A tablet formulation comprising hawthorn (crataegus) extract

Abstract

The present invention relates to a tablet formulation comprising an extract of various types of hawthorn (Crataegus). A method for preparing the tablet formulation of the invention is also provided within the scope of the invention. The hawthorn extract in the formulation of the present invention is obtained from Crataegus penlagyna. Crataegus szovitsii, Crataegus aronia. Crataegus curvisepala and Crataegus monogyna hawthorn species.

Description

[0001] A TABLET FORMULATION COMPRISING HAWTHORN (CRATAEGUS) EXTRACT

[0002] Technical Field

[0003] The present invention relates to a tablet formulation comprising hawthorn (Crataegus) extract. A method for preparing the tablet formulation of the invention is also provided within the scope of the invention.

[0004] State of the Art

[0005] Fruits, flowers, and leaves of hawthorn species (Crataegus species) are used in different geographies due to their therapeutic effects. Hawthorn species are known to be used as antioxidants and in aging-related cardiovascular system disorders, especially in European countries, USA and China. In addition to this widespread use of Crataegus species, the fact that it is registered in various pharmacopoeias, that a large number of studies have been conducted with animals and volunteers on its physiological activities and mechanisms of action, and that it does not have toxicity and side effects are the main reasons for its preference as a research subject.

[0006] Some of the most important plants in treatment and preventive medicine are used in cardiovascular diseases. Different hawthorn species are known to be used in the treatment of heart diseases in various geographies; for example, C. pinnatifida in China, C. pubesens in Mexico, C. cuneata in Japan, C. laevigata and C. monogyna in Europe, C. oxyacantha and C. aronica in the Middle East, C. Phaenopyrum and C. ambigua are used in Russia.

[0007] It has been revealed at the end of the studies that hawthorn species have a rich secondary metabolite content. It was determined that hawthorn fruits contain 0.1-1% flavonoids, 0.5- 1.4% triterpene acids, 1-2% oligomeric proanthocyanidins (OPCs) and 2-6% organic acids, as well as a mixture of leaves and flowers containing 1-2% flavonoids and 1-3% OPCs. Patent number CN 106938047 A relates to a coated pepsin tablet. The coated pepsin tablet consists of a tablet core and a coating film. The tablet core comprises 5% to 10% clove leaf extract, 5% to 10% hawthorn extract and 0.01% to 0.02% pepsin by weight. Said tablet is presented to eliminate the symptoms of indigestion.

[0008] Patent number US 5910308 A relates to a plant-based composition comprising Gynostemma pentaphyllum extract, Crataegus pinnatifida extract (hawthorn leaves or nuts) and Camellia sinensis (green tea) extract. In addition, a method for preparing an herbal extract-based composition including extracting each of the hawthorn fruits, green tea leaves and Gynostemma pentaphyllum leaves separately is also provided within the scope of the document.

[0009] In light of the information presented above, it is seen that studies involving hawthorn extracts that benefit human health and for the treatment of various diseases are provided in the known state of the art. However, no studies have been found for the tablet formulation of an extract comprising various hawthorn species together. Therefore, the need for tablet formulations comprising extracts of various types of hawthorn, which are presented for use in regulating blood pressure, lowering cholesterol, preventing, and / or treating cardiovascular diseases, and treating heart failure, is still ongoing in the relevant technical field. For this need, within the scope of the present invention, a tablet formulation comprising at least one excipient with the extract of Crataegus pentagyna, Crataegus szovitsii, Crataegus aronia. Crataegus curvisepala and Crataegus monogyna species is presented. The synergistic effect and high metabolite amount of Crataegus pentagyna, Crataegus szovitsii, Crataegus aronia, Crataegus curvisepala and Crataegus monogyna species in the tablet formulation of the invention make the formulation of the invention advantageous. In addition, the present inventors have revealed that a tablet formulation comprising the extract of these species provides an effect that exceeds the known state of the art in terms of bioavailability.

[0010] Brief Description of the Invention

[0011] In one aspect, the present invention provides a tablet formulation comprising at least one excipient with the extract of Crataegus pentagyna, Crataegus szovitsii, Crataegus aronia, Crataegus curvisepala and Crataegus monogyna species. The tablet formulation of the present invention preferably comprises at least one excipient selected from a group comprising high dispersion silicon dioxide (aerosol), magnesium stearate, Neusilin US2, fluorite, Avicel, Klucel LF, Klucel EXF, Polyplasdone XL, lactose monohydrate, sodium carboxymethyl starch (type A), macrogol 6000, talc, titanium dioxide, microcrystalline cellulose, povidone K 25, carmellose sodium, povidone K 90 and combinations thereof.

[0012] In a preferred embodiment of the present invention, at least one excipient in the formulation of the invention is fluorite, Avicel and magnesium stearate.

[0013] In the preferred embodiments of the invention, the extract is in the range of 20% to 40% by weight in the tablet formulation. The amount of said extract is preferably in the range of 100 to 200 mg. More preferably, the amount of hawthorn extract is 115 mg. In said Avicel tablet formulation, it is preferably in the range of 40% to 55% by weight. In said magnesium stearate tablet formulation, it is preferably in the range of 0.1% to 1% by weight.

[0014] In the preferred embodiments of the invention, the ratio of the extract to fluoride in the formulation of the invention is 1 : 1 to 1 :0.5.

[0015] In another aspect, the invention provides a method for preparing the tablet formulation according to the invention, said method comprising the following steps:

[0016] Collecting, drying, and pulverizing Crataegus penlagyna. Crataegus szovitsii, Crataegus aronia. Crataegus curvisepala and Crataegus monogyna species, subjecting the obtained powder to ultrasonic extraction using a solvent, obtaining the extract by subjecting the solution to lyophilization, combining the extract with at least one excipient, printing the obtained mixture as a tablet, and obtaining the final tablet formulation.

[0017] The method of the present invention is preferably to combine the at least one excipient and the step of combining the extract with fluorite, Avicel and magnesium stearate.

[0018] In another aspect, a tablet formulation according to the invention is presented to be used in the prevention and / or treatment of cardiovascular diseases. Detailed Description of the Invention

[0019] The tablet formulation of the invention is described in detail in this detailed description for a better understanding of the subject and in a way that does not have any limiting effect.

[0020] Said tablet formulation has anti-inflammatory activity as well as being effective in reducing blood pressure and blood cholesterol levels, preventing, and treating heart diseases, reducing skin aging symptoms and facilitating digestion. Species of the tablet formulation of the invention comprising at least one excipient with the extract of C. penlagyna, C. szovitsii, C. aronia, C. curvisepala and C. monogyna species are also known as C. pentagyna Waldst. & Kit. ex Willd., C. szovitsii Pojark, C. aronia (L.) Bosch, ex DC., C. curvisepala Lindman and C. monogyna Jacq.

[0021] There are 17 hawthorn species (21 taxa) in Tiirkiye, 4 (C. davisii Browicz, C. tanacetifolia (Lam.) Pers., C. x bornmuelleri Zabel, C. dikmensis Pojark.) of which are endemic according to their flora (Sect. Pentagynae Schneider 2 species; Sect. Azaroli Loud. 6 species; Sect. Crataegus 9 species). In addition, C. aronia (L.) Bose, species is divided into 3 varieties. Two of them (C. aronia var. dentata Browicz, C. aronia var. minuta Browicz) are endemic species. As a result of other comprehensive studies, a total of 27 species have been identified in Tiirkiye, 6 of which are hybrid species (Nothospecies) and 4 new species (C. turcicus Dbnmez, C. yaltirikii Dbnmez, C. christensenii Dbnmez, C. peshmenii Dbnmez).

[0022] Among the many substances isolated from hawthorn species, flavonoids and OPCs are two large groups of bioactive substances. The pharmaceutical activity of Crataegus leaves, flowers and fruits is considered to be caused by glucose-dependent derivatives of OPCs and flavonoids (flavonol-O-glycosides, vitex 2"-C-rhamnoside, acetyl vitex-2"-O-rhamnoside).

[0023] The flavonoids found in Crataegus species have numerous derivatives, primarily flavonol-O- glycoside and flavone-C-glycosides. It has been determined that there are up to 50 flavonoids and a total of 158 secondary metabolites in C. pinnatifida species. There are also many other compounds, such as flavones (e.g., apigenin, luteolin, orientin, vitexin, vitexin rhamnoside, isovitexin, hyperoside), flavonols (e.g., camferol, quercetin, bioceretin, rutin, pinnatifidin), flavanones, flavanol polymers. In China as well as in Europe and North America, Crataegus (especially C. pinnatifida, C. oxyacantha and C. laevigata) products have an important place due to their healing effects as well as their non-toxic or low toxicity. In particular, products derived from hawthorn species are recommended in the prevention and treatment of age-related diseases (e.g., cardiovascular diseases, arteriosclerosis, arthritis, hypertension), nervous system disorders (e.g., migraine), and upper respiratory tract infections, hypercholesterol, cellulite, obesity, and menopausal disorders.

[0024] As a result of the studies conducted by the inventors on the samples collected from the species in Tiirkiye, especially Crataegus penlagyna, Crataegus szovilsii, Crataegus aronia. Crataegus curvisepala and Crataegus monogyna species have come to the fore due to their high metabolite amounts. The inventors have noticed that said hawthorn species create a synergistic effect in combination within a formulation and that the therapeutic effects of the species are increased individually thanks to this combination. For this reason, Crataegus penlagyna, Crataegus szovilsii. Crataegus aronia, Crataegus curvisepala and Crataegus monogyna species were preferred while preparing the hawthorn extract of the invention.

[0025] The inventors present a tablet formulation of hawthorn dry extract containing the species of the invention, based on the dose usage values recommended by the ESCOP. In accordance with the relevant guidelines and monographs, formulation studies of the tablet dosage form with standardized hawthorn dry extract, whose quality control parameters have been tested, have been carried out.

[0026] In preferred embodiments of the invention, at least one excipient is preferably selected from a group comprising high dispersion silicon dioxide (aerosol), magnesium stearate, Neusilin US2, fluorite, Avicel, Klucel LF, Klucel EXF, Polyplasdone XL, lactose monohydrate, sodium carboxymethyl starch (type A), macrogol 6000, talc, titanium dioxide, microcrystalline cellulose, povidone K 25, carmellose sodium, povidone K 90 and combinations thereof. Thanks to the formulations developed primarily in the laboratory environment with the standardized hawthorn dry extract, said excipients, which are suitable for the purposes of the invention, have been determined. It has been proven that the tablet formulation of the present invention has the desired properties by analyzing the parameters such as friability (crumbling), dissolution, disintegration, content uniformity in the obtained hawthorn extract with the appropriate devices required.

[0027] It is an object of the present invention to prevent the extract obtained by providing the moisture content / balance of the formulation from becoming soft and sticky and from clumping. For this purpose, a tablet formulation containing fluorite, Avicel and magnesium stearate as excipients is presented with the hawthorn extract in a preferred embodiment of the present invention. It has been noticed that the combination of these three excipients allow to obtain a tablet formulation of the desired density and uniformity.

[0028] In particular, the inventors have noticed that the use of fluorite and Avicel, which are specific excipients together with the extract of Crataegus penlagyna, Crataegus szovitsii, Crataegus aronia, Crataegus curvisepala and Crataegus monogyna species of the invention, is effective. In this way, both the desired tablet properties can be provided and the transmission of the hawthorn extract of the invention can be provided with high bioavailability. Here, Avicel promotes dry blending of the components, provides compressibility, allows the production of a tablet formulation with ideal hardness and low crumbling level. Fluorite acts as a stabilizing agent and carrier. An ideal tablet formulation is revealed by the combination of these two excipients.

[0029] In addition, combining the extract of Crataegus penlagyna, Crataegus szovitsii, Crataegus aronia, Crataegus curvisepala and Crataegus monogyna species of the invention with the specific excipients fluorite, Avicel and magnesium stearate facilitates the tablet printing process by making the obtained powder formulation advantageous in terms of stability, compressibility and dispersibility.

[0030] The amount of hawthorn extract in the tablet formulation of the present invention is preferably in the range of 20% to 40% by weight. Preferably, the amount of said hawthorn extract is in the range of 100 to 200 mg. More preferably, the amount of extract is 115 mg. The specified amount of extract provides the body with a sufficient amount of metabolite intake.

[0031] The ratio of the hawthorn extract in the tablet formulation of the present invention to the fluoride excipient is preferably 1 : 1 to 1 :0.5. The number of another excipient, Avicel, is preferably in the range of 40% to 55% by weight. Preferably, the amount of magnesium stearate in the tablet formulation of the present invention is in the range of 0.1% to 1% by weight. The present inventors have noticed that these weight ratios and amounts both minimize the tablet dispersibility in printing the formulation as a tablet and provide the amount of hawthorn extract to be taken.

[0032] For the purposes of the invention, the inventors found that the bioavailability values were significantly higher by presenting the hawthorn extract prepared from C. pentagyna, C. szovitsii, C. aronia. C. curvisepala and C. monogyna species in the form of a tablet formulation. Thus, the therapeutically effective amount can be easily taken into the body by presenting the hawthorn extract in tablet form.

[0033] In another aspect, the present invention provides a method for preparing the tablet formulation according to the invention, said method comprising the following steps:

[0034] -Collecting, drying, and pulverizing Crataegus pentagyna, Crataegus szovitsii, Crataegus aronia, Crataegus curvisepala and Crataegus monogyna species,

[0035] -subjecting the obtained powder to ultrasonic extraction using a solvent,

[0036] -obtaining the extract by subjecting the solution to lyophilization,

[0037] -combining the extract with at least one excipient,

[0038] -printing the obtained mixture as a tablet, and

[0039] -obtaining the final tablet formulation.

[0040] In the extraction step of the method of the present invention, said solvent can be preferred as 45% EtOH. Thus, hawthorn species can be extracted from the plant with the highest efficiency. In addition, the solid / liquid (powder drug / solvent) ratio of the mixture in said extraction is preferably determined as 1 / 20.

[0041] In the method of the present invention, it is preferable to combine the at least one excipient and the step of combining the extract with fluorite, Avicel and magnesium stearate.

[0042] In another aspect, a tablet formulation according to the invention is presented to be used in the prevention and / or treatment of cardiovascular diseases. With the present invention, 36 different areas were recorded for Crataegus pentagyna Waldst. & Kit. ex Willd., C. szovitsii Pojark, C. aronia (L) Bosch, ex DC., C. curvisepala Lindman, C. monogyna Jacq., which are 5 hawthorn species grown in Tiirkiye for the first time, and the analyses of the collected samples were revealed.

[0043] The contribution of the tablet formulation containing the extract of the specific hawthorn species of the present invention to human health is revealed by the present invention. In addition to the above-described effects, the fact that the hawthorn extract of the present invention, which contributes to the treatment and prevention of cardiovascular diseases, is easily accessible in tablet form, the amount of metabolites in the formulation is high and the cost is low in industrial-scale production makes the formulations of the present invention advantageous compared to the existing plant-based tablet formulations.

[0044] As explained in detail in the Examples below, in the studies carried out with the hawthorn samples collected within the scope of the present invention, four different extraction methods, namely plunge, ultrasonic, microwave and subcritical water extraction, were tried and it was determined that the ultrasonic extraction method was the most suitable method. Firstly, samples were collected from the determined areas and made ready for extraction by drying. After the extraction processes were completed, standardization was carried out on the drug substance. The tablet formulation of the invention was developed, and prototype tablets were prepared. Based on the obtained data, more comprehensive tests and quality controls are carried out for the tablets prepared during the production phase and the necessary data for industrial-scale production are revealed.

[0045] EXAMPLES

[0046] The details of the preparation and testing of the tablet formulations of the present invention are shared below. Those skilled in the art will understand that the embodiments that can be designed within the scope of the appended claims cannot be limited to those given herein.

[0047] Example 1. Collection of Hawthorn Types Leaf + bud and leaf + flower mixture samples were collected for extraction from different geographical regions of Tiirkiye (Thrace, Western Black Sea, Aegean, Mediterranean, Eastern Anatolia, Southeastern Anatolia) and from different heights (sea level to 2000 m).

[0048] Voucher specimens representing the species studied are very effective in terms of showing whether the species is correctly identified or not. Therefore, care was taken to collect sufficient herbarium material.

[0049] Areas where species were collected: Samples of 5 species were collected from 18 different areas.

[0050] C. pentagyna in 2 areas: Thrace, Western Black Sea,

[0051] C. szovitsii in 2 areas: Thrace, Nigde Hasandagi, or Malatya-Elazig,

[0052] C. ar onia in 3 areas: Mugla, Kayseri, Adiyaman (or Hatay),

[0053] C. curvisepala in 3 areas: Kastamonu, Malatya, Hakkari

[0054] C. monogyna in 8 areas: Thrace, Adana (Saimbeyli), Erzincan, Izmir, Mardin, Taurus mountains (sea level - 500 m, 1500-2000 m, northern slope)

[0055] The flowering and fruit period of a tree was divided into phases and the drugs were collected. The following stages are described below:

[0056] • leaf + flower: the phase when all the flowers open

[0057] • leaf + young fruit: the phase when the fruits are green

[0058] Consequently, 36 different materials were collected from 18 areas in total. Ripe fruit characteristics (size, color, number of seeds, etc.) are decisive in determining hawthorn species.

[0059] Example 2. Preparation for Hawthorn Extract

[0060] Phytochemicals are usually found in low concentrations in plants and are chemically sensitive. Therefore, the extraction of useful components from the plants constitutes an important step in the identification and use of the components. Crataegus species are very rich in secondary metabolites. Therefore, the most appropriate extraction method should be used. The collected and dried samples were subjected to extraction after grinding in the July- December period. The collected and dried plants were pulverized with TOPER-brand KT 17 model mill and prepared for extraction.

[0061] After the field studies were completed and the samples were prepared, optimization and standardization studies were carried out to determine the appropriate extraction methods and solvents. It was observed that the ultrasonic extraction method was the most suitable method for obtaining the extract of the invention.

[0062] Ultrasonic wave frequency was set as 20 kHz-1 MH. Five different solvents were studied in the extraction: Ethanol (45% and 100%), Methanol, Ethyl acetate, Acetone and Distilled water. Herb-solvent ratios were set as 1 :5, 1 : 10 and 1 :20. Extractions were performed for 5 hours. After the extraction was completed, the solvent was removed until the evaporator was dry. In the same way, extractions were performed in 3 repetitions. Ultrasonic extraction was performed with Bandelin Sonorex brand ultrasonic extraction device and Heidolph Hei-VAP- Valve brand evaporator provided in laboratories.

[0063] In the ultrasonic extraction process, it was determined that the appropriate solvent was 45% EtOH and the most appropriate solid / liquid ratio (powder drug / solvent) was 1 / 20.

[0064] Then, samples were prepared for qualitative analysis. HPLC analysis studies were performed on the samples. With the determination of the routine and hyperostosis amounts contained in the hawthorn medicinal plant drug (Crataegi folium cum flore) qualitatively and quantitatively in UHPLC, Crataegus monogyna and Crataegus aronia species with the highest amount of substance were revealed.

[0065] The amount of dry sample as a result of field studies was determined as 6800 g. After the samples were prepared, they were subjected to lyophilization and completely dried and obtained as homogeneous dry powder. The total amount of powdered lyophilized samples was weighed on a precision balance and found to be 100 g.

[0066] The powder extract of the invention may comprise, for example, 35% by weight of Crataegus szovitsii, 30% of Crataegus curvisepala, 15% of Crataegus penlagyna. 10% of Crataegus monogyna and 10% of Crataegus aronia. As another example, the 100 g powder extract of the invention may comprise 35 g Crataegus szovitsii, 30 g Crataegus curvisepala, 15 g Crataegus penlagyna. 10 g Crataegus monogyna and 10 g Crataegus aronia.

[0067] Example 3. Preparation of Tablet Formulation Containing Hawthorn Extract

[0068] Excipients were mixed with the lyophilized hawthorn extract. Then, studies were carried out for fluidity and compressibility, which are the powder properties required for tablet compression.

[0069] Different adsorbents were used to improve this feature of the lyophilized powder extract, which has a lot of moisture absorption (hygroscopic). Fluorite, which has a higher adsorption capacity, was preferred among these adsorbents. In order to ensure that the tablet disintegration time is less than 15 minutes and also to improve the powder printing properties, another adsorbent excipient, as well as fluorite, was added to the formulation. 1 : 1 and 1 :0.5 ratios were preferred as the drug substance: adsorbent ratio. In order to facilitate the exit of the tablet from the seal, 0.1% magnesium stearate was added as lubricant. According to the results, the distribution of the extract by tableting was found to be <5 minutes. The compression of the tablets was performed by applying 200 psi. The results obtained are summarized in Table 1 below. The friability of the tablets was found to be <1%.

[0070] Table 1. Properties of the obtained tablet formulations

[0071] When the values presented for the tablet formulation of the invention in Table 1 are examined, it is seen that the appropriate tablet diameter, dispersion, and thickness values have been reached. The fact that the dispersibility values are less than 8 minutes reveals that the tablet formulation of the present invention has good dispersibility properties.

[0072] The present inventors have prevented the extract obtained by providing the moisture balance of the environment from becoming extra soft and sticky thanks to the specific composition of the present invention. In addition, it is revealed that there is no dust flow by preventing the agglomeration that may occur when the packaging of the extract is opened.

[0073] The scope of protection of the present invention is specified in the attached claims and cannot be limited to those explained for sampling purposes in this detailed description. A person skilled in the art will understand that similar products can be created by considering the scope of the invention in light of the above.

Claims

CLAIMS1. A tablet formulation comprising at least an extract of Crataegus pentagyna, Crataegus szovitsii, Crataegus aronia. Crataegus curvisepala and Crataegus monogyna species and at least one excipient.

2. The tablet formulation according to claim 1, characterized in that said at least one excipient is selected from a group comprising high dispersion silicon dioxide (aerosol), magnesium stearate, Neusilin US2, fluorite, Avicel, Klucel LF, Klucel EXF, Polyplasdone XL, lactose monohydrate, sodium carboxymethyl starch (type A), macrogol 6000, talc, titanium dioxide, microcrystalline cellulose, povidone K 25, sodium carmellose, povidone K 90 and combinations thereof.

3. The tablet formulation according to claim 1 or 2, characterized in that said at least one excipient is fluorite, Avicel and magnesium stearate.

4. The tablet formulation according to claim 1, characterized in that said extract is present in the tablet formulation in the range of 20% to 40% by weight.

5. The tablet formulation according to claim 1 or 4, characterized in that the amount of said extract is in the range of 100 to 200 mg.

6. The tablet formulation according to claim 5, characterized in that the amount of said extract is 115 mg.

7. The tablet formulation according to claim 3, characterized in that the ratio of extract to fluoride in said formulation is 1 : 1 to 1 :0.5.

8. The tablet formulation according to claim 3, characterized in that Avicel is present in the tablet formulation in the range of 40% to 55% by weight.

9. The tablet formulation according to claim 3, characterized in that the magnesium stearate is present in the tablet formulation in the range of 0.1% to 1% by weight.

10. A method for preparing the tablet formulation according to claim 1, characterized in that it comprises the following steps:Collecting, drying, and pulverizing Crataegus penlagyna. Crataegus szovitsii, Crataegus aronia. Crataegus curvisepala and Crataegus monogyna species, - subjecting the resulting powder to ultrasonic extraction using a solvent, obtaining the extract by subjecting the solution to lyophilization, combining the extract with at least one excipient, printing the obtained mixture as a tablet, and obtaining the final tablet formulation.

11. The method according to claim 10, characterized in that the step of combining with said at least one excipient is carried out by combining the extract with fluorite, Avicel and magnesium stearate.

12. The tablet formulation according to claim 1 for use in the prevention and / or treatment of cardiovascular diseases.

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