the drug, has a sustained-release effect, improves the effect of the drug, reduces the cost of medication, and indirectly reduces environmental pollution.

Description

Technical Field

[0001] The present invention relates to the field of veterinary medicine in the field of biomedicine, and specifically relates to a method for preparing lincomycin hydrochloride soluble powder. Background Art

[0002] Lincomycin hydrochloride is a white crystalline powder with a special odor and bitter taste.

[0003] Lincomycin hydrochloride is a lincosamide antibiotic. It is a highly lipid-soluble alkaline compound that is well absorbed in the intestine. It is primarily used against Gram-positive bacteria, but also exhibits strong antibacterial activity against mycoplasmas, with strong activity against Staphylococci, hemolytic Streptococci, and Pneumococci. It also has inhibitory effects against anaerobic bacteria, Clostridium tetani, and Bacillus aeruginosa. It also has some activity against Treponema hyodysenteriae and Toxoplasma.

[0004] Lincomycin hydrochloride is rapidly but incompletely absorbed after oral administration in animals, with an oral bioavailability of 20%-50% in pigs. Peak concentrations are reached in most animals within one hour after administration, and the drug is widely distributed to various body fluids and tissues, with the highest concentrations in the liver and kidneys, where tissue concentrations are several times higher than those in serum. Lincomycin hydrochloride can be distributed into milk, where concentrations are similar to those in blood. Some of the drug is metabolized in the liver, with unchanged drug and its metabolites excreted in bile, urine, and milk. 20% of the drug retains antimicrobial activity in urine. Following intramuscular injection in pigs, the half-life is 6.8 hours.

[0005] Lincomycin hydrochloride is relatively stable under natural conditions, showing little degradation over three years at room temperature in the absence of water. However, its excretion in animals can easily cause environmental pollution and increase the incidence of drug-resistant bacteria in farm environments. Furthermore, lincomycin is a drug used by both humans and animals, and its widespread use may pose a safety risk to humans.

[0006] Lincomycin hydrochloride has a distinctive odor and a bitter taste. In clinical use, it is typically administered through drinking water or mixed with feed. However, some pigs refuse to drink water and their feed intake decreases, resulting in decreased herd uniformity and an increase in feed-to-meat ratio. Therefore, it is crucial to mask the odor and bitterness while maintaining a consistent administration without affecting the animals' water intake and feed intake.

[0007] Lincomycin hydrochloride is a time-dependent drug. The drug is prepared into a sustained-release preparation so that it is gradually released in the animal body, prolonging the duration of its effective concentration (MIC) and improving its bioavailability. The dosage is reduced to make the efficacy consistent with conventional preparations or the same dose of the drug improves the cure rate and shortens the dosing cycle to achieve the purpose of saving costs and protecting the environment.

[0008] Therefore, we conducted relevant research and developed a method for preparing a lincomycin hydrochloride soluble powder that effectively masks bitterness and odor, is water-soluble, and can be administered via mixing with feed. This method effectively masks the bitterness and odor of the drug. When a large amount of water is added, the drug concentration is low, and the aqueous solution of the drug preparation is in a normal state, allowing administration through water supply pipes. When a small amount of water is added, the drug concentration is high, and the aqueous solution of the drug preparation forms a jelly state, which can be administered by mixing with feed or directly feeding. The drug is slowly absorbed by the animal body, causing it to be slowly released, thereby prolonging the drug's retention time in the animal body and achieving the purpose of prolonging the drug's effective concentration.

[0009] Poloxamers are high-molecular-weight, nonionic surfactants that are readily soluble in water. Different grades and concentrations of poloxamers can be used as emulsifiers, stabilizers, solubilizers, absorption enhancers, sustained-release agents, and solid dispersants. They are widely used in pharmaceuticals and cosmetics. They are physiologically inactive, non-hemolytic, non-irritating to skin and mucous membranes, and have low toxicity, making them excellent pharmaceutical excipients. Poloxamers with a molecular weight above 8000 exhibit good water solubility at low concentrations, while high concentrations form a stable, gel-like liquid.

[0010] Carboxymethyl cellulose is a white powder that is odorless, tasteless, and non-toxic. It is readily soluble in water, hygroscopic, and stable to light and heat. It is widely used in industry, food, and pharmaceuticals. It has excellent moisture retention properties.

[0011] Sodium alginate is a white or yellow-brown powder that dissolves in water. When it encounters divalent cations such as Ca2+ at an appropriate solubility, it undergoes rapid ion exchange to form a hydrogel.

[0012] Poloxamer increases drug solubility and absorption, slows gastrointestinal motility in animals, and exhibits gelling properties in high-concentration aqueous solutions. Sodium alginate also rapidly forms gels when exposed to divalent cation solutions, and the abundant calcium and magnesium ions in everyday drinking water, such as tap water and well water, create conditions for gel formation. Carboxymethyl cellulose exhibits strong hygroscopicity, maintaining its gel form. Based on this, we have developed a relatively effective method for preparing lincomycin hydrochloride soluble powder. Through different application methods, it can be administered both in drinking water and mixed with feed, exhibiting sustained-release properties, significantly improving bioavailability. This method can also mask the odor of lincomycin hydrochloride without affecting animal feed intake.

[0013] When administering the drug through drinking water, simply add water according to the clinical dosage and stir. When administering the drug through mixing with feed, add 1 part of the drug to 5 parts of water and stir evenly until a jelly-like substance appears. Then mix it evenly with the feed. You can also calculate the dosage and feed it directly. The jelly-like substance does not easily evaporate when left under natural conditions, and the water is not easily absorbed by the feed during the mixing process, so it can remain in a relatively intact state and be ingested by the animal. Administration through drinking water can significantly improve the bioavailability of animals compared to traditional preparation methods. Administration through mixing with feed or direct feeding not only significantly improves the bioavailability of animals, but also has a sustained release effect, increasing the retention time of the drug in the animal's body and prolonging the drug absorption time, thereby achieving the purpose of reducing drug use or improving drug efficacy. It indirectly reduces animal drug resistance and protects the degree of drug pollution to the environment. Summary of the Invention

[0014] The present invention adopts the following technical solutions:

[0015] The present invention aims to provide a method for preparing lincomycin hydrochloride soluble powder, which comprises the following components by weight: 10% lincomycin hydrochloride (calculated as lincomycin), 2% sustained-release agent, 5% solidifying agent, 1% humectant, 0.1% taste masking agent, and anhydrous glucose as a base.

[0016] The present invention provides a method for preparing lincomycin hydrochloride soluble powder. The sustained-release agent is poloxamer 338 or poloxamer 407, and poloxamer 338 is preferred.

[0017] The fixing agent is sodium alginate.

[0018] The moisturizing agent is carboxymethyl cellulose.

[0019] The taste masking agent is aspartame or neotame, preferably aspartame.

[0020] A method for preparing lincomycin hydrochloride soluble powder comprises the following steps:

[0021] Step 1. Dissolve 10g of lincomycin hydrochloride (calculated as lincomycin), 2g of poloxamer 338, and 0.1g of aspartame in 10ml of deionized cold water (2-10°C). Naturally warm to room temperature to obtain a mixed gel (taking advantage of the reversible transformation of poloxamer solutions from liquids at low temperatures to gels at room temperature, which prevents boiling in a vacuum drying oven). Dry under reduced pressure at 60°C in a vacuum drying oven to remove water, controlling the moisture content to below 3.0%. Grind and pass through an 80-mesh sieve for later use.

[0022] Step 2. Take 5g of sodium alginate and 1g of carboxymethyl cellulose, crush them and pass them through an 80-mesh sieve for later use.

[0023] Step 3. Grind anhydrous glucose and pass through an 80-mesh sieve for later use.

[0024] Step 4. Preliminarily mix the powders from step 1 and step 2, add anhydrous glucose from step 3 until the mixture reaches 100 g, mix well, and place in an aluminum foil bag.

[0025] The present invention provides a method for preparing lincomycin hydrochloride soluble powder. The prepared lincomycin hydrochloride soluble powder firstly solves the problem of the drug's odor and does not affect the animal's feed intake after feeding; secondly, the lincomycin hydrochloride soluble powder prepared by this method can be administered through normal routes such as drinking water, mixing with feed, and direct oral administration; thirdly, the lincomycin hydrochloride soluble powder prepared by this method can effectively improve the bioavailability of the drug, have a sustained-release effect, enhance the drug's efficacy, reduce drug costs, and reduce environmental pollution. DETAILED DESCRIPTION

[0026] The present invention will be further described below with reference to specific embodiments, and the advantages and features of the present invention will become clearer as the description proceeds. However, these embodiments are merely exemplary and do not limit the scope of the present invention in any way. It should be understood by those skilled in the art that the details and forms of the technical solutions of the present invention may be modified or replaced without departing from the spirit and scope of the present invention, and such modifications and replacements fall within the scope of protection of the present invention.

[0027] Example 1: Control sample

[0028] Take 10 g of lincomycin hydrochloride (calculated as lincomycin), add anhydrous glucose to 100 g, grind and pass through an 80-mesh sieve, mix evenly, and seal in an aluminum foil bag to obtain a control sample.

[0029] Example 2: Sample 1

[0030] Take 10g of lincomycin hydrochloride (calculated as lincomycin) and 0.1g of aspartame, add 20ml of water to dissolve, stir evenly, dry under reduced pressure at 60 degrees to constant weight, preliminarily grind, add anhydrous glucose to 100g, grind through an 80-mesh sieve and mix evenly, and seal the sample 1 in an aluminum foil bag.

[0031] Example 3: Sample 2

[0032] Take 10g of lincomycin hydrochloride (calculated as lincomycin) and 0.1g of neotame, add 20ml of water to dissolve, stir evenly, dry under reduced pressure at 60 degrees to constant weight, preliminarily grind, add anhydrous glucose to 100g, grind through an 80-mesh sieve and mix evenly, and seal the sample 1 in an aluminum foil bag.

[0033] Example 4: Feed intake test

[0034] 100g of each of the control sample, sample 1, and sample 2 was added to 200kg of feed and mixed evenly. In the same pig house on the farm, fattening pigs were all 90 days old. Forty pens of pigs, each containing 10 pigs, were randomly selected and divided into four groups. The pigs were fed according to their usual feeding schedule and method, and their daily feed intake was measured. A blank group was fed a normal diet.

[0035] Blank group Control samples Sample 1 Sample 2 Feed intake 155kg 148kg 153kg 156kg

[0036] Experiments have shown that lincomycin hydrochloride soluble powder without a taste masking agent can cause some pigs to experience a decrease in feed intake, while lincomycin hydrochloride soluble powder with a taste masking agent does not. From an effectiveness and cost perspective, the cheaper aspartame is not as effective as the more expensive neotame, so the cheaper aspartame is preferred as a taste masking agent.

[0037] Example 5:

[0038] Step 1. Dissolve 10g of lincomycin hydrochloride (calculated as lincomycin), 2g of poloxamer 338, and 0.1g of aspartame in 10ml of deionized cold water (2-10°C). Naturally warm to room temperature to obtain a mixed gel. Dry under reduced pressure at 60°C in a vacuum drying oven to remove water to below 3.0%. Grind and pass through an 80-mesh sieve for later use.

[0039] Step 2. Take 5g of sodium alginate, crush it and pass it through an 80-mesh sieve for later use.

[0040] Step 3. Grind anhydrous glucose and pass through an 80-mesh sieve for later use.

[0041] Step 4. Preliminarily mix the powders of step 1 and step 2, add anhydrous glucose from step 3 until the mixture reaches 100 g, mix well, and place in an aluminum foil bag to obtain sample 3.

[0042] Example 6:

[0043] Step 1. Dissolve 10g of lincomycin hydrochloride (calculated as lincomycin), 5g of poloxamer 338, and 0.1g of aspartame in 10ml of deionized cold water (2-10°C). Naturally warm to room temperature to obtain a mixed gel. Dry under reduced pressure at 60°C in a vacuum drying oven to remove water to below 3.0%. Grind and pass through an 80-mesh sieve for later use.

[0044] Step 2. Take 5g of sodium alginate, crush it and pass it through an 80-mesh sieve for later use.

[0045] Step 3. Grind anhydrous glucose and pass through an 80-mesh sieve for later use.

[0046] Step 4. Preliminarily mix the powders of step 1 and step 2, add anhydrous glucose from step 3 until the mixture reaches 100 g, mix well, and place in an aluminum foil bag to obtain sample 4.

[0047] Example 7:

[0048] Step 1. Dissolve 10g of lincomycin hydrochloride (calculated as lincomycin), 10g of poloxamer 338, and 0.1g of aspartame in 10ml of deionized cold water (2-10°C). Heat naturally to room temperature to obtain a mixed gel. Dry under reduced pressure at 60°C in a vacuum drying oven to remove water, reducing the moisture content to below 3.0%. Grind and pass through an 80-mesh sieve for later use.

[0049] Step 2. Take 5g of sodium alginate, crush it and pass it through an 80-mesh sieve for later use.

[0050] Step 3. Grind anhydrous glucose and pass through an 80-mesh sieve for later use.

[0051] Step 4. Preliminarily mix the powders of step 1 and step 2, add anhydrous glucose from step 3 until the mixture reaches 100 g, mix well, and place in an aluminum foil bag to obtain sample 5.

[0052] Example 8:

[0053] Sample 1 was divided into 2 g portions.

[0054] Weigh 2 g of each of samples 3, 4, and 5, add 10 ml of water, and stir until they become jelly-like.

[0055] 90-day-old fattening pigs were fed 200 mg of lincomycin per pig. Blood samples were collected every 10 minutes, centrifuged, and the supernatant was injected into a liquid chromatograph to record the peak area for analysis.

[0056] Sample 1 reached its peak at 60 minutes, with a half-life of 3 hours; sample 3 reached its peak at 70 minutes, with a half-life of 7 hours; sample 4 reached its peak at 80 minutes, with a half-life of 7 hours and 30 minutes; sample 5 reached its peak at 90 minutes, with a half-life of 8 hours.

[0057] Visually, the jelly-like object formed by sample 5 has the best formability, while the jelly-like object formed by sample 3 is poor.

[0058] Experiments have shown that adding poloxamer can prolong the half-life of the drug in pigs, achieving a sustained-release effect. Due to the high cost of poloxamer, although the cost of using the sample with a 2% addition was lower than that of the other samples, the effect was already very significant, representing the highest cost-effectiveness.

[0059] Example 9:

[0060] Step 1. Dissolve 10g of lincomycin hydrochloride (calculated as lincomycin), 2g of poloxamer 338, and 0.1g of aspartame in 10ml of deionized cold water (2-10°C). Naturally warm to room temperature to obtain a mixed gel. Dry under reduced pressure at 60°C in a vacuum drying oven to remove water to below 3.0%. Grind and pass through an 80-mesh sieve for later use.

[0061] Step 2. Take 5g of sodium alginate and 1g of carboxymethyl cellulose, grind them through an 80-mesh sieve and set aside.

[0062] Step 3. Grind anhydrous glucose and pass through an 80-mesh sieve for later use.

[0063] Step 4. Preliminarily mix the powders of step 1 and step 2, add anhydrous glucose from step 3 until the mixture reaches 100 g, mix well, and place in an aluminum foil bag to obtain sample 6.

[0064] Example 10:

[0065] Take 10g of Sample 3 and 10g of Sample 6, add 50ml of water, stir until a jelly-like substance forms, then mix with 10kg of feed and observe. Then, feed 2kg of feed to 90-day-old fattening pigs (equivalent to 200mg of lincomycin per pig). Blood samples are collected every 10 minutes, centrifuged, and the supernatant is injected into a liquid chromatograph, and the peak area is recorded for analysis.

[0066] After mixing, Sample 3 quickly dissolves into the feed in a jelly-like state, becoming invisible to the naked eye. Sample 6 forms fine particles that disperse in the feed. This is because the addition of carboxymethyl cellulose in Sample 6 helps retain moisture, preventing the sample from being quickly dehydrated by the drier feed after mixing.

[0067] Liquid chromatography analysis showed that sample 3 reached its peak at 65 minutes and had a half-life of 6.5 hours, while sample 6 reached its peak at 70 minutes and had a half-life of 6 hours and 50 minutes. Adding carboxymethyl cellulose to the sample can reduce the loss of drug efficacy when mixed with feed for administration.

[0068] Example 11 Drinking water administration test

[0069] Take 2 grams of sample 1, sample 3, and sample 6 respectively, add 50 ml, 100 ml, and 200 ml of water respectively to observe the water solubility.

[0070] Sample 1 Sample 3 Sample 6 50ml clear liquid Thicker liquid Thicker liquid 100ml clear liquid Slightly viscous liquid without precipitation Slightly viscous liquid without precipitation 200ml clear liquid Slightly viscous liquid without precipitation Slightly viscous liquid without precipitation

[0071] Take 50 ml of solution of sample 1, sample 3 and sample 6 respectively, add 150 ml of water and stir lightly to observe the solubility.

[0072] After slight stirring, samples 1, 3, and 6 all quickly formed a homogeneous liquid with no precipitation. All samples can be fed via drinking water.

[0073] Samples 1, 3, and 6 were orally administered to 90-day-old fattening pigs (200 mg of lincomycin). Blood samples were collected every 10 minutes, and the supernatant was centrifuged and injected into a liquid chromatograph to record the peak area for analysis.

[0074] Sample 1 reached its peak at 60 minutes, with a half-life of 3 hours; sample 3 reached its peak at 60 minutes, with a half-life of 3 hours and 40 minutes; sample 6 reached its peak at 60 minutes, with a half-life of 3 hours and 40 minutes.

[0075] The data showed that the absorption and degradation time for Sample 1 administered with drinking water and mixed with feed was consistent. However, Samples 3 and 6 administered with drinking water had significantly earlier peak absorption times and shorter half-lives than those administered with feed. This is because the jelly-like substance formed by mixing with feed is not immediately absorbed by pigs after consumption, resulting in a stronger sustained-release effect. Administration with drinking water, on the other hand, lacks a strong sustained-release effect, but rather the poloxamer's ability to slow gastrointestinal motility prolongs the drug's retention time in the body.

[0076] Through the implementation of the examples, it can be concluded that poloxamer has the effect of slowing down gastrointestinal motility, and the jelly-like substance formed by it and sodium alginate has a sustained-release effect, wherein sodium alginate acts as a solid agent and poloxamer plays a sustained-release role, while carboxymethyl cellulose can solve its role of maintaining structure during the mixing process, and aspartame plays a role of taste masking.

[0077] Finally, a method for preparing lincomycin hydrochloride soluble powder was optimized. The powder comprises the following components by weight: 10% lincomycin hydrochloride (calculated as lincomycin), 2% poloxamer 338, 5% sodium alginate, 1% carboxymethyl cellulose, 0.1% aspartame, and anhydrous glucose as a matrix.

Claims

1. A lincomycin hydrochloride soluble powder, characterized in that: The invention comprises the following components: 10% lincomycin hydrochloride calculated as lincomycin, 2-10% sustained-release agent, 5% sodium alginate, 1% carboxymethyl cellulose, 0.1% taste masking agent, and anhydrous glucose as the matrix; The sustained-release agent is poloxamer 338; The taste masking agent is aspartame or neotame.

2. The lincomycin hydrochloride soluble powder according to claim 1, wherein The usage ratio of poloxamer 338 is 2%.

3. The method for preparing the lincomycin hydrochloride soluble powder according to claim 1 or 2, characterized in that: The following steps are involved: Step 1: Dissolve 10 g of lincomycin hydrochloride, 2 g of poloxamer 338, and 0.1 g of aspartame in 10 ml of 2-10°C deionized cold water; naturally warm the mixture to room temperature to obtain a mixed gel; dehydrate the mixture in a vacuum drying oven at 60°C to reduce moisture to below 3.0%; and pulverize the mixture through an 80-mesh sieve for later use. Step 2: Take 5g of sodium alginate and 1g of carboxymethyl cellulose, crush them and pass them through an 80-mesh sieve for later use; Step 3: Grind anhydrous glucose and pass through an 80-mesh sieve for later use; Step 4: Preliminarily mix the powders from step 1 and step 2, add the anhydrous glucose from step 3 until it reaches 100g, mix well and put into an aluminum foil bag.