HRP20030816A2

HRP20030816A2 - Capsulated herbal composition as auxilary medicament against diabetes mellitus type (i) and (ii)

Info

Publication number: HRP20030816A2
Application number: HR20030816A
Authority: HR
Inventors: Leko Vladimir
Original assignee: Leko Vladimir
Priority date: 2003-10-10
Filing date: 2003-10-10
Publication date: 2005-06-30
Also published as: WO2005034973A1; HRP20030816B1; EP1675604A1

Description

Područje na koje se izum odnosi The field to which the invention relates

Ovaj izum se odnosi na područje farmaceutike, pobliže na područje ljekovitih biljnih pripravaka. Prema međunarodnoj klasifikaciji patenata predmetni izum označen je klasifikacijskim simbolom A61K 35/78. Medicinski pripravci koji sadrže tvari ili produkte njihovih reakcija s neodređenim sastavom, pri čemu se radi o tvarima iz biljaka. This invention relates to the field of pharmaceuticals, more specifically to the field of herbal medicinal preparations. According to the international classification of patents, the subject invention is marked with the classification symbol A61K 35/78. Medicinal preparations containing substances or products of their reactions with an undetermined composition, where these are substances from plants.

Tehnički problem Technical problem

Tehnički problem, čije je rješenje razotkriveno u ovoj patentnoj prijavi sastoji se u pronalaženju jeftinijeg i jednostavnijeg načina dobivanja i proizvodnje aktivne supstancije koja je opisana u sklopu patentne prijave istog prijavitelja, objavljene pod brojem WO 99/55351, kao i u pronalaženju efikasnijeg farmaceutskog pripravka na bazi navedene aktivne supstancije, kao i optimizacija postupka dobivanja i proizvodnje istog pripravka. The technical problem, the solution of which is revealed in this patent application, consists in finding a cheaper and simpler way of obtaining and producing the active substance that is described in the patent application of the same applicant, published under the number WO 99/55351, as well as in finding a more efficient pharmaceutical preparation based on the mentioned active substances, as well as the optimization of the process of obtaining and producing the same preparation.

Osim toga, ova patentna prijava rješava i problem liječenja dijabetes melitusa tipa I. In addition, this patent application also solves the problem of treating type I diabetes mellitus.

Stanje tehnike State of the art

Dobivanje aktivne supstancije koja se koristi za liječenje dijabetes melitusa tipa II iz biljne mješavine razotkriveno je u sklopu patentne prijave WO 99/55351. U istoj prijavi razotkriven je i farmaceutski pripravak koji sadrži aktivnu tvar, prirodnu mikrocelulozu, prirodni zeolit, monosaharide i Mg stearat u omjerima 16,7 : 22,2 : 50,0 : 9,7 : 1,4. Ista prijava razotkriva nam i postupak dobivanja tog farmaceutskog pripravka. Obtaining an active substance used for the treatment of type II diabetes mellitus from a herbal mixture is disclosed in patent application WO 99/55351. In the same application, a pharmaceutical preparation containing an active substance, natural microcellulose, natural zeolite, monosaccharides and Mg stearate in the proportions 16.7 : 22.2 : 50.0 : 9.7 : 1.4 was disclosed. The same application reveals to us the procedure for obtaining that pharmaceutical preparation.

Opis izuma Description of the invention

Postupak dobivanja aktivne supstancije prema patentnoj prijavi WO 99/55351 podrazumijeva evaporaciju u vakuumu uz vremenski linearni gradijent, te smrzavanje evaporacijom dobivene suspenzije zrakom na -186°C, nakon čega je slijedila liofilizacija. Primjenom izuma iznašlo se kako varijacije vremenskog temperaturnog gradijenta u bitnome utječe na iskorištenje, dok smrzavanje na -186°C utječe na kvalitetu (tako dobivena aktivna tvar je jako higroskopna s problematičnom nasipnom gustoćom) kao i na troškove proizvodnje konačnog proizvoda koje naravno bitno poskupljuje. Nadalje primijećena varijacibilnost kakvoće konačnog proizvoda može se pripisati i primjeni visokih tlakova koji izazivaju plastičnu deformaciju čestica, te deformaciju intramolekularnih sila čime se narušava biološka aktivnost istih. The procedure for obtaining the active substance according to patent application WO 99/55351 involves evaporation in a vacuum with a time linear gradient, and freezing the suspension obtained by evaporation with air at -186°C, followed by lyophilization. By applying the invention, it was found that the variation of the time temperature gradient significantly affects the utilization, while freezing to -186°C affects the quality (the active substance thus obtained is very hygroscopic with problematic bulk density) as well as the production costs of the final product, which of course significantly increases the price. Furthermore, the observed variability of the quality of the final product can be attributed to the application of high pressures that cause plastic deformation of the particles, and the deformation of intramolecular forces, which impairs their biological activity.

Osim toga, primijećeno je da zeolit koji je sastojak farmaceutskog pripravka opisanog u WO 99/55351 često puta sadrži olovni pentoksid. Čišćenje zeolita od tragova olovnog pentoksida također predstavlja značajno poskupljenje troškova proizvodnje konačnog proizvoda. In addition, it has been observed that the zeolite which is an ingredient of the pharmaceutical composition described in WO 99/55351 often contains lead pentoxide. Cleaning the zeolite from traces of lead pentoxide also represents a significant increase in the production costs of the final product.

Navedeni nedostaci uklonjeni su manje agresivnom metodom pripravljanja aktivne supstancije i farmaceutskog pripravka kao i promjenom nosača, punila i ostalih pomoćnih tvari. Tako je zeolit zamijenjen korijenom vodopije (Cichorii radix), a umjesto prirodne mikroceluloze u farmaceutski pripravak prema ovom izumu stavlja se fino samljeveni pulvis biljne mješavine opisane u patentnoj prijavi WO 99/55351. The mentioned shortcomings were removed by a less aggressive method of preparing the active substance and pharmaceutical preparation, as well as by changing the carrier, filler and other auxiliary substances. Thus, the zeolite was replaced by the root of cichorii (Cichorii radix), and instead of natural microcellulose, finely ground pulvis of the herbal mixture described in the patent application WO 99/55351 is added to the pharmaceutical preparation according to this invention.

Tim postupcima otklonjeni su svi navedeni nedostaci izuma razotkrivenog u citiranoj prijavi. With these procedures, all the mentioned defects of the invention disclosed in the cited application were eliminated.

Povrh toga, neočekivano se utvrdilo u provedenim testovima na dobrovoljcima bolje djelovanje pripravaka koji su dobiveni na taj način koji je opisan u ovoj prijavi i to za 7-10%. On top of that, it was unexpectedly established in the conducted tests on volunteers that the preparations obtained in the manner described in this application were 7-10% more effective.

Postupak za dobivanje aktivne tvari iz ekstrakta dobivenog iz biljne mješavine koju čine slijedeći usitnjeni i osušeni sastojci: The procedure for obtaining the active substance from the extract obtained from the herbal mixture consisting of the following chopped and dried ingredients:

biljka kičice (Centaurii herba) 10-15 masenih % centaurii herba (Centaurii herba) 10-15% by mass

korijen maslačka (Taraxaci radix) 6-12 masenih % dandelion root (Taraxaci radix) 6-12 mass %

plod borovice (Juniperi communis fructus) 5-8 masenih % juniper fruit (Juniperi communis fructus) 5-8 mass %

biljka koprive (Urticae herba) 5-10 masenih % nettle plant (Urticae herba) 5-10 mass %

korijen koprive (Urticae radix) 5-10 masenih % nettle root (Urticae radix) 5-10 mass %

korijen vodopije (Cichorii radix) 12-20 masenih % Watercress root (Cichorii radix) 12-20% by mass

list crnog duda (Morus n. Folium) 5-10 masenih % black mulberry leaf (Morus n. Folium) 5-10 mass %

cvijet stolisnika (Achilleae millefolii flos) 2-5 masenih % yarrow flower (Achilleae millefolii flos) 2-5 mass %

list borovnice (Vaccinii myrtilli folium) 4-10 masenih % blueberry leaf (Vaccinii myrtilli folium) 4-10 mass %

komuška graha (Phaseoli fructus sine semeni) 10-20 masenih % Komuska beans (Phaseoli fructus sine semeni) 10-20 mass %

korijen odoljena (Valerianae officinalis radix) 5-10 masenih % valerian root (Valerianae officinalis radix) 5-10 mass %

izvodi se prema ovom izumu na način da se navedena biljna mješavina prelije sa 60% etanolom na sobnoj temperaturi i ostavi stajati u zatvorenoj posudi kroz 28 dana nakon čega se dekantira tekućina iznad sedimenta, te da se preostali biljni ekstrakt podvrgne ugušćivanju vrtložnom sprej granulacijom uz nasprejavanje bezvodnim plinom pod tlakom 1-3 bara, pri čemu je temperatura plina barem za 10°C viša od ulazne temperature ekstrakta, kroz vremenski period od 30-40 min. Plin se u aparat za vrtložnu sprej granulaciju WSG-GLATT-50 uvodi dvoaznom mlaznicom. Ulazna temperatura aktivne supstancije iznosi, u povoljnoj izvedbi izuma, 25±5°C, dok temperatura kisika iznosi, u povoljnoj izvedbi izuma, 48±3°C. is carried out according to this invention in such a way that the mentioned plant mixture is poured with 60% ethanol at room temperature and left to stand in a closed container for 28 days, after which the liquid above the sediment is decanted, and that the remaining plant extract is subjected to thickening by vortex spray granulation with spraying with anhydrous gas under a pressure of 1-3 bar, whereby the gas temperature is at least 10°C higher than the inlet temperature of the extract, for a period of 30-40 min. The gas is introduced into the device for vortex spray granulation WSG-GLATT-50 with a double nozzle. The inlet temperature of the active substance is, in a favorable embodiment of the invention, 25±5°C, while the oxygen temperature is, in a favorable embodiment of the invention, 48±3°C.

Tako dobivena aktivna supstancija miješa se do homogene smjese s pulvisom biljne mješavine, korijenom vodopije (Cichorii radix) i Mg-stearatom da bi se dobio farmaceutski pripravak. The active substance obtained in this way is mixed to a homogeneous mixture with the pulvis of the herbal mixture, the root of watercress (Cichorii radix) and Mg-stearate to obtain a pharmaceutical preparation.

Neočekivano, provedbom komparativnih testova, ovako pripravljen farmaceutski pripravak pokazao je 7-10% veću učinkovitost u snižavanju razine glukoze u krvi od pripravka opisanog u patentnoj prijavi WO 99/55351. Unexpectedly, by carrying out comparative tests, the pharmaceutical preparation prepared in this way showed 7-10% greater efficiency in lowering blood glucose levels than the preparation described in patent application WO 99/55351.

Dakle, manje agresivnim postupkom dobivanja, zamjenom zeolita sa korijenom vodopije, prirodne mikroceluloze s pulvisom biljne mješavine opisane u prethodno citiranom dokumentu te usitnjavanjem biljne mješavine prije tretiranja s 60% alkoholom do 40±5 mesha dobiven je farmaceutski pripravak s istom aktivnom tvari, ali s poboljšanom učinkovitošću za 7-10% u odnosu na prethodno opisani pripravak. So, with a less aggressive production process, by replacing zeolite with water lily root, natural microcellulose with pulvis of the plant mixture described in the previously cited document, and by crushing the plant mixture before treatment with 60% alcohol to 40±5 mesh, a pharmaceutical preparation with the same active substance was obtained, but with improved efficiency by 7-10% compared to the previously described preparation.

Osim toga, primijećeno je ljekovito djelovanje u ovoj patentnoj prijavi opisanog izuma na dijabetes melitus tipa I. In addition, the curative effect in this patent application of the described invention on type I diabetes mellitus has been observed.

Primjer izvođenja izuma An example of an embodiment of the invention

Iznijeti primjer samo je jedan od mogućih načina dobivanja aktivne supstancije i farmaceutskog pripravka prema predmetnom izumu i ni u kom slučaju ne sužava opseg predmetnog izuma. The given example is only one of the possible ways of obtaining the active substance and the pharmaceutical preparation according to the present invention and in no case narrows the scope of the present invention.

Koraci potrebni za pripravu aktivne tvari i farmaceutskog pripravka su slijedeći: The steps required for the preparation of the active substance and the pharmaceutical preparation are as follows:

1.) 7,2 kg 60% etilnog alkohola prelije se preko 1 kg biljne mješavine koja se sastoji iz slijedećih komponenti: 1.) 7.2 kg of 60% ethyl alcohol is poured over 1 kg of herbal mixture consisting of the following components:

biljka kičice (Centauri herba) 12,3 masenih % centauri herb (Centauri herba) 12.3 mass %

korijen maslačka (Taraxaci radix) 9,7 masenih% dandelion root (Taraxaci radix) 9.7 mass%

plod borovice (Juniperi communis fructus) 6,2 masenih% juniper fruit (Juniperi communis fructus) 6.2 mass%

biljka koprive (Urticae herba) 7,4 masenih% nettle plant (Urticae herba) 7.4 mass%

korijen koprive (Urticae radix) 7,0 masenih% nettle root (Urticae radix) 7.0 mass%

korijen vodopije (Cichorii radix) 17,7 masenih% watercress root (Cichorii radix) 17.7 mass%

list crnog duda (Morus n. Folium) 7,4 masenih% black mulberry leaf (Morus n. Folium) 7.4 mass%

cvijet stolisnika (Achilleae millefolii flos) 3,5 masenih % yarrow flower (Achilleae millefolii flos) 3.5 mass %

list borovnice (Vaccinii myrtilli folium) 6,6 masenih % blueberry leaf (Vaccinii myrtilli folium) 6.6 mass %

komuška graha (Phaseoli fructus sine semeni) 14,4 masenih% Komuska beans (Phaseoli fructus sine semeni) 14.4 mass%

korijen odoljena (Valerianae officinalis radix) 7,8 masenih% valerian root (Valerianae officinalis radix) 7.8 mass%

2.) navedena biljna mješavina ostavi se stajati u zatvorenoj posudi na sobnoj temperaturi i tlaku 1 bar kroz 28 dana nakon čega se tekućina iznad sedimenta dekantira, pri čemu je prosječno iskorištenje 63 masena %. 2.) the mentioned herbal mixture is left to stand in a closed container at room temperature and a pressure of 1 bar for 28 days, after which the liquid above the sediment is decanted, whereby the average utilization is 63% by mass.

3.) Dobiveni alkoholni ekstrakt uvodi se u aparat za vrtložnu sprej granulaciju pri temperaturi od 25°C u kojem se nasprejava s bezvodnim zrakom koji ima temperaturu 48°C i koji se u aparat uvodi dvofaznom mlaznicom i ugušćuje za faktor 5. Nasprejavanje zrakom izvodi se pod tlakom od 3 bara. Cijeli postupak izvodi se na WSG-GLATT-50. 282 mg 60% alkoholnog ekstrakta daje 56,4 mg suhe aktivne tvari. 3). is under a pressure of 3 bar. The entire procedure is performed on WSG-GLATT-50. 282 mg of 60% alcoholic extract gives 56.4 mg of dry active substance.

4.) Aktivna tvar, pulvis biljne mješavine, korijen vodopije i Mg- stearat miješaju se u masenom omjeru 16,7: 37,0: 45,0: 1,3 do homogene smjese, te se kapsuliraju u želatinozne kapsule. 4.) The active substance, the pulvis of the herbal mixture, the root of water lily and Mg-stearate are mixed in a mass ratio of 16.7: 37.0: 45.0: 1.3 to a homogeneous mixture, and are encapsulated in gelatinous capsules.

Prema povoljnoj izvedbi izuma kapsule mogu sadržavati 200 mg ili 480 mg. According to a favorable embodiment of the invention, the capsules can contain 200 mg or 480 mg.

Za kapsulu od 200 mg For a 200 mg capsule

Aktivna supstancija 33 mg Active substance 33 mg

Pulvis 74 mg Pulvis 74 mg

Korijen vodopije 90 mg Watercress root 90 mg

Mg- stearat 3 mg Mg-stearate 3 mg

Za kapsulu od 480 mg: For a 480 mg capsule:

Aktivna supstancija 79 mg Active substance 79 mg

Pulvis 37 mg Pulvis 37 mg

Korijen vodopije 216 mg Watercress root 216 mg

Mg- stearat 7 mg Mg-stearate 7 mg

Način doziranja i primjene Method of dosage and application

Za dijabetes melitus tipa II For type II diabetes mellitus

1. Oboljeli kojima je razina glukoze u krvi između 4,5-7 mmol/L trebaju uzimati dva puta dnevno po jednu kapsulu od 200 mg 1. Patients whose blood glucose level is between 4.5-7 mmol/L should take one 200 mg capsule twice a day

2. Oboljeli kojima je razina glukoze u krvi između 7-10 mmol/L trebaju uzimati dva puta dnevno po jednu kapsulu od 480 mg 2. Patients whose blood glucose level is between 7-10 mmol/L should take one 480 mg capsule twice a day

3. Oboljeli kojima je razina glukoze u krvi preko 10 mmol/L trebaju uzimati tri puta dnevno po jednu kapsulu od 480 mg 3. Patients whose blood glucose level is over 10 mmol/L should take one 480 mg capsule three times a day.

Za dijabetes melitus tipa I For diabetes mellitus type I

a) djeca do 10 godina trebaju uzimati jedan puta dnevno po jednu kapsulu od 200 mg a) children up to 10 years old should take one 200 mg capsule once a day

b) djeca starija od 10 godina trebaju uzimati dva puta dnevno po jednu kapsulu od 200 mg b) children older than 10 years should take one 200 mg capsule twice a day

c) odrasli kojima je razina glukoze do 10 mmol/L trebaju uzimati jednom dnevno po jednu kapsulu od 480 mg c) adults whose glucose level is up to 10 mmol/L should take one 480 mg capsule once a day

d) odrasli kojima je razina glukoze u krvi preko 10 mmol/L trebaju uzimati jedan do dvaput dnevno po jednu kapsulu od 480 mg d) adults whose blood glucose level is over 10 mmol/L should take one 480 mg capsule once or twice a day

e) oboljeli koji su rezistentni na inzulin trebaju uzimati kapsule kako je opisano od a) do d) e) patients who are resistant to insulin should take capsules as described from a) to d)

Kod zdravstvenih tegoba koje se pojavljuju uz dijabetes melitus: In the case of health problems that appear with diabetes mellitus:

a) u slučaju povišenog kolesterola potrebno je uzimati dva puta po jednu kapsulu od 200 mg dnevno a) in case of elevated cholesterol, it is necessary to take one capsule of 200 mg twice a day

b) u slučaju visokih triglicerida treba se uzimati dva puta na dan po jednu kapsulu od 480 mg. b) in case of high triglycerides, one capsule of 480 mg should be taken twice a day.

Claims

1. Postupak za dobivanje aktivne tvari naznačen time da se sastoji od a) dobivanje ekstrakta dobivenog iz biljne mješavine koju čine slijedeći usitnjeni i osušeni sastojci: biljka kičice (Centaurii herba) 10-15 masenih% korijen maslačka (Taraxaci radix) 6-12 masenih % plod borovice (Juniperi communis fructus) 5-8 masenih% biljka koprive (Urticae herba) 5-10 masenih % korijen koprive (Urticae radix) 5-10 masenih % korijen vodopije (Cichorii radix) 12-20 masenih % list crnog duda (Morus n. Folium) 5-10 masenih % cvijet stolisnika (Achilleae millefolii flos) 2-5 masenih % list borovnice (Vaccinii myrtilli folium) 4-10 masenih % komuška graha (Phaseoli fructus sine semeni) 10-20 masenih % korijen odoljena (Valerianae officinalis radix) 5-10 masenih % na način da se navedena biljna mješavina prelije sa 60% etanolom na sobnoj temperaturi i ostavi stajati u zatvorenoj posudi kroz 28 dana nakon čega se dekantira tekućina iznad sedimenta, b) da se biljni ekstrakt podvrgne ugušćivanju vrtložnom sprej granulacijom uz nasprejavanje s plinom pod tlakom 1-3 bara, pri čemu je temperatura bezvodnog plina barem za 10°C veća od ulazne temperature ekstrakta, kroz vremenski period od 30-40 min.1. The procedure for obtaining an active substance characterized by the fact that it consists of a) obtaining an extract obtained from a herbal mixture consisting of the following chopped and dried ingredients: centaurii herba (Centaurii herba) 10-15% by weight dandelion root (Taraxaci radix) 6-12 mass % juniper fruit (Juniperi communis fructus) 5-8 mass% nettle plant (Urticae herba) 5-10 mass % nettle root (Urticae radix) 5-10 mass % Watercress root (Cichorii radix) 12-20% by mass black mulberry leaf (Morus n. Folium) 5-10 mass % yarrow flower (Achilleae millefolii flos) 2-5 mass % blueberry leaf (Vaccinii myrtilli folium) 4-10 mass % Komuska beans (Phaseoli fructus sine semeni) 10-20 mass % valerian root (Valerianae officinalis radix) 5-10 mass % in such a way that the mentioned plant mixture is poured with 60% ethanol at room temperature and left to stand in a closed container for 28 days, after which the liquid above the sediment is decanted, b) that the plant extract is subjected to thickening by vortex spray granulation with spraying with gas under pressure 1 -3 bar, where the temperature of the anhydrous gas is at least 10°C higher than the inlet temperature of the extract, over a period of 30-40 minutes.

2. Postupak prema zahtjevu 1, naznačen time da bezvodni zrak predstavlja bezvodni plin kojim se ekstrakt nasprejava.2. The method according to claim 1, characterized in that the anhydrous air is an anhydrous gas with which the extract is sprayed.

3. Postupak prema zahtjevu 2, naznačen time da se zrak u aparat za vrtložnu sprej granulaciju uvodi dvofaznom mlaznicom.3. The method according to claim 2, characterized in that the air is introduced into the device for vortex spray granulation with a two-phase nozzle.

4. Postupak prema zahtjevu 1, naznačen time da je ulazna temperatura ekstrakta 25±5 °C.4. Process according to claim 1, characterized in that the inlet temperature of the extract is 25±5 °C.

5. Postupak prema zahtjevu 1, naznačen time da je temperatura bezvodnog zraka kojim se ekstrakt nasprejava 48±3°C.5. The method according to claim 1, characterized in that the temperature of the anhydrous air with which the extract is sprayed is 48±3°C.

6. Postupak prema zahtjevu 1, naznačen time da se vrtložnom sprej granulacijom ekstrakt ugusti za faktor 5.6. The method according to claim 1, characterized in that the extract is thickened by a factor of 5 by vortex spray granulation.

7. Postupak prema zahtjevu 1, naznačen time da se biljna mješavina kao osnovna sirovina usitnjava na 40±5 mesha.7. The method according to claim 1, characterized in that the herbal mixture as the basic raw material is crushed to 40±5 mesh.

8. Farmaceutski pripravak, naznačen time da se sastoji od aktivne substance prema zahtjevu 1, pulvisa biljne mješavine prema zahtjevu 1, korijena vodopije i Mg stearata u slijedećim masenim omjerima 16,7: 37,0 :0,45: 1,3.8. Pharmaceutical preparation, characterized by the fact that it consists of the active substance according to claim 1, the pulvis of the herbal mixture according to claim 1, the root of water lily and Mg stearate in the following mass ratios: 16.7: 37.0: 0.45: 1.3.

9. Postupak za dobivanje farmaceutskog pripravka, naznačen time da se aktivna supstanca dobivena postupkom prema zahtjevu 1, pulvis biljne mješavine iz zahtjeva 1, korijen vodopije i Mg stearat miješaju u omjeru do homogene smjese i da se dobivena homogena smjesa kapsulira u želatinozne kapsule.9. Process for obtaining a pharmaceutical preparation, characterized in that the active substance obtained by the process according to claim 1, the pulvis of the herbal mixture from claim 1, root water and Mg stearate are mixed in a ratio to a homogeneous mixture and that the obtained homogeneous mixture is encapsulated in gelatin capsules.

10. Upotreba farmaceutskog pripravka prema zahtjevu 7, naznačena time da se isti koristi za proizvodnju lijeka za liječenje dijabetes melitusa tipa I.10. The use of a pharmaceutical preparation according to claim 7, characterized in that it is used for the production of a medicine for the treatment of type I diabetes mellitus.