CN1753658A - Film coated tablet comprising an extract of red vine leaves - Google Patents

Abstract

The invention relates to a film coated tablet comprising the following constituents: a) at least 50 % by weight of a dried extract of red vine leaves, which is obtainable by extraction of red vine leaves with water and drying; b) up to 50 % by weight of an excipient consisting essentially of at least one binder, at least one disintegrant, at least one filler, and a lubricant; and c) a tablet film consisting essentially of a film former, a plastiziser, a coating agent and optionally a coloring agent.Furthermore, the invention relates to an aqueous extract of red vine leaves is obtainable by a method comprising the steps of: a) collecting red vine leaves at a point of time when the content in flavonoids has reached an optimum; b) drying and crushing the leaves; c) cutting the leaves to pieces; d) extracting the leaves with water at elevated temperatures for 6 to 10 hours; e) concentrating and drying the obtained extract, andaddition of up to 10 % by weight of a flow regulator during the relating to the final total amount of the resulting extract during the drying process (e).

Description

Coated tablet containing extract of red vine leaves

technical field of invention

The present invention relates to a coated tablet comprising dry extract of red liana leaves, excipients and tablet coating, and its use for improving blood circulation and/or oxygen supply of lower extremities.

current technology

Chronic venous insufficiency (CVI) is a progressive disease and in many patients - especially untreated - edema, coronary venous dilatation (Widmer stage I), hyperpigmentation, induration, Fatty skin sclerosis, white atrophy (Widmer stage II) or varicose leg ulcers (Widmer stage III). Chronically disturbed hemodynamics of deep or superficial veins due to obstructed venous sections or valvular insufficiency often results in skin disease of the medial ankle region of the lower extremities. Disturbances in the microcirculation of the skin are thought to be a major contributor to the skin changes associated with chronic venous hypervolemia and venous hypertension (e.g., Fagrell B, "Vital tissue microscopy and pathophysiology of deep venous insufficiency" (Vital microscopy and the pathophysiology of deep venous insufficiency), Int Angiol 1995;14:18-22; Junger M, Klyscz T, Hahn M, RassnerG, "Disturbed blood flow regulation in venous leg ulcers ", Int J Microcirc 1996;16:259-265).

Clearly, clinically relevant cutaneous microangiopathy, eg, dilated, distorted capillaries surrounded by microedema, drives cutaneous changes in the lower extremities and can determine the course of CVI (Fagrell B, supra and Junger M et al, supra).

The use of laser Doppler technology in venous disorders has been well described (eg, Tulevski II, Ubbink DT, Jacobs MJHM, "Red and green laser Doppler (Doppler) Microvasc Res 1999; 58(2): 83-88; and Bollinger A, Jager K, Junger M, Seifert H," Vascular Laboratory: Advances in Non-Invasive Techniques ( The vascular laboratory: advance non-invasive techniques.)", World J Surg 1998; 12:724-731).

Different techniques have been developed to study microcirculation in two different functional skin layers: a deeper, primarily thermoregulatory layer, and a shallower vegetative layer, where microcirculatory disturbances are most responsible for nutritional skin changes. Correlation. (Junger M et al., supra and Gschwandtner ME, Ambrozy E, Fasching S, Willfort A, Schmeider B, Bohler K, et al., "Microcirculation in venous ulcers and surrounding skin: observations using capillary microscopy and laser Doppler imaging." Discovery", Eur J Clin Invest 1999; 29: 708-716).

British Patent GB 934,554 discloses that the capillary resistance of guinea pigs deficient in vitamins can be enhanced by intraperitoneal administration of alcoholic extracts of vine leaves.

International patent application WO 01/28363 discloses a method of preventing or alleviating discomfort associated with mild-to-moderate chronic venous insufficiency of the lower extremities by means of an aqueous extract of red vine leaves. In addition, a daily dose of 80 to 1000 mg divided into 1 to 3 capsules is recommended.

The problem underlying the present invention is to provide a dosage form that allows the administration of such high doses of aqueous extracts of red vine leaves in the suggested regimen. Considering patient suitability, it is desirable that these dosage forms should not be too large for ease of swallowing. On the other hand, the dosage form must have a high stability in order to ensure a long shelf life in storage. Furthermore, high bioavailability is only a prerequisite for the therapeutic and/or prophylactic success of this dosage form.

Contents of the invention

It has surprisingly been found a coated tablet comprising:

(a) at least 50% by weight of a dry extract of red vine leaves obtainable by extracting red vine leaves with water and drying;

(b) up to 50% by weight of excipients consisting essentially of:

at least one adhesive,

at least one disintegrant,

at least one filler, and

lubricants; and

(c) tablet coatings consisting essentially of film formers, plasticizers, coating agents and, where appropriate, colorants;

The tablet meets these requirements and can be used to significantly enhance microcirculation and oxygen supply in the mainly affected juxta-ankle region of the leg in patients with CVI.

Accordingly, the present invention relates to a coated tablet comprising:

(a) at least 50% by weight of a dry extract of red vine leaves obtainable by extracting red vine leaves with water and drying;

(b) up to 50% by weight of excipients consisting essentially of:

at least one adhesive,

at least one disintegrant,

at least one filler, and

lubricants; and

(c) A coating film mainly composed of a film-forming agent, a plasticizer, a coating agent, and an optional coloring agent.

Another aspect of the present invention is a method of preparing such a coated tablet comprising the steps of:

(A) mixing the dry aqueous extract of red vine leaves (a) with excipient (b), optionally in the presence of a volatile diluent;

(B) the mixture obtained by sieving as appropriate;

(C) compressing the mixture with a suitable tablet press; and

(D) Coat the obtained tablet with a coating film (C).

Furthermore, the invention relates to the use of such coated tablets for the preparation of pharmaceutical or dietary compositions for the treatment or prevention of discomforts, disorders and/or diseases associated with chronic venous hyperemia and venous hypertension.

Furthermore, the present invention relates to an aqueous extract of red vine leaves obtainable by a process comprising the following steps:

(a) at the moment when the flavonoid content has reached the optimum, collect the red liana leaves;

(b) drying and crushing the leaves;

(c) cutting the leaves into pieces;

(d) extracting the leaves with water for 6 to 10 hours at high temperature;

(e) concentrating and drying the resulting extract, and

(f) Adding up to 10% by weight of silica relative to the final total amount of the extract obtained.

Brief description of the drawings

Figure 1 shows the protocol design of a clinical study to demonstrate the efficacy of the coated tablets according to the invention.

Figure 2 shows that 360 mg of coated tablets AS 195 containing liana leaf extract - - placebo - o - versus microcirculation as measured by laser Doppler (Doppler) blood flow measurement (LDF 10-37kHz) impact comparison.

Figure 3 shows the comparison of the effect of 360 mg coated tablets AS 195 -·- with placebo -o- containing vine leaf extract on the transcutaneous partial pressure of oxygen (tpO ₂ ).

Detailed description of the invention

The coated tablet of the present invention is a herbal component (a), excipient (b) and tablets obtained by drying the water extract of red vine leaves (foliate vitis viniferae; Extractum Vitis viniferae e folium spissum et siccum) Agent coating (c) composition. This extract contains flavonoids (alcohol)-glucuronides, -glucuronides and flavonoids, with quercetin-3-O-β-D-glucuronide and isoquercin (quercetin-3-O-β-glucuronide ) as its main active ingredient. Although the extent of its pharmacological action has not been fully elucidated, in vitro studies indicate that it has antioxidant and anti-inflammatory properties, and that it inhibits platelet aggregation and hyaluronidase, and reduces edema by reducing capillary permeability. Preclinical in vivo experiments confirmed its anti-inflammatory and capillary wall thickening effects.

The coated tablet according to the invention comprises 50% to 70% aqueous extract of dried red liana leaves with a high flavonoid content of 2-15%.

Typically, the weight relationship of dry extract to excipients for the production of tablet cores is between 1:1 and 2:1, preferably between 1.1:1 and 1.8:1, especially between 1.25:1 and 1.75: between 1.

A coated tablet preferably containing the following based on the total weight of the coated tablet:

(a) 50 to 70% by weight of a dry extract of red liana leaves;

(b) 25 to 49% by weight of excipients, and

(c) 1 to 5% by weight of a coating film.

More preferred are coated tablets comprising the following ingredients (based on the total weight of the coated tablet):

(a) 51 to 59% by weight, especially about 55% by weight, of a dry extract of red liana leaves;

(b) 38 to 48% by weight, especially about 43% by weight of excipients, and

(c) 1 to 3% by weight, especially about 2.7% by weight of film coating.

Another preferred embodiment is a coated tablet, wherein the excipient (b) mainly consists of the following (based on the total mass of the combined excipients):

70 to 85% by weight of at least one binder,

0.5 to 12.5% by weight of at least one disintegrant,

5 to 15% by weight of at least one filler, and

1 to 5% by weight of at least one lubricant.

The term "binder" as used above and hereinafter denotes an excipient suitable for binding other components to each other. Preferred binders according to the invention are selected from the group consisting of powdered cellulose, microcrystalline cellulose, sorbitol, starch, povidon, copolymers of vinylpyrrolidone and other vinyl derivatives (copolyvinylpyrrolidone), cellulose derivatives, especially methylhydroxypropylcellulose (eg Methocel A15LV), and mixtures of these compounds. Preferred binders are powdered cellulose, especially microcrystalline cellulose and/or copolyvinylpyrrolidone. If the above-mentioned binder is used, the weight based on the total mass of the tablet of the present invention is preferably in the range of 15-45 wt%, more preferably 25-40 wt%, most preferably about 33 wt%. Since the particularly preferred binder is microcrystalline cellulose, it is possible to provide tablets with high stability and good adaptability to patients who have to administer the aqueous extract of red vine leaves.

The tablet according to the present invention, in addition to the above ingredients, also contains a disintegrant. Within the scope of the present invention, these disintegrants are optionally also referred to as disintegrators. According to the present invention, these disintegrants are preferably selected from the following: sodium starch glycolate, cross-linked polyvinylpyrrolidone (crospovidone), cross-linked carboxymethylcellulose sodium salt (cross-linked cellulose carboxymethyl ether sodium salt), sodium carboxymethylcellulose, dried corn starch, colloidal anhydrous silicon dioxide, and mixtures thereof. Within the scope of the present invention, particular preference is given to using sodium starch glycolate, cross-linked polyvinylpyrrolidone and, preferably, the sodium salt of cross-linked polyvinylpyrrolidone or cross-linked carboxymethylcellulose and colloidal anhydrous silicon dioxide. Most preferred is a mixture of croscarmellose sodium, colloidal anhydrous silicon dioxide and, if desired, crospovidone. If the above-mentioned disintegrant is used, the weight based on the total mass of the tablet of the present invention is preferably in the range of 0.5-10% by weight, more preferably in the range of about 1.5-7.5% by weight. Due to the particularly preferred composition of disintegrants, tablets with high stability can be obtained and can provide high bioavailability of the aqueous extract of red vine leaves.

Tablets according to the invention also contain fillers. Typically, fillers are inert compounds such as inorganic metal oxides or inorganic phosphates or hydrogen phosphates. The filler is preferably anhydrous calcium hydrogen phosphate. If the above-mentioned fillers are used, the weight based on the total mass of the tablet of the present invention is preferably in the range of about 1-10% by weight, more preferably in the range of about 2-8% by weight.

Tablets according to the invention also contain flow agents or flow regulators and lubricants as additional ingredients. Within the scope of the present invention, such ingredients include, for example, silicon dioxide, talc, stearic acid, sodium stearyl fumarate, magnesium stearate and glyceryl tribehenate. According to the invention, magnesium stearate is preferably used. If the above-mentioned preferred lubricants are used, the weight based on the total mass of the tablet of the present invention is preferably in the range of about 0.1-10 wt%, preferably about 0.5-5 wt%, more preferably between 0.6 and 1.5 wt%.

In addition, a preferred coated tablet, wherein the coating film (c) is mainly composed of the following (based on the total mass of the coating film (c)):

50 to 85% by weight of at least one film former,

5 to 10% by weight of at least one plasticizer,

10 to 20% by weight of at least one coating agent such as talc, and

0 to 15% by weight of at least one colorant.

Tablets according to the invention also contain one or more synthetic or natural, pharmaceutically acceptable colorants, preferably one or more inorganic metal oxides, such as titanium dioxide (E 171) and/or iron oxide ( E 172). If the above-mentioned preferred colorants are used, their weight is from 0.01 to 0.5% by weight, based on the total mass of the tablet according to the invention.

Another object of the present invention is to provide a coated tablet comprising herbal ingredients for preventing and/or alleviating discomfort associated with mild-to-moderate chronic venous insufficiency of the lower extremities, wherein the tablet Manufactured according to a controlled process that maintains the herbal curing quality of the ingredients.

Yet another object of the present invention is to provide a coated tablet that is effective for preventing and/or alleviating discomfort associated with mild-to-moderate chronic venous insufficiency of the lower extremities.

Yet another object of the present invention is to provide a coated tablet useful for preventing and/or alleviating discomfort associated with mild-to-moderate chronic venous insufficiency of the lower extremities, which tablet contains herbal ingredients and has minimal Side effects or no side effects and therefore safe for internal consumption, high stability and good patient compliance.

The aqueous extract prepared from dried red vine leaves is characterized by a high content of 2 to 20% bioactive flavonoids, preferably 2 to 10% bioactive flavonoids.

The term "person in need thereof" or "patient" as used above or hereinafter refers to a patient with clinically irrelevant early chronic venous insufficiency (CVI), proven to be in stage I and II according to Wiedemann's CVI Period female or male personnel. Usually, such patients are middle-aged and elderly people between 30 and 80 years old, preferably between 32 and 76 years old, with an average age (±standard deviation) of 55.2±7.7 years. In general, CVI may be more readily manifested in female patients than in male patients.

In order that the present invention may be more fully understood, the following examples are set forth. These examples are examples for illustrating the present invention and should not be construed as limiting the scope of the present invention.

The following examples are illustrative and, as recognized by those skilled in the art, can be modified for individual compositions as necessary for a particular condition. Materials used in the following tests were either commercially available or readily prepared from commercially available materials by those skilled in the art.

The main ingredient of the tablet is an aqueous extract of red vine leaves (foliae vitis vinferae L.). The starting material for the preparation of the extract was red vine leaves collected when the flavonoid content had reached the optimum value. Usually, this happens around the time of the grape harvest. Dry and break leaves carefully. For extraction, the leaves are cut into pieces preferably 5 to 10 mm. To obtain a high content of flavonoids, extraction may be performed at elevated temperature, preferably in the temperature range of 60° to 80° C., for a period of at least 6 up to 10 hours. A preferred method is that of exhaustive percolation.

The so-called fluid extract obtained during the extraction is concentrated by using a suitable evaporator. The thick extract obtained in this step is dried, for example by using a vacuum drying oven or a vacuum drying conveyor.

During drying, all or some excipients may be added to facilitate further processing of the extract. Typically up to 10% of one or more excipient ingredients may be added during drying.

It is preferable to add a part of flow regulator (such as colloidal anhydrous silica) to the extract during drying or before mixing with other components. The resulting extraction composition preferably comprises 0.5 to 10% by weight, especially 2.5 to 7.5% by weight, optimally about 4% by weight of colloidal anhydrous silica.

Surprisingly, tablets obtained from extracts to which a portion of excipients have been added during drying show enhanced stability.

The coated tablet according to the invention optimally consists of:

300 to 500 mg, preferably 320 to 400 mg, especially about 355 to 380 mg of dry aqueous extract of red vine leaves (4-6:1) (extractum vitis vinferae foliaeaquosum siccum), which may contain up to 10 % by weight of flow regulator, especially colloidal anhydrous silicon dioxide;

■The following are excipients for tablet cores:

Microcrystalline cellulose, croscarmellose sodium, calcium hydrogen phosphate (anhydrous), colloidal silicon dioxide (anhydrous), magnesium stearate and optionally crospovidone, and

■Coating film consisting of:

Hypromellose, Glyceryl Tristearate, Titanium Dioxide (E 171), Talc, Iron Oxides, Red (E 172).

Coated tablets were prepared with the ingredients listed in Tables A and B below:

Table A ingredient name Content in each coated tablet [mg/658.000mg] Function Tablet core Vitis viniferae folium dry aqueous extract (4-6:1) microcrystalline cellulose croscarmellose sodium anhydrous dibasic calcium phosphate colloidal anhydrous silicon dioxide magnesium stearate 360.000219.00018.00030.0004.0009.000 Active ingredient Binder, Disintegrant Disintegrant Filler Flow Regulator, Disintegration Accelerator Lubricant Coating film Hypromellose tristearate Titanium dioxide (E171) Talc Iron oxide, red (E172) 11.3831.1380.7833.1311.565 Film former Plasticizer Colorant Coating agent Colorant

The extract is mixed with excipients for tablet cores and compressed in a suitable tablet press.

Form B ingredient name Content in each coated tablet [mg/658.000mg] Function Tablet core Vitis viniferae folium dry aqueous extract (4-6:1) colloidal anhydrous silica microcrystalline cellulose croscarmellose sodium anhydrous calcium hydrogen phosphate colloidal anhydrous silica hard Magnesium fatty acid cross-linked polyvinylpyrrolidone 360.00015.000214.00018.00030.0006.0009.00018.000 Active ingredient binder binder, disintegrant disintegrant filler flow regulator, disintegration accelerator lubricant disintegrant Coating film Hypromellose tristearate Titanium dioxide (E171) Talc Iron oxide, red (E172) 11.3831.1380.7833.1311.565 Film former Plasticizer Colorant Coating agent Colorant

During drying, the extract was mixed with 15.000 mg of silica, resulting in an extract consisting of 96% by weight of extract components and 4% of silica. The resulting mixture is mixed with the remaining excipients of the tablet core and compressed in a suitable tablet machine.

The compression force required to produce a tablet with a suitable resistance to breaking and thus the desired breakdown times depends on the shape and size of the punching tool used. The pressing force is preferably in the range of 2-20-kilonewtons (kN). Higher compression forces lead to prolonged release of the active substance from the tablet. Lower compression forces produce mechanically unstable tablets. Tablet cores can have different shapes; circular biplanar or biconvex and oval or oblong are preferred.

Coating solutions are prepared by mixing film formers with colorants and plasticizers in water. Using a suitable coating pan, coat the coating solution onto the tablet cores.

Tablets preferably have an oblong shape to facilitate swallowing. In the case of a coated tablet comprising 360 mg of extract and having the ratio of extract to excipient described above, the oblong tablet may be about 17-18 mm long and have a width of about 8 to 9 mm. Hereinafter, these coated tablets of Table A are coded " AS 195 ".

To enhance blood circulation and/or oxygen supply to the lower extremities, tablets equivalent to 150 and 1000 mg of the extract, preferably 300-800 mg, especially 350-750 mg, should be taken daily. The total amount of extract can be divided into 1 to 3 coated tablets per day. The daily dose should be taken in one go, preferably in the morning.

Expectation: The symptoms can be significantly improved within 6 weeks of continuous use. Long-term use can maintain or enhance the best effect.

method

participant

Male and female patients aged 18 years or older who had been diagnosed with CVII or CVI as confirmed by Wiedemann and who had been suffering for at least one year participated in the study. There must be no medically related comorbidities. Patients who have taken drugs to relieve their CVI symptoms within 4 weeks before the first examination or patients who have been treated with theophylline (theophyllin, diuretics, cardiac glycosides, ACE inhibitors, or calcium antagonists within 8 days before the first examination) Participation in experiments is not permitted. The use of compression bandages or the administration of concomitant treatments for venous problems while participating in the trial was prohibited.

Design and Methods

Double-blind, randomized, placebo-controlled crossover trials can be conducted in accordance with the principles of the Declaration of Helsinki and the International Conference of Harmonization of Good Clinical Practice.

Each patient participated in the 17-week trial: a one-week wash-out (treatment with placebo), a 6-week treatment period (group_1 started with AS 195 , group_2 started with placebo), A 4-week washout period (treatment with placebo) and a second 6-week treatment period (Group_1 continued with placebo, Group_2 continued with AS 195 ).

In the morning, a single dose of AS 195 (coated tablet containing 360 mg of dried extract of red vine leaves) or a placebo tablet was taken at random times. Both tablets had the same size, shape, weight, inner appearance and taste. For laser Doppler flow measurement, equipment was provided by LMTB Berlin, Germany (eg Doerschel K, Mueller G. Velocity resolved laserDoppler flow measurement in skin. Lasermedizin 1996; 12: 163-171.). The device is a computer based mobile unit using a laser frequency of 785nm. Fix the laser probe 35 cm from the medial ankle of the more affected leg. After sitting for 30 minutes to adapt to the room temperature, the measurement was started after standing for another 10 minutes (measurement of 256 points, measurement duration: about 0.4 seconds). In the frequency range between 0.2 kHz and 37.2 kHz, two diodes check for backscattered light. Process the data using a Fast Fourier Transform. Finally, for vessels in the reticular venous plexus (larger primary thermoregulatory vessels, greater than 30 microns in diameter), output refers to the frequency range between 0.2 kHz and 10.0 kHz, and for subpapillary For capillaries in the venous plexus (small, superficial nutrient vessels, 6 μm to 30 μm in diameter), the output refers to the frequency range between 10.1 kHz and 37.2 kHz.

Transcutaneous oxygen pressure (tcPO2) was measured using a modified clark-type polarographic electrode (TCM3, Radiometer Brφnshφj, Copenhagen, Denmark) comprising a noble metal cathode and a silver/silver chloride anode. A heating element adjacent to the anode maintains the skin temperature at 43 degrees Celsius. At this temperature, arterioles expand maximally and tcPO2 approaches that of arterial blood (eg, Bollinger A, Jager K, Junger M, Seifert H. The vascular laboratory: Advances in noninvasive techniques. (The vascular laboratory: advances non-mvasive techniques.) World J Surg 1988;12:724-731.).

The electrodes were attached to the skin surface 3.5 cm anterolaterally from the laser Doppler probe via a saline-filled adhesive ring device. After sitting for 30 minutes to acclimatize to room temperature, then stand for 10 minutes before starting the measurement. The measurement lasts about 15 minutes. Express the pcPO2 value in millimeters of mercury (mmHg). Normal values obtained from the instep of patients without CVI are in the range of 40 mmHg to 80 mmHg.

Using a thermistor fixed adjacent to the oxygen electrode, measure the local skin temperature in the peri-ankle region. To minimize effects on skin perfusion, LDF and tcPO2 measurements were performed at local skin temperatures between 28 and 32°C.

Use a measuring tape to measure around the calf and ankle. Measure on the outside and inside of the ankle and mid-calf.

Subjective symptoms of CVI (leg fatigue, heaviness, tightness, tingling, and pain) were measured using a 10-cm visual analogue scale with 0 for "none" and 10 for "very strong." ).

At the end of each treatment cycle, the efficacy of the overall treatment was assessed by the patient and the investigator on a 4-level verbal rating scale (good, satisfactory, unsatisfactory, and poor).

Overall tolerability was assessed by patients and investigators on a 4-level verbal rating scale (good, satisfactory, unsatisfactory, and poor). At each visit, the patient's well-being is generally asked.

result

A total of 71 women and men between the ages of 32 and 76 years, with confirmed stages I and II of the CVI stages according to Wiedmann, participated. Mean age (± standard deviation) was 55.2±7.7 years; 55 females, 16 males. Venous status revealed that 47 (67.1%) patients had moderate or severe varicose veins, 27 (38.6%) had pigmentation, 26 (37.1%) had ankle edema and 25 (35.7%) had lower extremity edema. Signs of mild atrophy were present in 13 (18.6%) patients and none developed eczema (Table 1).

Table 1: Demographics and benchmark characteristics of CVI AS 195/placebo (n=36) Placebo/AS 195 (n=35) Continuous variable (mean (range)) age [years] height [cm] weight [kg] body mass index [kg/m ² ] systolic blood pressure [mmHg] diastolic blood pressure [mmHg] 66(32-76)168(150-186)76.5(48-97)27.6(20.6-32.0)130(100-150)80(60-90) 66(37-76)165(150-191)73(55-120)26.7(20.1-42.5)135(120-140)80(65-90) Categorical variables (n(%)) female current smoker CVI stage I stage II moderate to severe venous condition varicose veins pigmentation atrophy eczema ankle edema lower extremity edema 24(66.7)4(11.1)26(72.2)10(27.8)26(72.2)11(30.6)0(0.0)0(0.0)13(36.1)12(33.3) 31(88.6)1(2.9)23(65.7)12(34.3)22(62.9)17(48.6)0(0.0)0(0.0)14(40.0)14(40.0)

There were no protocol violations in the remaining patients. Therefore, all patients were retained for treatment analysis (Fig. 1). Patient characteristics were evenly distributed across the two treatment sequences (Group_1, Group_2) except for the male to female ratio (12 males in Group_1 and 4 males in Group_2) (Table 1). Baseline values for laser Doppler parameters, transcutaneous oximetry, ankle and calf circumference, and subjective symptoms (Table 2) were comparable between groups 1 and 2. The suitability of the coated tablets according to the invention was approximately 100% in both treatment sequences.

Table 2: Means (±SD) of baseline characteristics per treatment cycle Phase 1 season2 AS 195 (n=36) Placebo (n=34) AS 195 (n=34) Placebo (n=36) Laser Doppler blood flow measurement {AU] 10-37kHz<10kHz Percutaneous blood oxygen measurement [mmHg] Perimeter [cm] Ankle calf subjective symptoms [cm] Leg fatigue / heavy leg pain Tension tingling 303.5(135.2)352.7(87.7)32.1(7.0)20.3(2.2)34.7(3.1)4.3(2.8)4.0(3.2)4.5(2.9)3.3(3.1) 333.5(153.0)370.8(120.0)32.3(6.4)20.4(2.4)34.2(3.0)3.7(2.9)3.2(3.1)4.1(2.8)2.7(2.9) 275.4(126.4)174.7(77.0)30.1(6.2)20.2(2.6)34.0(3.1)4.6(2.9)4.5(2.7)4.5(2.6)3.7(2.6) 293.3(119.9)189.4(67.6)30.8(6.4)20.3(2.2)34.6(3.2)5.2(2.6)4.9(3.1)5.1(2.5)4.2(2.8)

The frequency range of 10-37 kHz was chosen for primary endpoint laser Doppler blood flow measurements. These frequencies are determined from the amount of erythrocytes and their movement (flow velocity) in capillaries in the superficial layer of the skin of the legs. After 6 weeks, laser Doppler frequency (10-37kHz) increased in the AS 195 group (positive 241.8±18.7AU) but decreased in the placebo group (negative 41.0±18.7AU, p<0.0001) (Table 3) . This effect appeared as early as 3 weeks after the start of treatment (p<0.0001) (Table 4, Figure 2).

Table 3: Mean (±SEM) and p-values of change from baseline at 95% confidence interval for treatment control with period-adjusted effect after 3 weeks of treatment with 360 mg AS 195 or placebo treat treatment control AS 195 (n=70) Placebo (n=70) Difference (n=70) Credible Interval (n=70) p-value 3 weeks laser Doppler blood flow measurement [AU] 10-37kHz < 10kHz percutaneous oximetry [mmHg] peripheral [cm] ankle calf subjective symptoms [cm] leg fatigue / bulky leg pain tension tingling 132.2(11.9)-3.7(9.2)0.62(0.97)-0.19(0.09)-0.24(0.04)-0.94(0.25)-1.17(0.23)-1.00(0.24)0.99(0.26) -28.2(11.9)-99.9(9.2)-3.84(0.97)0.21(0.09)0.04(0.04)0.21(0.25)-0.24(0.23)-0.52(0.24)-0.20(0.26) 160.596.24.46-0.40-0.28-0.73-0.94-0.49-0.79 127.0 to 194.070.2 to 122.21.72 to 7.20-0.65 to -0.15-0.40 to -0.17-1.42 to -0.04-1.59 to -0.28-1.17 to 0.191.52 to -0.06 <0.0001<0.00010.00180.0025<0.00010.03960.00610.15880.0335

Table 4: Means (±SEM) and p-values of the change from baseline at the treatment control 95% confidence interval for the period-adjusted effect after 6 weeks of treatment with 360 mg AS 195 or placebo treat treatment control AS 195 (n=70) Placebo (n=70) Difference (n=70) Credible Interval (n=70) p-value 6 weeks Laser Doppler blood flow measurement [AU] 10-37kHz (initial target) < 10kHz Transcutaneous oximetry [mmHg] Peripheral [cm] Ankle calf subjective symptoms [cm] Leg fatigue / heavy leg pain tightness Tingling 241.8(18.7)57.0(12.4)1.35(0.97)-0.39(0.09)-0.54(0.05)-0.78(0.33)-0.76(0.35)-0.96(0.35)-0.55(0.30) -41.0(18.7)-107.7(12.4)-7.27(0.97)0.29(0.09)0.14(0.05)-0.94(0.33)-0.86(0.35)-1.40(0.35)-0.66(0.30) 282.8164.78.63-0.68-0.680.160.100.440.11 229.9 to 335.7129.7 to 199.75.88 to 11.38-0.94 to -0.43-0.83 to -0.53-0.76 to 1.09-0.88 to 1.09-0.46 to 1.44-0.75 to 0.96 <0.0001<0.0001<0.0001<0.0001<0.00010.72850.83230.38190.8044

Laser Doppler flow measurements were performed in the frequency range below 10 kHz as determined by the number of red blood cells and their movement (flow velocity) in the deep capillaries of the main thermoregulatory capillaries of the skin of the legs. After 6 weeks, laser Doppler frequency (below 10 kHz) increased in the AS 195 group (+57.0±12.4 AU) but decreased in the placebo group (minus 107.7±12.4 AU, p<0.0001) (Table 3) . This effect appears to depend on the climatic conditions during the treatment cycle. During the moderate temperature (April/May) study period, laser Doppler measurements (<10 kHz) remained unchanged after an initial decline in the AS 195- treated group, whereas those in the placebo-treated group decreased (p<0.0001). During the higher temperature (July/August) study period, laser Doppler measurements (<10 kHz) increased in the AS 195- treated group but remained constant in the placebo-treated group (p<0.0001).

Transcutaneous oxygen pressure increased in the AS 195 group (plus 1.35±0.97 mmHg) but decreased in the placebo group (minus 7.27±0.97 mmHg, p<0.0001). This observation was consistent across both treatment cycles, and thus consistent with laser Doppler flux in the trophic superficial layer of the skin (ie, 10-37 kHz) (Tables 3, 4, Figure 3).

Statistically significant and clinically relevant ankle circumference (after 3 weeks: AS 195 minus 0.19±0.09 cm, placebo plus 0.21±0.09 cm, p=0.0025) and calf circumference (after 3 weeks: AS 195 minus 0.24±0.04 cm, placebo + 0.04 ± 0.04 cm, p < 0.0001) indicated an onset of action as early as 3 weeks after treatment initiation (Table 3). This effect was more obvious after 6 weeks (AS 195 ankle: minus 0.39±0.09cm, calf: minus 0.54±0.05; placebo ankle: plus 0.29±0.09cm, calf: plus 0.14±0.05cm, p<0.0001) (Table 4).

There were no relevant changes in subjective symptom intensity for CVI after 6 weeks of treatment. This result is consistent with that in a previous study in which subjective symptoms measured on a visual analog scale were reduced only after a longer treatment period (12 weeks).

Adverse events rarely occurred in this study. Thirteen of 71 patients experienced at least one adverse event, 12 of whom experienced the onset of action on placebo and one patient experienced an adverse event on AS 195 stage (moderate bronchitis, which the investigators considered unrelated to the drug). Patients who died of cardiac arrest had been treated with placebo ( AS 195 was never administered in this trial). Overall tolerability was rated as good or satisfactory for all patients. The experimental parameters were not changed during the study.

discuss

It has been shown in a previous study (WO 01/28363) that the red vine leaf extract AS 195 , in addition to improving subjective symptoms of chronic venous insufficiency in patients treated ⁷ times a day for 12 weeks, also reduced the Edema, calf circumference and ankle circumference. This study was designed to provide additional information on the lower mechanism of action by studying microcirculation as a clinically relevant surrogate parameter for leg problems with CVI. This study, the first of its kind in CVI patients, aimed to investigate additional clinically relevant effects associated with red liana leaf extract treatment in addition to reduction in leg edema. The reduced venous return leads to poor skin microcirculation, which leads to skin dystrophy. If CVI is left untreated, the condition may even lead to venous leg ulcers. Laser Doppler flowmetry as used in this study is an effective and sensitive method for measuring the objective treatment effect, which can be compared with the subjectively experienced volume after 3 months of treatment. related to reduction.

These findings are in line with the clinical data for AS 195 and they add to the information on initiation. Leg volume as an objective parameter will decrease to a clinically relevant and statistically significant extent after 6 weeks of treatment. Extracts of horse chestnut seeds have been reported in recent years (eg, Diehm C, Trampisch HJ, Lange S, Schmidt C, "Comparison of leg compression stockings with oral horse chestnut seeds in patients with chronic venous insufficiency Extract therapy (Comparison of legcompression stocking and oral horse-chestnut seed extract therapy in patient with chronic venous insufficiency), Lancet 1996; 347:292-294) and Butehers Broom (eg, Vanscheidt W, Jost V , Wolna P et al., "Comparison of efficacy and safety of a Butcher's Broom preparation (Ruscus aculeatus L. extract) with placebo in the treatment of patients with chronic venous insufficiency" (Efficacy and safety of a Butcher's Broom preparation (Ruscus aculeatusL.extract) compared to placebo in patients suffering from chronic venous insufficiency.), Drug Res 2002; 52(4):243-250).

In the present study it was shown that laser Doppler blood flow measurement parameters, ankle and calf circumference, and percutaneous oxygen pressure were affected as early as 3 weeks after treatment. In contrast, subjective symptoms of CVI, as assessed by the visual analog scale, were not significantly different after 6 weeks of treatment compared with placebo, as shown in previous studies. In order to reduce the subjective symptoms of CVI accordingly, a 12-week treatment is mandatory.

The results of this study suggest that the main role of red vine leaf extract is to prevent the development of CVI and the occurrence of skin dystrophy, and even prevent or delay the transformation from the early stage of CVI to CVII, which is clinically irrelevant.

Claims (16)

1. A coated tablet comprising: (a) at least 50% by weight of a dry extract of red vine leaves, the dry extract can be obtained by extracting red vine leaves with water, drying and optionally adding up to 10% by weight relative to the total amount of component (a) % silica obtained; (b) up to 50% by weight of an excipient consisting essentially of: - at least one adhesive, - at least one disintegrant, - at least one filler, and - lubricants; and (c) A tablet coating consisting essentially of a film-forming agent, a plasticizer, a coating agent and, if necessary, a coloring agent. 2. The coated tablet according to claim 1, which comprises the following ingredients based on the gross mass of the coated tablet: (a) 50 to 70% by weight of a dry extract of red liana leaves; (b) 25 to 49% by weight of excipients, and (c) 1 to 5% by weight of tablet coating. 3. The coated tablet according to claim 1 or 2, which comprises the following ingredients based on the total mass of the coated tablet: (a) 51 to 59% by weight dry extract of red liana leaves; (b) 38 to 48% by weight of excipients, and (c) 1 to 3% by weight tablet coating. 4. The coated tablet according to any one of the preceding claims, wherein the aqueous extract of red vine leaves is obtained by a process comprising the steps of: (a) collect red vine leaves when their flavonoid content has reached an optimal value; (b) drying and crushing the leaves; (c) cutting the leaves into pieces; (d) extracting the leaves with water for 6 to 10 hours at high temperature; (e) concentrating and drying the obtained extract, and (f) Up to 10% by weight of a flow regulator relative to the final total amount of the extract obtained is added, if desired, during the drying process (e). 5. The method of claim 4, wherein the leaves in step (iv) are extracted with water at a temperature of 60 to 80°C. 6. The coated tablet according to any one of the preceding claims, wherein the excipient (b) consists essentially of the following components based on the total mass of the excipient (b): 70 to 85% by weight of at least one binder, 0.5 to 12.5% by weight of at least one disintegrant, 5 to 15% by weight of at least one filler, and 1 to 5% by weight of at least one lubricant. 7. The coated tablet according to any one of the preceding claims, wherein the binding agent is selected from powdered cellulose, microcrystalline cellulose, starch, polyvinylpyrrolidone, copolymerization of vinylpyrrolidone and other vinyl derivatives substances, cellulose derivatives, and mixtures of these compounds. 8. A coated tablet according to any one of the preceding claims, wherein the disintegrant is selected from the group consisting of colloidal silicon dioxide, sodium starch glycolate, cross-linked polyvinylpyrrolidone (cross-linked polyvinylpyrrolidone), cross-linked Dicarboxymethylcellulose sodium salt (cross-linked cellulose carboxymethyl ether sodium salt), sodium carboxymethylcellulose, dried cornstarch and mixtures thereof. 9. A coated tablet as claimed in any one of the preceding claims, wherein the filler is an inorganic phosphate or hydrogen phosphate. 10. A coated tablet according to any one of the preceding claims, wherein the filler is selected from silicon dioxide, talc, stearic acid, sodium stearyl fumarate, magnesium stearate and tribehenate. 11. The coated tablet of any one of the preceding claims, wherein based on the total mass of the tablet film (c), the tablet film (c) consists essentially of the following ingredients: 50 to 85% by weight of at least one film former, 5 to 10% by weight of at least one plasticizer, 10 to 20% by weight of at least one coating agent, and 0 to 15% by weight of at least one colorant. 12. A method for preparing a coated tablet as claimed in one of claims 1 to 11, comprising the steps of: (A) mixing the dry aqueous extract of red vine leaves (a) with excipient (b), optionally in the presence of a volatile diluent; (B) sieving the obtained mixture if necessary; (C) compressing the mixture using a suitable tablet press; and (D) Coat the obtained tablet with the tablet coating (c). 13. Use of a coated tablet as claimed in one of claims 1 to 11 for the preparation of a medicament or dietary combination for the treatment or prevention of discomfort, disorders and/or diseases associated with chronic venous hyperemia and venous hypertension things. 14. An aqueous extract of red liana leaves obtainable by a process comprising the steps of: (a) collect red vine leaves when their flavonoid content has reached an optimal value; (b) drying and crushing the leaves; (c) cutting the leaves into pieces; (d) extracting the leaves with water for 6 to 10 hours at high temperature; (e) concentrating and drying the resulting extract, and (f) Adding in the drying process (e) up to 10% by weight of a flow regulator relative to the final total amount of the extract obtained. 15. The aqueous extract according to claim 14, comprising 2.5 to 7.5% by weight of colloidal anhydrous silica. 16. The aqueous extract of claim 15 comprising about 4.0% by weight colloidal anhydrous silica.

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