DESC:FORM 2

THE PATENTS ACT, 1970
(39 of 1970)
&
THE PATENT RULES, 2003

COMPLETE SPECIFICATION
(See Section 10 and Rule 13)

Title of invention:
MULTILAYER NUTRACEUTICAL DOSAGE FORMS FOR WEIGHT MANAGEMENT

Applicant:

HERBAXT FORMULATIONS PVT. LTD.
Plot No. SC-1/48, Phase 1, Verna Industrial Estate, Verna, Goa, 403722

The following specification describes the invention:

CROSS-REFERENCE TO RELATED APPLICATIONS AND PRIORITY

[001] The present application claims priority from Indian provisional patent application no. 202121018320 filed on 20th April 2021.

TECHNICAL FIELD

[002] The present invention relates to sustained release of active ingredients. More particularly, the invention relates to a multilayer nutraceutical dosage forms for immediate and sustained release of the active ingredients (hydroxy citric acid derived from Garcinia and chlorogenic acid from green coffee in particular w/w ratios).

BACKGROUND
[003] Chlorogenic acid in green coffee became popular for weight loss after it was mentioned on the Dr. Oz show in 2012. The Dr. Oz show referred to it as "The green coffee bean that burns fat fast" and claims that no exercise or diet is needed. Consuming Garcinia product containing 60% HCA by mouth in three doses daily 30 to 60 minutes before meals for 8 weeks, together with a healthy diet, seems to improve weight loss more than just diet alone.

[004] Therapies with novel mechanisms of action to combat glucose and lipid metabolic disorders would therefore have significant medical and economic impacts. Chlorogenic acid (CGA), one of the most abundant polyphenol compounds in the human diet, is a group of phenolic secondary metabolites produced by certain plant species and an important component of coffee. CGA is possibly effective against weight gain and fat accumulation by inhibition of fat absorption and activation of fat metabolism in the liver.

[005] Chlorogenic acid (CGA) has been shown to affect glucose metabolism. It has been shown to delay glucose absorption in the intestine through inhibition of G- 6-pase translocase and reduction of the sodium gradient- driven apical glucose transport. It was reported that CGA inhibited approximately 40% of glucose-6-phosphatase (G- 6-Pase) activity in the microsomal fraction of hepatocytes. Thus, CGA can decrease hepatic glucose output through inhibition of the activity of G-6-Pase.

[006] Normally the body converts carbohydrates (glucose, fructose, and galactose) taken by meal into energy (ATP) and the excess carbohydrates that cannot be used immediately for energy convert into glycogen. Glycogen is the storage form of carbohydrates, deposited in muscles and the liver. When the glycogen stores are reasonably full, additional carbohydrates are then converted into excess of extramitochondrial Acetyl CoA required for fatty acid synthesis using ATP Citrate lyase enzyme. (-)-Hydroxy citric acid [(-)-HCA] is the principal acid of fruit rinds of Garcinia cambogia (-)-HCA was shown to be a potent inhibitor of ATP citrate lyase.

[007] The inhibition of this reaction limits the availability of acetyl-CoA units required for fatty acid synthesis and lipogenesis during a lipogenic diet, that is, a diet high in carbohydrates. This added glycogen load in the liver stimulates a longer lasting neuro- signal from the liver to the brain, indicating satiety (satisfaction), thus helping to suppress appetite longer. (-)-HCA as weight-controlling agent.

[008] US6447807 discloses a method for making the potassium and sodium salts of (-)-hydroxy citric acid and mixtures thereof workable, non-hygroscopic and non-reactive in acidic media by encasement in hydrophobic and acidophobic polymers.

[009] WO 2009152190 discloses a novel topiramate compositions as well as methods for effecting weight loss, e.g., in the treatment of obesity and related conditions, including conditions associated with and/or caused by obesity per se. U.S. patent 20020187943 discloses a combination of hydroxy citric acid, obtained from Garcinia cambogia plant, and antioxidants, garcinol and anthocyanins, that gave synergistic therapeutic effects in murine and human studies in reduction in total body weight, body mass index, body fat, and perceived appetite level, an increase in lean body mass and content of body water. WO 02/014477 relates to a composition comprising hydroxycitric acid (HCA) in combination with either one or both of garcinol and anthocyanin. 2283/DEL/2013 discloses a herbal formulation prepared for treatment of obesity comprising green tea (Camellia senensis) 200 mg to 1000 mg; Malabar tamarind (Garcinia cambogia) 100 mg to 400 mg; green coffee (Coffea arabica) 100 mg to 400 mg.

[010] Existing technologies are immediate release formulation of individual contents are available in market, but those were administered three times of four time day. These formulations can cause dose dumping at GIT and may not achieve actual i intended action. Also,since high dose is administered individually, one may require diet control and or physical activity to reduce obesity.

[011] Thus, it is desired to address the above-mentioned disadvantages and at least provide a useful alternative.

OBJECT OF INVENTION
[0011] The principal object of the embodiments herein is to provide multilayer nutraceutical dosage forms of herbal formulation for immediate and sustained release of hydroxy citric acid derived from Garcinia cambogia and chlorogenic acid from green coffee.
[012] Another objective of the present invention is to provide a process for preparing immediate release and controlled/delayed release granules by dry granulation or wet granulation method using suitable diluents, polymers and lubricants.

[013] Yet another objective of the present invention is directed towards preparation of controlled release tablets using novel polymers like Hypromellose of particular viscosity alone or in combination with hydroxy propyl cellulose to reduce multiple dose by controlling the release of active constituents in obese patients for reducing belly fat.

[014] Yet another objective of the present invention is to design a double layer formulation consisting of immediate release and sustained release layer for releasing one part/layer at gastrointestinal tract and other part target to release at intestine to exert targeted therapy as per mechanism of action to reduce dose and dosing frequency by controlling the rate of release.

[015] Yet another objective of the present invention is to determine the ratio of novel polymer combinations used is important to meet scheduled delivery of drug throughout 12-hour time.

SUMMARY OF INVENTION
[016] Accordingly, embodiments herein disclose formulation of hydroxy citric acid derived from Garcinia combining with chlorogenic acid from green coffee in particular ratio to make nutraceutical oral solid dosage formulations.

[017] The present invention directs towards preparing immediate release and controlled/delayed release granules by dry granulation or wet granulation method using suitable diluents, polymers, and lubricants. This invention also directs preparation of controlled release tablets using novel polymers like hypromellose of defined viscosity alone or with combination of hydroxy propyl cellulose to reduce multiple doses by controlling the release of active constituents in obese patients for reducing belly fat. A multilayer nutraceutical dosage form for weight management comprises immediate release layer comprising Garcinia cambogia extract and sustained release layer comprising Green coffee extract and a polymer and nutraceutically acceptable inert excipients is disclosed.

[018] These and other aspects of the embodiments herein will be better appreciated and understood when considered in conjunction with the following description and the accompanying drawings. It should be understood, however, that the following descriptions, while indicating preferred embodiments and numerous specific details thereof, are given by way of illustration and not of limitation. Many changes and modifications may be made within the scope of the embodiments herein without departing from the spirit thereof, and the embodiments herein include all such modifications.

DESCRIPTION OF FIGURES

[0020] For the purpose of illustrating of the present subject matter, the dissolution profile for Garcinia is provided as figures; however, the invention is not limited to the specific system disclosed in the document and the figures.

[020] In the figures, the left-most digit(s) of a reference number identifies the figure in which the reference number first appears. The same numbers are used throughout the drawing to refer various features of the present subject matter.

[0021] Figure 1 illustrates the dissolution profile for Garcinia.

[0022] Figure 2 illustrates the dissolution profile for Green Coffee.

DETAILED DESCRIPTION

[0023] Some embodiments of this disclosure, illustrating all its features, will now be discussed in detail. The words "comprising," "having," "containing," and "including," and other forms thereof, are intended to be equivalent in meaning and be open ended in that an item or items following any one of these words is not meant to be an exhaustive listing of such item or items, or meant to be limited to only the listed item or items. It must also be noted that as used herein and in the appended claims, the singular forms "a," "an," and "the" include plural references unless the context clearly dictates otherwise.

[0024] Various modifications to the embodiment will be readily apparent to those skilled in the art and the generic principles herein may be applied to other embodiments of the present invention. However, one with ordinary skill in the art will readily recognize that the disclosure for the present invention is not intended to be limited to the embodiments described, but is to be accorded the widest scope consistent with the principles and features described herein.

[0025] The term ‘sustained release’ as used herein includes modified release, extended release, controlled release, delayed release.

[0026] Conventional dosage forms need to be administered several times (3-4 times). The present invention aims to solve the dosing frequency and dosage form of the nutraceutical dosage formulation that reduce weight by designing of double layer formulation consist of immediate release and sustained release layer or extended-release layer. In an embodiment of the present disclosure, the nutraceutical dosage form comprises Garcinia cambogia extract; green coffee extract; and nutraceutically acceptable inert excipients, wherein the ratio of the Garcinia cambogia extract to the green coffee extract is in the ratio of 5:2.

[0027] In an embodiment of the present disclosure, the nutraceutical dosage form comprises Garcinia cambogia extract having a weight percentage in the range of 35 – 50% with respect to total ingredients in the formulation. In an embodiment of the present disclosure, the nutraceutical dosage form comprises Green coffee extract having a weight percentage in the range of 10 – 20% with respect to total ingredients in the formulation.

[0028] In an embodiment of the present disclosure, the nutraceutical dosage form comprises Garcinia cambogia extract; green coffee extract; and nutraceutically acceptable inert excipients, wherein the ratio of the Garcinia cambogia extract to the green coffee extract is in the ratio of 5:2, and wherein Garcinia cambogia extract having a weight percentage in the range of 35 – 50% with respect to total ingredients in the formulation, and wherein green coffee extract having a weight percentage in the range of 10 – 20% with respect to total ingredients in the formulation.

[0029] In an embodiment of the present invention, the nutraceutical dosage form comprises nutraceutically acceptable inert excipients such as adsorbents, fillers, antioxidants, buffering agents, colorants, flavorants, sweetening agents, tablet antiadherents, lubricants, tablet binders, diluents, tablet direct compression nutraceutically acceptable inert excipients, tablet disintegrants, tablet glidants, polishing agents, and other equivalent nutraceutically acceptable inert excipients.

[0030] In an embodiment, the binder is selected from the group of dry granulation binders and/or the group of wet granulation binders, depending on the manufacturing process chosen. Suitable dry binders are, e.g., cellulose powder and microcrystalline cellulose. Specific examples of wet granulation binders are corn starch, polyvinyl pyrrolidone (Povidon), vinylpyrrolidone-vinylacetate copolymer (Copovidone) and cellulose derivatives like hydroxymethylcellulose, hydroxyethylcellulose, hydroxypropylcellulose and hydroxypropylmethylcellulose. Suitable disintegrants are, e.g., sodium starch glycolate, Crospovidon, Croscarmellose, sodium carboxymethylcellulose and dried corn starch, sodium starch glycolate being preferred.

[0031] The other nutraceutically acceptable inert excipients and adjuvants, if used, are preferably selected from diluents and carriers such as cellulose powder, microcrystalline cellulose, cellulose derivatives like hydroxymethylcellulose, hydroxyethylcellulose, hydroxypropylcellulose and hydroxypropylmethylcellulose, dibasic calcium phosphate, corn starch, pregelatinized starch, polyvinyl pyrrolidone (Povidone) etc.; lubricants such as stearic acid, magnesium stearate, sodium stearylfumarate, glycerol tribehenate, etc.; crystallization retarders such as povidone, etc.; solubilizers such as pluronic, povidone, etc.; coloring agents, including dyes and pigments such as Iron Oxide Red or Yellow, titanium dioxide, talc, etc.; and mixtures of two or more of these nutraceutically acceptable inert excipients and/or adjuvants.

[0032] Multilayer formulation for the instant and then prolonged release of active substances comprising Garcinia cambogia (Hydroxycitric acid) and chlorogenic acid comprising at least two layers, which when used in defined weight ratios is effective for weight management.

[0033] In an embodiment, the first layer is an immediate release layer consisting of Garcinia cambogia, microcrystalline cellulose, povidone K 30, colloidal silica, cross povidone, magnesium stearate.

[0034] In another embodiment, the second layer is sustained release or delayed release or controlled release layer consisting of green coffee extract, microcrystalline cellulose, povidone K 30, colloidal silica, cross povidone, magnesium stearate and Hypromellose.

[0035] In an embodiment, the first layer and the second layer are in contact with each other. In another embodiment, the first layer or the second layer or the formulation may optionally be coated with a film.

[0036] In an embodiment, the formulation of the present invention is administered 1-2 times a day.

[0037] In another embodiment of the present disclosure, the net weight of the formulation is in the range of 1000-1500mg.

[0038] In another embodiment of the present disclosure, the polymer concentration is in the range of 8 – 35% in the formulation.

[0039] In an embodiment of the present disclosure, the present invention provides for effervescent tablets of Garcina and green coffee tablets for those individuals (obsess children’s and geriatric population) having difficult to swallow tablets or capsules.

[0040] In an embodiment of the present disclosure, the present invention discloses a multilayer nutraceutical dosage form for weight management comprising immediate release layer comprising Garcinia cambogia extract and sustained release layer comprising Green coffee extract and a polymer and nutraceutically acceptable inert excipients.

[0041] In an embodiment of the present disclosure, the present invention discloses the multilayer nutraceutical dosage form wherein the weight ratio of Garcinia cambogia extract to Green coffee extract is 5:2.

[0042] In an embodiment of the present disclosure, the present invention discloses the multilayer nutraceutical dosage form wherein the Garcinia cambogia extract is present in a weight ratio of 35 – 50% with respect to total weight of the dosage form.

[0043] In an embodiment of the present disclosure, the present invention discloses the multilayer nutraceutical dosage form wherein the Green coffee extract is present in a weight ratio of 10 – 20% with respect to total weight of the dosage form.

[0044] In an embodiment of the present disclosure, the present invention discloses the multilayer nutraceutical dosage form wherein the dosage form is tablet.

[0045] In an embodiment of the present disclosure, the present invention discloses the multilayer nutraceutical dosage form wherein the polymer is present in a weight of 8 – 35% of the total weight of the dosage form.

[0046] In an embodiment of the present disclosure, the present invention discloses the multilayer nutraceutical dosage form wherein the polymer is hydroxypropyl methyl cellulose.

[007] In an embodiment of the present disclosure, the present invention discloses the multilayer nutraceutical dosage form wherein hydroxypropyl methyl cellulose has a viscosity in the range of 4000 cps to 10000 cps.

[0048] In an embodiment of the present disclosure, the present invention discloses the multilayer nutraceutical dosage form wherein the immediate release layer and sustained release layers are in contact with each other.

[0049] In an embodiment of the present disclosure, the present invention discloses the multilayer nutraceutical dosage wherein the nutraceutically acceptable inert excipients are adsorbents, fillers, antioxidants, buffering agents, colorants, flavorants, sweetening agents, tablet antiadherents, lubricants, tablet binders, diluents, tablet direct compression nutraceutically acceptable inert excipients, tablet disintegrants, tablet glidants, polishing agents.

[0050] In one embodiment of the invention as shown in Figure 1, the dissolution graph for Garcinia is shown which is the immediate release layer.

[0051] In another embodiment of the invention as shown in Figure 2, the dissolution graph for green coffee is shown which is the sustained release layer.

EXAMPLES
[0052] The following examples are presented to illustrate presently preferred practice thereof. As illustrations they are not intended to limit the scope of the invention. All quantities are in weight %.

Formulation 1
Formula 1 (IR+XR layer)
Name of ingredient Mg /tab % weight Sustained release polymer Layer 1 IR granulation Layer 2 XR/SR/DR granulation
Garcinia cambogia (Hydroxycitric acid) 500 40.00 Active Garcinia cambogia Green coffee
Green coffee extract (Chlorogenic acid) 200 16.00 Active Microcrystalline cellulose Microcrystalline cellulose
Hypromellose 400 32.00 Sustained release polymer povidone k 30 povidone k 30
Microcrystalline cellulose 100 9.52 Diluent
povidone k 30 30 2.85 Binder Lubrication Lubrication
colloidal silica 12 1.14 Glidant colloidal silica Hypromellose
cross povidone 5 0.47 Disintegrant cross povidone colloidal silica
magnesium stearate 3 0.28 Lubricant magnesium stearate cross povidone
1250 magnesium stearate

Formulation 2
Formula 2 (IR+XR layer)
Name of ingredient Mg /tab % weight Sustained release polymer Layer 1 IR granulation Layer 2 XR/SR/DR granulation
Garcinia cambogia (Hydroxycitric acid) 500 45.45 Active Garcinia cambogia Green coffee
Green coffee extract (Chlorogenic acid) 200 18.18 Active Microcrystalline cellulose Microcrystalline cellulose
Hypromellose K 4 50 4.55 Sustained release polymer povidone k 30 povidone k 30
Hypromellose k 100 100 9.09 Sustained release polymer
Microcrystalline cellulose 200 18.18 Diluent Lubrication Lubrication
Povidone k 30 30 2.73 Binder colloidal silica Hypromellose K100 & K4
Colloidal silica 12 1.09 Glidant cross povidone colloidal silica
Cross povidone 5 0.45 Disintegrant magnesium stearate cross povidone
Magnesium stearate 3 0.27 Lubricant magnesium stearate
1100

Formulation 3
Formula 3 (IR+XR layer)
Name of ingredient Mg /tab % weight Sustained release polymer Layer 1 IR granulation Layer 2 XR/SR/DR granulation
Garcinia cambogia (Hydroxycitric acid) 500 45.45 Active Garcinia cambogia Green coffee
Green coffee extract (Chlorogenic acid) 200 18.18 Active Microcrystalline cellulose Microcrystalline cellulose
Hypromellose 150 13.64 Sustained release polymer povidone k 30 povidone k 30
Microcrystalline cellulose 200 18.18 Diluent
povidone k 30 30 2.73 Binder Lubrication Lubrication
colloidal silica 12 1.09 Glidant colloidal silica Hypromellose
cross povidone 5 0.45 Disintegrant cross povidone colloidal silica
magnesium stearate 3 0.27 Lubricant magnesium stearate cross povidone
1100 magnesium stearate

Formulation 4
Formula 4 (IR+XR layer)
Name of ingredient Mg /tab % weight Sustained release polymer Layer 1 IR granulation Layer 2 XR/SR/DR granulation
Garcinia cambogia (Hydroxycitric acid) 500 40.00 Active Garcinia cambogia Green coffee
Green coffee extract (Chlorogenic acid) 200 16.00 Active Microcrystalline cellulose Microcrystalline cellulose
Hypromellose 250 20.00 Sustained release polymer povidone k 30 povidone k 30
Microcrystalline cellulose 257 20.56 Diluent Lubrication Lubrication
povidone k 90 15 1.20 Binder+ retardant polymer colloidal silica Hypromellose
colloidal silica 15 1.20 Glidant cross povidone colloidal silica
cross povidone 10 0.80 Disintegrant magnesium stearate cross povidone
magnesium stearate 3 0.25 Lubricant magnesium stearate
1250

Formulation 5
Formula 5 (IR+XR layer)
Name of ingredient Mg /tab % weight Sustained release polymer Layer 1 IR granulation Layer 2 XR/SR/DR granulation
Garcinia cambogia (Hydroxycitric acid) 500 38.46 Active Garcinia cambogia Green coffee
Green coffee extract (Chlorogenic acid) 200 15.38 Active Microcrystalline cellulose Microcrystalline cellulose
Hypromellose 300 23.08 Sustained release polymer HPC HPC
Microcrystalline cellulose 250 19.23 Diluent Lubrication Lubrication
HPC 25 1.92 Binder+ retardant polymer colloidal silica Hypromellose
colloidal silica 10 0.77 Glidant cross povidone colloidal silica
cross povidone 12 0.92 Disintegrant magnesium stearate cross povidone
magnesium stearate 3 0.23 Lubricant magnesium stearate
1300

[0053] Compositions according to the present invention have an advantage that they may release part of the active agent immediately avoiding lag time and then the compositions may be retained for a long period of time in the stomach of a mammal, thereby delivering an active agent over a period that is significant for the clinical need with once-a-day administration which offers better patient compliance.

[0054] In one embodiment the characterization of dosage tablets are caplet shaped , with a dimension of 19X9 mm; hardness: 20-40 newton and thickness: 3.5-4 mm

[0055] In one embodiment the method of manufacturing the tablet is as follows:
a. the raw materials are weighed as per the batch size,
b. the raw material are sifted using 20# mesh to remove any foreign materials.
c. the powder is charged to Planetary mixture and mixed for 15 minutes
d. povidone k 30 binder fluid is added to in planetary mixture for 10-15 min until dough mass formed.
e. the dough mass is dried using fluid bed drier for 40-60 min at inlet temperature 65 degree Celsius until loss on drying reaches to less than 5%.
f. the dried mass is sifted or milled to get uniform granules and bled with polymers, glidants and lubricating agents in bin blender for 15 min.
g. the blend is unloaded and sent for compression to make tablets and
h. packed in HDPE containers.

[0056] In one embodiment the biologically occurring materials green coffee beans are commercially procured from Coorg and Chikmangalore area and the Garcinia Camobiga extract is extracted from dried fruit commercially procured from Mangalore and Karwar.

[0057] It is to be understood that the examples and embodiments described hereinabove are for the purposes of providing a description of the present invention by way of examples and are not to be viewed as limiting the present invention in any way. It is further to be understood that various changes and modifications may be made to that described in above examples by those of ordinary skill in the art is also contemplated by the present invention and is to be included within the scope of the invention without departing from the scope of the invention.


[0058] In view of the foregoing, it will be appreciated that the present application discloses
The preceding description has been presented with reference to various embodiments. Still, it should be understood that the foregoing relates only to the exemplary embodiments of the present invention, and that numerous changes may be made thereto without departing from the spirit and scope of the invention.

,CLAIMS:We claim
1. A multilayer nutraceutical dosage form for weight management comprising
a. Immediate release layer comprising Garcinia cambogia extract;
b. Sustained release layer comprising Green coffee extract and a polymer
and nutraceutically acceptable inert excipients.

2. The multilayer nutraceutical dosage form as claimed in claim 1, wherein the weight ratio of Garcinia cambogia extract to Green coffee extract is 5:2.

3. The multilayer nutraceutical dosage form as claimed in claim 1, wherein the Garcinia cambogia extract is present in a weight ratio of 35 – 50% with respect to total weight of the dosage form.

4. The multilayer nutraceutical dosage form as claimed in claim 1, wherein the Green coffee extract is present in a weight ratio of 10 – 20% with respect to total weight of the dosage form.

5. The multilayer nutraceutical dosage form as claimed in claim 1, wherein the dosage form is tablet.

6. The multilayer nutraceutical dosage form as claimed in claim 1, wherein the polymer is present in a weight of 8 – 35% of the total weight of the dosage form.

7. The multilayer nutraceutical dosage form as claimed in claim 1, wherein the polymer is hydroxypropyl methyl cellulose.

8. The multilayer nutraceutical dosage form as claimed in claim 7, wherein hydroxypropyl methyl cellulose has a viscosity in the range of 4000 cps to 10000 cps.

9. The multilayer nutraceutical dosage form as claimed in claim 1, wherein the immediate release layer and sustained release layers are in contact with each other.

10. The multilayer nutraceutical dosage form as claimed in claim 1, wherein the nutraceutically acceptable inert excipients are adsorbents, fillers, antioxidants, buffering agents, colorants, flavorants, sweetening agents, tablet antiadherents, lubricants, tablet binders, diluents, tablet direct compression nutraceutically acceptable inert excipients, tablet disintegrants, tablet glidants, polishing agents.

Dated this 20th day of April 2022

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