CN115300533A

CN115300533A - Pharmaceutical composition containing pollen derivative

Info

Publication number: CN115300533A
Application number: CN202211002680.1A
Authority: CN
Inventors: 李丹; 刘珺; 孙莉文
Original assignee: Liaoning Tianrong Biotechnology Co ltd
Current assignee: Liaoning Tianrong Biotechnology Co ltd
Priority date: 2022-08-19
Filing date: 2022-08-19
Publication date: 2022-11-08

Abstract

The invention provides a pharmaceutical composition containing a pollen derivative, which comprises an effective amount of the pollen derivative and a lipase inhibitor. The pollen derivative comprises sporopollen and pollen charcoal, has excellent oleophylic property and oil adsorption capacity, and is compounded with the lipase inhibitor into the pharmaceutical composition for the first time in the research of the invention. At the same time, the phenomena of anus oil leakage and oily excrement brought by the lipase inhibitor can be effectively reduced.

Description

Pharmaceutical composition containing pollen derivative

Technical Field

The invention relates to the technical field of medicines, in particular to a pharmaceutical composition containing a pollen derivative.

Background

Obesity is a common chronic disease and a global public health problem. In 2013, the american medical association formally considers obesity as a disease. Complications associated with obesity include cardiovascular disease, risk of cancer development, and diabetes.

The lipase inhibitor prevents or treats obesity and hyperlipidemia by inhibiting the activity of lipase, which hydrolyzes triglyceride to form glycerol and free fatty acid, thereby reducing the absorption of fat to the body. Such lipase inhibitors include lipstatin, orlistat, pantocrine, hesperidin, etc., wherein orlistat is derived from natural substances secreted by streptomyces toxigenica, is the only OTC weight-loss drug worldwide, is taken by more than 40,000,000 people worldwide and successfully loses weight, and is the most marketable weight-loss product currently. Orlistat is a typical gastrointestinal lipase inhibitor that inhibits hydrolysis of dietary Triglycerides (TG) in the gastrointestinal tract (GI) by covalently blocking lipase active sites, thereby reducing subsequent intestinal absorption of fat breakdown products (free fatty acids and monoglycerides), and is administered at a dose of 120mg per meal to inhibit about 30% of dietary fat intake, thereby reducing body weight and treating obesity.

Lipase inhibitors have been reported to have severe gastrointestinal adverse effects such as oily spotting, fecal urgency, fatty/oily stools, oil drainage, fecal incontinence, increased defecation, diarrhea, and abdominal pain. These adverse reactions are caused by the formation of separated oil components in the feces of unabsorbed fat due to the action of lipase inhibitors. Increased stool output and fecal incontinence, which results in poor patient compliance with lipase inhibitor doses. Therefore, it is an urgent need to reduce the above-mentioned adverse reactions of lipase inhibitors.

Disclosure of Invention

In view of the above, the present invention provides a pharmaceutical composition containing a pollen derivative to solve the above-mentioned adverse reaction problem of lipase inhibitors. The technical scheme of the invention is as follows:

in a first aspect, the present invention provides a pharmaceutical composition formulated for oral administration comprising an effective amount of a pollen derivative and a lipase inhibitor.

Further, the pharmaceutical composition comprises the following components in parts by weight: 3-30 parts of pollen derivative and 1 part of lipase inhibitor.

Preferably, the proportion of the pollen derivative in the pharmaceutical composition is 5-20 parts.

Further, the pollen derivative is sporopouenin and/or pollen char.

Preferably, the pollen derivative is selected from at least one of sunflower sporopollen essence, pine pollen sporopollen essence and pine pollen carbon.

Further, the lipase inhibitor is selected from one of orlistat, lipstatin, pantocrine, hesperidin, sesquilactone, esterasum and derivatives thereof, and valactone.

Preferably, the lipase inhibitor is orlistat.

Further, the pharmaceutical composition also comprises pharmaceutically acceptable auxiliary materials.

In a second aspect, the present invention provides a medicament for preventing and treating obesity or hyperlipidemia, comprising the above-described pharmaceutical composition formulated for oral administration.

Further, the dosage form of the medicine comprises a drinking preparation, a chewing preparation or a swallowing preparation, the drinking preparation comprises a solution or suspension prepared from powder, granules and effervescent tablets, the chewing preparation comprises tablets and pills, and the swallowing preparation comprises tablets, capsules or pills.

Preferably, the medicament is in the form of tablets or capsules.

More preferably, in the tablet or the capsule, the single dose specification is: orlistat 60-120 mg, pollen derivant 0.3-3.6 g.

Most preferably, in the tablet, the single dose specification is: orlistat 120mg, sporopollenin 0.5-1.5g or pollen charcoal 1-3g; or other formulations of equal scale.

In a third aspect, the present invention provides a health food for preventing and treating obesity or hyperlipidemia, comprising the above pharmaceutical composition formulated for oral administration.

Further, the food includes biscuits, bread, pastries, composite tea, and the like.

In a fourth aspect, the present invention provides a medicament for the prevention and treatment of anal leakage syndrome, said medicament comprising a pharmaceutical composition as defined above formulated for oral administration.

Preferably, the lipase inhibitor in the pharmaceutical composition is orlistat.

Further preferably, in the pharmaceutical composition, the orlistat content in the unit dosage form is 60 to 360mg, and the pollen derivative content in the unit dosage form is 0.3 to 10.8g.

More preferably, orlistat is present in an amount of 60 to 120mg and the pollen derivative is present in an amount of 0.3 to 3.6g in a unit dosage form.

Most preferably, the above medicament or the above food product is administered orally to the subject at breakfast, lunch and dinner or within 1 hour of the meal, wherein the subject ingests 120mg orlistat and sporopollenin 0.5-1.5g or pollen char 1-3g per meal.

The series of researches on the group of the invention find that the pollen derivatives (sporopollenin and pollen charcoal) have excellent oleophylic property and oil adsorption capacity, so that the pollen derivatives and the lipase inhibitor are compounded into the pharmaceutical composition for the first time, and related experiments show that the pharmaceutical composition is expected to become a novel complementary weight-reducing partner which does not cause gastrointestinal adverse reactions and has a synergistic weight-reducing effect. At the same time, the phenomena of anus oil leakage and oily excrement brought by the lipase inhibitor can be effectively reduced.

Drawings

FIG. 1 shows the adsorption of soybean oil by various pollen derivatives in example 1 of the present invention.

FIG. 2 shows the adsorption of the pollen derivatives to different kinds of edible oils according to example 2 of the present invention.

Fig. 3 shows the adsorption of vitamin B folic acid by pollen derivatives in example 3 of the present invention.

FIG. 4 shows that the pharmaceutical composition of example 4 of the present invention is effective in alleviating oily leakage from the fecal surface.

FIG. 5 shows that the pharmaceutical composition of example 4 of the present invention is effective in alleviating anal leakage of oil.

Fig. 6 shows the result of the synergistic effect of the pharmaceutical composition for reducing weight in example 4 of the present invention.

Detailed Description

In the description of the present invention, it is to be noted that those whose specific conditions are not specified in the examples are carried out according to the conventional conditions or the conditions recommended by the manufacturers. The reagents or instruments used are not indicated by the manufacturer, and are all conventional products available commercially.

The invention evaluates the oil absorption performance of different types of pollen derivatives and evaluates the oil absorption performance of the pollen derivatives on different types of edible oil, verifies that the pollen derivatives can specifically adsorb oil and fat components without influencing the absorption of water-soluble nutrients through the adsorption of the pollen derivatives on the water-soluble nutrients, evaluates the obesity treatment effect of the pollen derivatives and lipase inhibitors through the pharmacodynamic verification of the combination of the pollen derivatives and the lipase inhibitors, and evaluates the influence on gastrointestinal adverse reactions through the influence of the combination of the pollen derivatives and the lipase inhibitors.

Further the invention provides a pharmaceutical composition formulated for oral administration comprising an effective amount of a pollen derivative and a lipase inhibitor.

Further, the pollen derivative is sporopollen and/or pollen charcoal.

The sporopouenin is prepared by the following method: (1) Mixing 10g of pollen, dispersing in 100mL of purified water, sieving with 80-mesh sieve, discarding impurities which can not pass through the sieve, vacuum filtering, washing, dispersing the product in 100mL of purified water again, and repeating washing until the filtrate is colorless. Then 50% and 75% ethanol are respectively usedAnd washing with anhydrous alcohol repeatedly until the filtrate is colorless, and drying in a fume hood to obtain defatted pollen. (2) 2g of defatted pollen was suspended in 15mL of phosphoric acid (85%) ^-1 ) In (5), it was placed in a 50mL single-necked flask equipped with a glass condenser and treated at 70 ℃ for 5 hours with mild stirring. After the treatment is finished, collecting a crude sporopouenin product through vacuum filtration; and washing (suction filtration) the crude sporopollenin product according to a series of steps as follows: 1) washing 4 times with 100mL of water at 80-100 ℃, 2) washing 1 time with 100mL of NaOH at 60-70 ℃ and 2mol/L, 3) washing 5 times with 100mL of water at 80-100 ℃, 4) washing 5 times with 100mL of acetone at 40-50 ℃, 5) washing 1 time with 100mL of hydrochloric acid at 40-50 ℃ and 2mol/L, 6) washing 5 times with 100mL of water at 80-100 ℃, 7) washing 5 times with 100mL of acetone at 40-50 ℃, 8) washing 5 times with 100mL of ethanol at 50-60 ℃, 9) washing 1 time with 100mL of water at 80-100 ℃, stirring and staying for 5min in a solvent for each washing of pollen, and finally collecting a product through vacuum filtration. (3) Washed sporopouenin was transferred to a clean glass dish, spread and air dried overnight in a fume hood. The sporopouenin microcapsules were then dried in an oven at 60 ℃ for 4 hours and stored in a dry cabinet at room temperature.

The preparation method of the pollen charcoal comprises the following steps: and (3) taking a proper amount of pollen, calcining at the high temperature of 500 ℃ for a certain time until the pollen is completely carbonized to be black, and cooling to room temperature to obtain the pollen charcoal.

Preferably, the pollen derivative is at least one selected from sunflower sporopollen extract, pine pollen sporopollen extract and pine pollen charcoal.

Preferably, the lipase inhibitor is orlistat.

Orlistat is a typical lipase inhibitor, chemical name: N-formyl-L-leucine- (S) -1- { [ (2S, 3S) -3-hexyl-4-oxo-2-oxocyclobutyl]Methyl dodecyl ester, formula C ₂₉ H ₅₃ NO ₅ Molecular weight 495.73, whose formula is as follows:

although orlistat is the only OTC antiobesity agent worldwide today, adverse effects associated with orlistat (e.g., oily stool and leakage) cause patients to have great trouble in use. During the two decades in which orlistat formulations were marketed, several studies have been conducted in an attempt to find ways to reduce these side effects, and researchers have attempted to reduce the adverse effects associated with orlistat using adsorptive materials (e.g., chitosan, xanthan gum, and mesoporous silica), emulsifiers (e.g., surfactants), high viscosity materials (e.g., dietary fiber FBR), however, the addition of mesoporous silica and surfactants improves the bioavailability of orlistat while improving anal leakage of oil, and the dissolved orlistat tends to be absorbed into the blood through the gastrointestinal tract (GI), which may cause unexpected side effects. Because the gastrointestinal tract environment is unstable, a stable emulsion is difficult to form in the gastrointestinal tract by adding a surfactant, the absorption of fat in the upper colon can be increased by adding an emulsifier, and the effect of a thickening agent on the aspect of adsorbing free oil is not good enough. Whereas konjac (glucomannan) is only possible under in vitro experimental conditions with limited moisture content, not in the colon which is subject to frequent water absorption. In conclusion, the key to reduce the adverse reaction of the lipase inhibitor (such as orlistat) is to find a suitable oil and fat absorbing material which has ideal oil absorption characteristics and does not influence the lipase inhibition activity of orlistat.

The present invention also provides a medicament for preventing and treating obesity or hyperlipidemia, which comprises the above pharmaceutical composition formulated for oral administration.

Preferably, the medicament is in the form of tablets or capsules.

More preferably, in the tablet or the capsule, the single dose specification is: 60-120 mg of orlistat and 0.3-3.6 g of pollen derivative.

The present invention also provides a health food for preventing and treating obesity or hyperlipidemia, which comprises the above pharmaceutical composition formulated for oral administration.

The invention also provides a medicament for preventing and treating anal leakage oil syndrome, which comprises the pharmaceutical composition prepared for oral administration.

Preferably, the lipase inhibitor in the pharmaceutical composition is orlistat.

Further preferably, in the pharmaceutical composition, orlistat is present in an amount of 60 to 360mg in a unit dosage form, and the pollen derivative is present in an amount of 0.3 to 10.8g in the unit dosage form.

More preferably, the orlistat is present in an amount of 60 to 120mg and the pollen derivative is present in an amount of 0.3 to 3.6g in a unit dosage form.

Most preferably, the above medicament or the above food is administered orally to the subject at breakfast, lunch and dinner or within 1 hour of the meal, with 120mg orlistat and sporopollenin 0.5-1.5g or pollen char 1-3g per meal. The invention is further illustrated by the following examples in combination with the accompanying drawings:

example 1

Adsorption of various pollen derivatives to soybean oil

100mg of sporopouenin, pollen charcoal and activated carbon of different plants were packed in a non-woven bag, and then immersed in peanut oil for 30min without stirring. The oil-absorbed sample was then suspended for 30min to allow excess oil to drip off. The weight of oil adsorbed by the empty nonwoven fabric pouch was measured and the difference between the two weights was noted to indicate the oil adsorption capacity.

The results are shown in FIG. 1, and it is understood from the results that different species of sporopouenin and pollen char have different adsorption amounts to soybean oil, and the adsorption amounts of sporopouenin are sequentially from large to small: pine pollen, sunflower, rape, red date and wild chrysanthemum flower; the adsorption capacity of the pollen carbon is sequentially from large to small as follows: pine pollen, red date, rape, sunflower and wild chrysanthemum flower.

Example 2

Adsorption of pollen derivatives to various oils and fats

Packaging 100mg of Helianthus annuus sporopollen essence/pollen Pini charcoal in a non-woven bag, and soaking in different edible oils for 6 hr without stirring. The oil-absorbed sample was then suspended for 30min to allow excess oil to drip off. The weight of oil adsorbed by the empty nonwoven fabric pouch was measured and the difference between the two weights was noted to indicate the oil adsorption capacity.

The results are shown in FIG. 2, and it can be seen that the adsorption amounts of Helianthus annuus sporopollenin in different edible oils are sequentially from large to small: olive oil > soybean oil ≈ peanut oil; the adsorption capacity of the pollen pini sporopollen essence in different types of edible oil is sequentially from large to small: soybean oil > peanut oil > olive oil; the adsorption capacity of the pine pollen carbon in different kinds of edible oil is sequentially from large to small, namely, the adsorption capacity of the pine pollen carbon is approximately equal to that of soybean oil and approximately equal to that of peanut oil and olive oil.

Example 3

Adsorption of water-soluble nutrients by pollen derivatives

Common water-soluble nutrient substances mainly comprise B vitamins and vitamin C, and the adsorption of the pollen derivatives and the activated carbon on the water-soluble nutrient substances is researched by taking the B vitamins and the folic acid as model medicines in the experiment.

100mg sporopouenin, pollen charcoal and active carbon of different plants are packaged in a non-woven fabric bag, then the non-woven fabric bag is immersed in 8 mu g/ml folic acid solution for 30min, and the change of the absorbance value of folic acid before and after adsorption is measured to show the adsorption capacity to folic acid.

The results are shown in fig. 3, and it can be seen from the results that none of the sunflower sporopollenin, the pollen pini sporonin and the pollen pini charcoal can adsorb folic acid, and the activated carbon can adsorb folic acid of about 50% within 30min, so that the sunflower sporonin, the pollen pini sporonin and the pollen pini charcoal can specifically adsorb oil and fat components, and the absorption of water-soluble nutrient substances cannot be influenced, and the activated carbon can absorb edible oil and water-soluble nutrient components to a certain extent.

Example 4

The composition of the pollen derivative and the lipase inhibitor orlistat is used for evaluating the fecal fat excretion rate and anal leakage of SD rats, and the specific process is as follows:

1. material

The tested drugs are: sunflower sporopollenin and pine pollen charcoal are self-made in laboratories, and orlistat is a commercially available product.

2. Laboratory animal

SD rats weighing 180-220g.

3. Grouping

High fat group: 6, only one of the raw materials is used;

orlistat group: 6, 37mg/kg/d;

orlistat + sunflower sporopollenin group: 6, 37mg/kg/d + 300mg/kg/d of sunflower sporopollenin;

orlistat + pine pollen charcoal group: 6 orlistat 37mg/kg/d + pine pollen charcoal 600mg/kg/d.

4. Experimental protocol

The method comprises the steps of performing intragastric administration on all groups of soybean oil (1.5 mL/200g, sudan III is added into soybean oil and serves as an oily dye) every day 10min before administration, performing intragastric administration on each group of rats according to an administration scheme, performing intragastric administration on high-fat groups of 0.5% sodium carboxymethyl cellulose solution with the same amount as the intragastric administration, continuously performing intragastric administration for 10 days, taking images of oil leakage of tail anus of the rats during administration, measuring and measuring oily leakage on the surface of excrement by using oil absorption paper to evaluate adverse reactions of gastrointestinal tracts after administration, collecting excrement of the rats 24h after the last administration, measuring excrement fat excretion rate within 24h, and evaluating weight-losing effect.

5. As a result, the

Orlistat formulations are currently marketed for 3 times daily, 60 or 120mg each, and the dosage regimen in example 4 is designed to be 3 times daily for human, 120mg each, i.e. human is dosed 360 mg/day, adult body weight is calculated as 60kg, giving a dose of 6 mg/kg/day, and the conversion factor for the rat dose per kg body weight is 6.25, so the rat dose is designed to be 37 mg/kg/day in the examples. Combining the test results of example 1 and example 2, the oil absorption rate of Helianthus annuus sporopollen essence and pollen Pini sporopollen essence is 7-11 times of its own weight, the oil absorption rate of pollen Pini charcoal is 4-6 times of its own weight, and orlistat inhibits the absorption of grease by about 30%, the density of grease is about 0.92g/mL, then rats need sporopollen essence with 225-375 mg/kg/day or pollen charcoal with 400-600 mg/kg/day, then example 4 uses 300mg/kg/d Helianthus annuus sporopollen essence and 600mg/kg/d pollen Pini charcoal as design dosage.

The results are shown in fig. 4-6, and it can be seen from fig. 4-5 that significant anal leakage and fecal surface oily leakage occurred after orlistat group administration, while none of the compositions of orlistat and sunflower sporopollenin, nor of orlistat and pine pollen charcoal, indicating that the composition of orlistat and sunflower sporonin or pine pollen charcoal can significantly reduce adverse gastrointestinal reactions of orlistat. As can be seen from fig. 6, in addition to the group with high fat, the fecal fat excretion rate of each group was significantly increased, and the fecal fat excretion rate of the group administered with the composition of orlistat and sunflower sporopollenin or pine pollen charcoal was higher than that of the group with orlistat, indicating that the combination of orlistat and sunflower sporonin or pine pollen charcoal could effectively increase fecal fat excretion, and further indicating that the absorption of dietary fat was reduced, thereby achieving the purpose of losing weight.

In combination with the above results, the weight of an adult is 60kg, the conversion coefficient of the dose of orlistat to the dose of rat is 6.25, and the combination of sporopollenin of 0.5 to 1.5g or pollen charcoal of 1 to 3g is suitable in a single dose specification of 120mg orlistat after conversion.

In conclusion, the medicinal composition of the natural pollen derivative and the lipase inhibitor can realize better weight-reducing and fat-reducing effects, reduce adverse reactions of gastrointestinal tracts to the maximum extent, realize complementary weight-reducing and fat-reducing combination, and meanwhile, the pollen derivative does not influence the absorption of water-soluble nutrient substances.

The above-mentioned embodiments only express several embodiments of the present invention, and the description thereof is more specific and detailed, but not construed as limiting the scope of the present invention. It should be noted that, for a person skilled in the art, several variations and modifications can be made without departing from the inventive concept, which falls within the scope of the present invention. Therefore, the protection scope of the present patent shall be subject to the appended claims.

Claims

1. A pharmaceutical composition formulated for oral administration, comprising: the pharmaceutical composition comprises an effective amount of a pollen derivative and a lipase inhibitor.

2. A pharmaceutical composition formulated for oral administration according to claim 1, wherein: the pharmaceutical composition comprises the following components in parts by weight: 3-30 parts of pollen derivative and 1 part of lipase inhibitor.

3. A pharmaceutical composition formulated for oral administration according to claim 2, wherein: the proportion of the pollen derivative in the pharmaceutical composition is 5-20 parts.

4. A pharmaceutical composition formulated for oral administration according to claim 1, wherein: the pollen derivative is sporopouenin and/or pollen charcoal.

5. A pharmaceutical composition formulated for oral administration according to claim 4, wherein: the pollen derivative is at least one selected from sunflower sporopollen extract, pollen Pini sporopollen extract and pollen Pini charcoal.

6. A pharmaceutical composition formulated for oral administration according to claim 1, wherein: the lipase inhibitor is one selected from orlistat, lipstatin, pantocrin, hesperidin, sesquilactone, estersin and derivatives thereof, and valactone.

7. A pharmaceutical composition formulated for oral administration according to any one of claims 1 to 6, wherein: the pharmaceutical composition also comprises pharmaceutically acceptable auxiliary materials.

8. A medicine for preventing and treating obesity or hyperlipidemia is characterized in that: the medicament comprises a pharmaceutical composition formulated for oral administration according to any one of claims 1 to 7.

9. A health food for preventing and treating obesity or hyperlipidemia is characterized in that: the health food comprising the pharmaceutical composition formulated for oral administration of any one of claims 1 to 7.

10. A medicine for preventing and treating anus oil leakage syndrome is characterized in that: the medicament comprises a pharmaceutical composition formulated for oral administration according to any one of claims 1 to 7.