TR2022016665A2

TR2022016665A2 - ORAL PHARMACEUTICAL SOLUTION FORMULATION CONTAINING MELATONIN AND VITAMIN B6

Info

Publication number: TR2022016665A2
Application number: TR2022/016665
Authority: TR
Inventors: Pembec O Lu Ece; Kub Lay Aslihan; Dem Korkmaz C; Mutlu A Ik Sefa
Original assignee: Tab İlaç Sanayi̇ Anoni̇m Şi̇rketi̇
Filing date: 2022-11-03
Publication date: 2024-05-21

Abstract

Buluş, sağlık sektöründe ilaç ve gıda takviyesi alanlarında, rahatlatıcı, uyku düzenleyici ve destekleyici olarak kullanılmak üzere melatonin içerikli bir likit kompozisyon ile ilgilidir. Melatonin çözünürlüğünü iyileştirmek üzere bir takım teknikler içermektedir.The invention relates to a liquid composition containing melatonin to be used as a relaxant, sleep regulator and supporter in the fields of medicine and food supplements in the healthcare sector. It includes a number of techniques to improve melatonin solubility.

Description

TARIFNAME MELATONIN VE VITAMIN BG IÇEREN ORAL FARMASÖTIK ÇÖZELTI FORMÜLASYONU Teknolojik Alan: Bulus, saglik sektöründe ilaç ve gida takviyesi alanlarinda, rahatlatici, uyku düzenleyici ve destekleyici olarak kullanilmak üzere melatonin içerikli bir likit kompozisyon ile ilgilidir. Teknigin Bilinen Durumu: Melatonin, genellikle geceleri epifiz bezi tarafindan salgilanan bir hormondur ve uzun süredir uyku-uyaniklik döngüsünün kontrolü ile iliskilendirilmektedir. Tarifnameye konu bulus, rahatlatici, uyku düzenleyici ve destekleyici özellige sahip melatonin içeriginin etkisini artiran bilesenler ile hazirlanmis bir likit kompozisyon ile ilgilidir. Bilinen teknikte melatonin içerikli çok sayida likit veya kati komposizyon yer almaktadir. Bu komposizyonlarda melatoninin sudaki çözünürlügünün düsük olmasi sebebi ile genellikle propilen glikol farkli konsantrasyonlarda denemeler yapilmistir. Propilen glikolün düsük dozlarda kullanimi böbrekler kan alkalinitesini dengeleyebilse de, yüksek dozlarda propilen glikol kullanimi kani asitlestirebilmekte, böbreklere zarar verebilmekte ve toksisiteye neden olabilmektedir. Bu nedenle yüksek miktarlarda tutarli tüketim kötü saglik kosullarinin olusmasina neden olabilmektedir. Bilenen teknikte melatonin çözünürlügü yeterli bulunmamaktadir. Kompozisyona alinan melatoninin tamami, kompozisyon içerisinde çözünememektedir. Tarifnameye konu bulus bu soruna çözüm sunmaktadir. patent dokümaninda melatonin ve bir antihistaminik ajandan olusan sivi formülasyonu anlatilmaktadir. Sivi formülasyonu uyku düzenleyici olarak kullanilmaktadir. Bahsedilen dokümanda, melatonin çözünürlügünü artirmak üzere mevcut bulusta kullanilan teknikler yer almamaktadir. Ilave olarak vitamin Bö ve stevia bilesenleri de ilgili dokümanda bulunmamaktadir. patent dokümaninda yine melatonin içerikli bir kompozisyon anlatilmaktadir. Bahsedilen dokümanda, melatonin çözünürlügünü artirmak üzere mevcut bulusta kullanilan teknikler yer almamaktadir. Ilave olarak potasyum sorbat ve vitamin Bö bilesenleri de ilgili dokümanda bulunmamaktadir. patent dokümaninda melatonin içerikli topikal sivi bilesimi anlatilmaktadir. Bahsedilen topikal sivi bilesimi, mevcut bulusta melatonin çözünürlügünü artirmak için kullanilan teknikleri ve sorbitol, stevia ve vitamin Bö bilesenlerini içermemektedir. Ayrica çözücü olarak propilen glikol kullanilmistir. patent dokümaninda yine çözücü olarak propilen glikol içeren bir kompozisyon anlatilmaktadir. Bahsedilen kompozisyon, mevcut bulusta melatonin çözünürlügünü artirmak için kullanilan teknikleri ve gliserol, stevia ve vitamin Bö'yi içermemektedir. Yapilan literatür arastirmasinda karsilasilan EP3530289A1 numarali Avrupa patent dokümaninda melatonin içerikli bir farmasötik çözeltiden bahsedilmektedir. Bahsedilen çözelti propilen glikol ve sorbitol içermektedir. Bahsedilen çözelti, mevcut bulusta melatonin çözünürlügünü artirmak için kullanilan teknikleri, stevia ve vitamin Bö'yi içermemektedir. Sonuç olarak teknigin bilinen durumunun asildigi ve dezavantajlarinin giderildigi yeni bir likit kompozisyona ihtiyaç duyulmaktadir. Bulusun Amaci: Bulus, teknigin bilinen durumunun asildigi, dezavantajlarinin giderildigi, melatonin içerikli bir likit kompozisyon ve buna uygun üretim yöntemidir. Bulusun amaci, rahatlatici, uyku düzenleyici ve destekleyici etkilere sahip, melatonin içerikli bir likit kompozisyon ortaya koymaktir. Bulusun bir diger amaci, melatonin çözünürlügünü artirmak üzere tekniklere sahip yeni bir likit kompozisyon ortaya koymaktir. Bulusun bir diger amaci, içerisinde melatoninin etkisini artiracak alternatif ilave bilesenler içeren yeni bir likit kompozisyon ortaya koymaktir. Bulusun Açiklanmasi: Bu detayli açiklamada bulus konusu likit kompozisyon, konunun daha iyi anlasilmasina yönelik olarak, hiçbir sinirlayici etki olusturmayacak örneklerle açiklanmaktadir. Tarifnamede, saglik sektöründe ilaç ve gida takviyesi alanlarinda, rahatlatici, uyku düzenleyici ve destekleyici olarak kullanilmak üzere melatonin içerikli bir likit kompozisyon anlatilmaktadir. Bulusa konu likit kompozisyon içerisindeki ana etken madde melatonindir. Melatonin, beyin tarafindan özellikle geceleri salgilanan bir hormondur. Baslica görevleri arasinda vücudun biyolojik saatini koruyup ritmini ayarlamak olan melatonin hormonunun salinimi, gecenin erken saatlerinde hava karardiktan sonra baslayip, saat 02.00-04.00 gibi en yüksek seviyeye ulasmaktadir. Bulusta melatoninin, kompozisyonda çözünmesi amaci ile gliserol kullanilmaktadir. Gliserol berrak, renksiz, tatli, higroskopik, viskoz bir sividir. Su ve alkol ile karisabilmektedir. Topikal farmasötik formülasyonlarda nemlendirici ve yumusatici etkisi için kullanilirken, çogunlukla parenteral formülasyonlarda bir çözücü olarak faydalidir. Bulusa konu likit kompozisyonda tatlandirici ve tasiyici görevi görmek üzere sorbitol kullanilmaktadir. Sorbitol, sekersiz sivi müstahzarlarda hem tasiyici hem de tatlandirici görevi görür. Ayrica antasit süspansiyonlarda stabilizatör olarak da kullanilir. Sorbitol aslinda mannitolün bir izomeri olan heksahidrik bir alkoldür. Kokusuz, tatli tadi olan, higroskopik, beyaz veya renksiz, kristal tozdur. Bulusta sorbitol yerine ksilitol, maltitol ve benzeri seker alkolleri kullanilabilmektedir. Bulusa konu likit kompozisyonda beyin, sinir sistemi ve nörolojik fonsiyonlari destekleyici görevi gören etkili miktarlarda Bö vitamini yer almaktadir. Bö vitamini uyku ve ruh halini düzenlemede rol oynayan melatonin ve seratonin üretimini artirmaktadir. Bö vitamini eksikliginin, uyuyamama hastaligi yani insomnia ve depresyon semptomlarini artirabildigi arastirmalarda yer almaktadir. Asagida Bö vitamininin bulusta kullanilma sebeplerini gösteren bir takim literatür arastirmalari verilmektedir. Bulusa konu likit kompozisyonda bakteri ve fungilere karsi koruyucu olarak etkili miktarda potasyum sorbat yer almaktadir. Potasyum sorbat yerine antimikrobiyal koruyucular olarak, sodyum benzoat, benzoik asit, benzylalkonyum klorur, metilparaben, propilparaben, etilparaben ve benzeri içerikler kullanilabilmektedir. Ayni zamanda tatlandirici olarak stevia kullanilmistir. Stevia yerine hayvansal veya bitkisel ürünlerden bir sekilde elde edilen herhangi bir aromanin kullanilmasi mümkündür. Bulusta tatlandirici olarak, sukraloz, sukroz, stevia veya erititrol veya bunlarin belirli oranda karisimi kullanilabilir. Bulusa konu likit kompozisyonda ana etken madde olarak etkili miktarda melatonin, çözdürücü olarak gliserol, tatlandirici ve tasiyici görevi görmek üzere sorbitol, beyin, sinir sistemi ve nörolojik fonsiyonlari destekleyici görevi gören B6 vitamini yer almaktadir. Bulusta, o agirlikça tercihen %0.1 - 0.6, daha tercihen %02 - 0.5, daha da tercihen o agirlikça tercihen %5 - 99, daha tercihen %15 - 90, daha da tercihen o agirlikça tercihen %2 - 50, daha tercihen %5 - 40, daha da tercihen %10 - 30, daha da tercihen %15 - 25 araliginda sorbitol, o agirlikça tercihen %0.1 - 10, daha tercihen %0.3 - 6, daha da tercihen almaktadir. Bu oranlarda melatonin, gliserol, sorbitol ve vitamin B6 içeren likit kompozisyon agirlikça tercihen %0.1 - 10, daha tercihen %0.3 - 6, daha da tercihen %0.5 - 2.5, daha da tercihen %0.7 - 2 araliginda potasyum sorbat veya agirlikça daha da tercihen %0.07 - 0.2 araliginda stevia veya agirlikça tercihen %0.05 - tamamlanana kadar su içermektedir. Bulusun tercih edilen versiyonunda, o agirlikça %0.3 melatonin, o %50 gliserol, o %20 sorbitol, 0 %0.1 vitamin B6 yer almaktadir. Yukaridaki tercih edilen versiyon, agirlikça %0.1 potasyum sorbat veya agirlikça kadar su içerebilmektedir. Bulusa konu likit kompozisyonun üretim yönteminde, melatonin çözünürlügünü artirmak üzere bir takim teknikler uygulanmistir. Bu tekniklere karar verilirken deneysel çalismalardan faydalanilmistir. Söyle ki, kompozisyonda farkli miktarlarda gliserol oranlari ile deney yapilmis, melatoninin en etkili çözündügü gliserol orani kullanilmistir. Ayni sekilde kompozisyonun hazirlanma sicakligi için de deney yapilarak farkli sicaklik degerleri test edilmis, optimum sicaklik araligina karar verilmistir. Asagidaki tabloda farkli gliserol miktarlarinin, melatoninin çözünürlügüne olan etkisi üzerine yapilan deneyin sonuçlari paylasilmistir. . Melatonin çözünürlügü Gliserol Gliserol konsantrasyon farki % Miktar konsantrasyonu çalismasi Elde edilen sonuçlarda DU10A ve DU1OB çalismasinda %96 altinda melatonin miktari bulunmustur. DU10C ve DU10D çalismalarinda ise hedef sonuçta benzer degerler elde edilmistir. Laksatif etkiye sebep olmamasi açisindan 500 mg/ml ile çalismalar uygun bulunmustur. 500 mg/ml gliserol kompozisyonda kütlece %50 gliserol oranina denk gelmektedir. Asagidaki tabloda farkli sicaklik degerlerinin melatoninin çözünürlügüne olan etkisi üzerine yapilan deneyin sonuçlari paylasilmistir. Sicaklik farki çalismasi Melatonin çözünürlügü Proses sicakligi Elde edilen sicaklik farki sonuçlarinda proses sicaklik ile dogru orantili olarak çalismalar ortaya çikmistir. Melatonin çözünürlügü için 45-50°C yapilan çalismada hedef degerde sonuçlar alinmis ve bu proses ile çalismalar TR TR TR TR TR TR TR TR TR TR TR TRDESCRIPTION ORAL PHARMACEUTICAL SOLUTION FORMULATION CONTAINING MELATONIN AND VITAMIN BG Technological Field: The invention relates to a liquid composition containing melatonin for use as a relaxant, sleep regulator, and supporter in the fields of medicine and food supplements in the healthcare sector. State of the Art: Melatonin is a hormone generally secreted by the pineal gland at night and has long been associated with the control of the sleep-wake cycle. The invention subject to the description relates to a liquid composition prepared with components that enhance the effect of melatonin, which has relaxing, sleep regulator, and supporter properties. The prior art includes numerous liquid or solid compositions containing melatonin. Due to the low water solubility of melatonin in these compositions, experiments have generally been conducted with different concentrations of propylene glycol. While low doses of propylene glycol can balance blood alkalinity in the kidneys, high doses can acidify the blood, damage the kidneys, and cause toxicity. Therefore, consistent consumption of high amounts can lead to adverse health conditions. The state of the art does not provide sufficient solubility for melatonin. Not all of the melatonin contained in the composition can dissolve in the composition. The invention described herein addresses this problem. The patent document describes a liquid formulation containing melatonin and an antihistamine. The liquid formulation is used as a sleep aid. The aforementioned document does not address the techniques used in the present invention to increase melatonin solubility. Additionally, the components vitamin B1 and stevia are not included in the relevant document. The patent document also describes a composition containing melatonin. The document in question does not include the techniques used in the present invention to increase melatonin solubility. Additionally, potassium sorbate and vitamin Bö components are not included in the relevant document. The patent document describes a topical liquid composition containing melatonin. The topical liquid composition in question does not include the techniques used in the present invention to increase melatonin solubility, nor the components sorbitol, stevia, or vitamin Bö. Furthermore, propylene glycol was used as a solvent. The patent document also describes a composition containing propylene glycol as a solvent. The composition in question does not include the techniques used in the present invention to increase melatonin solubility, nor the components glycerol, stevia, or vitamin Bö. A European patent document numbered EP3530289A1, encountered during the literature search, describes a melatonin-containing pharmaceutical solution. The solution contains propylene glycol and sorbitol. The solution does not contain the techniques used in the present invention to increase melatonin solubility, stevia, and vitamin B1. Consequently, there is a need for a new liquid composition that exceeds the state of the art and eliminates its disadvantages. Purpose of the Invention: The invention is a melatonin-containing liquid composition and a suitable production method that exceeds the state of the art and eliminates its disadvantages. The purpose of the invention is to provide a melatonin-containing liquid composition with relaxing, sleep-regulating, and supportive effects. Another purpose of the invention is to provide a new liquid composition with techniques to increase melatonin solubility. Another purpose of the invention is to provide a new liquid composition containing alternative supplementary ingredients that will enhance the effect of melatonin. Description of the Invention: This detailed description describes the liquid composition in question using examples that will not create any limiting effects for better understanding. The specification describes a liquid composition containing melatonin for use as a relaxant, sleep-regulating, and supportive agent in the healthcare sector, as a pharmaceutical and food supplement. The main active ingredient in the liquid composition in question is melatonin. Melatonin is a hormone secreted by the brain, particularly at night. Among its primary functions is to maintain the body's biological clock and regulate its rhythm. The release of the melatonin hormone begins in the early hours of the night after dark and reaches its peak between 2:00 AM and 4:00 AM. The invention utilizes glycerol to solubilize melatonin in the composition. Glycerol is a clear, colorless, sweet, hygroscopic, and viscous liquid. It is miscible with water and alcohol. It is used for its humectant and emollient properties in topical pharmaceutical formulations and is often useful as a solvent in parenteral formulations. Sorbitol is used as a sweetener and carrier in the liquid composition of the invention. Sorbitol serves as both a carrier and a sweetener in sugar-free liquid preparations. It is also used as a stabilizer in antacid suspensions. Sorbitol is a hexahydric alcohol, essentially an isomer of mannitol. It is an odorless, sweet-tasting, hygroscopic, white or colorless crystalline powder. Xylitol, maltitol, and similar sugar alcohols can be used instead of sorbitol in the invention. The liquid composition of the invention contains effective amounts of vitamin Bö, which supports the brain, nervous system, and neurological functions. Vitamin Bö increases the production of melatonin and serotonin, which play a role in regulating sleep and mood. Studies have shown that vitamin Bö deficiency can exacerbate symptoms of insomnia and depression, a condition characterized by insomnia. Below are some literature studies demonstrating the reasons for using vitamin Bö in the invention. The liquid composition of the invention contains an effective amount of potassium sorbate as a preservative against bacteria and fungi. Antimicrobial preservatives such as sodium benzoate, benzoic acid, benzylalkonium chloride, methylparaben, propylparaben, ethylparaben, and similar ingredients can be used instead of potassium sorbate. Stevia was also used as a sweetener. Any flavoring derived from animal or plant products can be used instead of stevia. Sucralose, sucrose, stevia, or erythritol, or a mixture of these in a certain ratio, can be used as sweeteners in the invention. The liquid composition of the invention contains an effective amount of melatonin as the main active ingredient, glycerol as a solubilizer, sorbitol as a sweetener and carrier, and vitamin B6, which supports brain, nervous system, and neurological functions. In the invention, it preferably takes 0.1 - 0.6% by weight, more preferably 0.2 - 0.5%, even more preferably 5 - 99% by weight, more preferably 15 - 90%, even more preferably 2 - 50% by weight, more preferably 5 - 40%, even more preferably 10 - 30%, even more preferably 15 - 25% of sorbitol, it preferably takes 0.1 - 10% by weight, more preferably 0.3 - 6%, even more preferably. The liquid composition containing melatonin, glycerol, sorbitol and vitamin B6 in these proportions preferably contains 0.1 - 10% by weight, more preferably 0.3 - 6%, more preferably 0.5 - 2.5%, more preferably 0.7 - 2% potassium sorbate or more preferably 0.07 - 0.2% by weight stevia or preferably 0.05% by weight water until complete. In the preferred version of the invention, it contains 0.3% by weight melatonin, 50% glycerol, 20% sorbitol, 0.01% vitamin B6. The preferred version above may contain 0.1% by weight potassium sorbate or up to 0.05% by weight water. In the production method of the liquid composition of the invention, a number of techniques have been applied to increase the solubility of melatonin. Experimental studies were utilized when deciding on these techniques. For example, experiments were conducted with different glycerol ratios in the composition, and the glycerol ratio that most effectively dissolved melatonin was used. Similarly, experiments were conducted for the preparation temperature of the composition, testing different temperature values, and the optimum temperature range was determined. The table below shows the results of experiments on the effects of different glycerol amounts on melatonin solubility. Melatonin Solubility Glycerol Glycerol Concentration Difference % Amount Concentration Study The results obtained showed that the amount of melatonin was below 96% in the DU10A and DU1OB studies. Similar values were obtained in the target results in the DU10C and DU10D studies. Studies using 500 mg/ml were deemed appropriate due to its lack of laxative effects. 500 mg/ml glycerol corresponds to 50% glycerol by mass in the composition. The table below shows the results of experiments conducted on the effects of different temperature values on melatonin solubility. Temperature Difference Study Melatonin Solubility Process Temperature The temperature difference results obtained revealed that the process temperature was directly proportional to the results. In the study conducted at 45-50°C for melatonin solubility, results were obtained at the target value, and studies were conducted with this process.

Claims

STEMS

. The invention is a liquid composition and its feature is; It is characterized by containing an effective amount of melatonin as the main active ingredient, an effective amount of glycerol that acts as a solvent, sorbitol, xylitol, sugar alcohol that can be maltitol, which acts as a carrier and sweetener, and effective amounts of vitamin B, which acts as a support for the brain, nervous system and neurological functions.

. It is a liquid composition in accordance with claim 1, and its feature is; It preferably contains melatonin by weight.

. It is a liquid composition in accordance with any of the above claims and its feature is; It preferably contains glycerol in the range of 5 - 99%, more preferably 15 - 90%, even more preferably 25 - 80%, even more preferably 35 - 65% by weight.

. It is a liquid composition in accordance with any of the above claims and its feature is; It preferably contains 2 - 50%, more preferably 5 - 40%, more preferably 10 - 30%, even more preferably 15 - 25% sugar alcohol, which can be sorbitol, xylitol, maltitol, by weight.

. It is a liquid composition in accordance with any of the above claims and its feature is; It preferably contains vitamin B6 in the range of 0.1 - 10%, more preferably 0.3 - 6%, even more preferably 0.5 - 2.5%, even more preferably 0.7 - 2% by weight.

. It is a liquid composition in accordance with any of the above claims and its feature is; It contains an effective amount of antimicrobial preservatives, which can be potassium sorbate, sodium benzoate, benzoic acid, benzylalkonium chloride, methylparaben, propylparaben or ethylparaben, or a mixture of these in certain proportions, as a preservative against bacteria and fungi.

7. It is a liquid composition according to claim 5, and its feature is; The antimicrobial preservative should preferably be included in the food supplement in the range of 0.1 - 10% by weight.

8. It is a liquid composition according to any of the above claims and its feature is; It contains an effective amount of sweetener, which can be sucralose, sucrose, stevia or erythritrol or a mixture of these in certain proportions.

9. It is a liquid composition according to claim 7, and its feature is; The stevia component is preferably present in the food supplement in the range of 0.01 - 1%, more preferably 0.03% by weight.

10. It is a liquid composition in accordance with any of the above claims and its feature is; It contains an effective amount of flavor obtained from animal or plant products in order to adjust the taste.

11. It is a liquid composition according to claim 9, and its feature is; The aroma is preferably 0.05 - 5%, more preferably 0.15 - 3% by weight in the food supplement.

12. It is a liquid composition in accordance with any of the above claims and its feature is; It contains water until the mixture reaches 1 mL.

13.The invention is a liquid composition and its feature is; It is characterized by containing o 0.3% melatonin, o 50% glycerol, o 20% sugar alcohol, which can be sorbitol, xylitol, maltitol, and 0.1% vitamin B by weight.

14. It is a liquid composition according to claim 13, and its feature is; It contains 0.1% antimicrobial preservative by weight.

15. It is a liquid composition according to claim 13, and its feature is; It contains 0.01% sweetener by weight.

16. It is a liquid composition according to claim 13, and its feature is; It contains 0.05% aroma by weight.

17. It is a liquid composition according to claim 13, and its feature is; It contains water until it reaches 100% by weight.

18.The invention is a liquid composition containing melatonin and its feature is; More preferably, it contains 35 - 65% glycerol by weight.

19. The invention is a production method for a liquid composition and its feature is; It is characterized by o adding glycerol at a rate of 50% by weight of the composition into a certain amount of water, o heating the glycerol - water mixture to 40 - 50 C°, o adding melatonin and vitamin B to the mixture and mixing it in a mechanical mixer.

20. It is a production method for a liquid composition according to claim 19, characterized in that; An effective amount of sugar alcohol, which can be sorbitol, xylitol, maltitol, is added into it.

21. It is a production method for a liquid composition according to claim 19, characterized in that; It involves adding an effective amount of sweetener and mixing it.

22. It is a production method for a liquid composition according to claim 19, characterized in that; Adding an effective amount of aroma and mixing it.

23. It is a production method for a liquid composition according to claim 19, characterized in that; Adding an effective amount of antimicrobial preservative into 5 and mixing it.

24. The production method for a liquid composition according to claim 19, characterized in that; The final form of the mixture is obtained by completing the volume with water.