DESC:PHARMACEUTICAL COMPOSITIONS OF BOSWELLIA SERRATA

Field of invention:
The present invention relates to the pharmaceutical compositions of Boswellia serrata. The present invention further relates to the Gastro resistant and / or colon targeted delivery composition of Boswellia serrata and combination.

Background Of The Invention
Boswellia serrata contains chemical constituents, such as ß-boswellic acid, acetyl-ß-boswellic acid, 11-keto-ß-boswellic acid and acetyl-11-keto-ß-boswellic acid (AKBA). AKBA is an organic acid extract of plants of the Boswellia genus. Boswellia serrata has been used in traditional Indian ayurvedic medicine for the treatment of a number of inflammatory diseases, including chronic colitis, ulcerative colitis, osteoarthritis, Crohn's disease, and bronchial asthma. It possesses potent anti-inflammatory properties due to inhibition of 5-lipoxygenase, human leukocyte elastase and the nuclear factor ?B pathway. Even though it is known to have anti-in?ammatory activity, its poor aqueous solubility and permeability pose challenge for its bioavailability.
The pentacyclic triterpenic acids isolated from the oleo gum resin of various Boswellia species are collectively called as Boswellic acids (BA). The oleo gum resin obtained from Indian variety i.e. Boswellia serrata (Family – Burseraceae) is commonly known as Salai guggal. The resin fraction of Salai guggal is rich in Boswellic acids and its essential oil is composed of a mixture of mono, di and sesquiterpenes while gum fraction chie?y contains pentose and hexose sugars. This oleo-gum resin is quite popular among traditional practitioners of traditional Chinese and Indian Systems of medicine owing to their wide range of useful biological properties such as anti-in?ammatory, anti-arthritic, antirheumatic, anti-diarrheal, anti-hyperlipidemic, anti-asthmatic, anti-cancer, anti-microbial anti-fungal and analgesic activity, etc. It has been used as a herbal medicine since the prehistoric time to cure acute and chronic ailments including in?ammatory diseases.

Example 16 of PCT publication number WO 2008059522 describes preparation of extended release boswellic acid pellets and tablets. In this example, boswellic acid pellets are prepared by coating non-pareil seeds and the pellets were coated with Poly ethyl acrylate and methyl methacrylate (2:1) aqueous dispersion polymer.
Bhatkal et al in IAJPS 2017, 4 (01), 46-59, describes a chronotherapeutic tablet formulation containing Boswellia serrata extracts and Ginger extracts. This combination was used to achieve synergistic effects. The core tablets were prepared by using different super-disintegrants like Cross PVP and Sodium starch glycolate. The core tablet was then coated using a variety of enteric coated polymers like Eudragit S-100 and Cellulose acetate phthalate. These coats remain intact in stomach, and dissolve in small intestine providing the essential lag time and allowing the drug to release when it is actually needed, thereby achieving the chronotherapy for Rheumatoid arthritis (RA).The above arts describe processes that are complex and high amount of active such as 80 % cannot be incorporated. The release pattern provided is also quite different.
Thus, while Boswellia serrata (AKBA) have numerous potential therapeutic applications, it has poor solubility and bioavailability. As a result, there is a great need in the medical and pharmaceutical industries to increase its solubility and bioavailability to improve its therapeutic efficacy.

Object Of The Invention
First object is to provide solubilized compositions of Boswellia Serrata. The second object is to provides Gastro resistant and / or colon targeted delivery composition of Boswellia serrata.
Third object is to provide simple processes to arrive at the Gastro resistant and / or colon targeted delivery composition of Boswellia serrata of the present invention.

Summary Of The Invention
Under the first aspect, the present invention provides solubilized compositions of Boswellia Serrata alone or with Curcumin containing from 5 – 35 % solubilizer.
In second aspect, the present invention provides Gastro resistant and / or colon targeted delivery composition of Boswellia serrata and combination with other actives such as Curcumin wherein the compositions do not release more than 10 % active in acidic media for 2 hrs and thereafter release at least 90 – 95 % in a media of 6.8 pH phosphate buffer over next 8 – 10 hrs.
Under third aspect, various processes are provided such as direct compression, wet granulation, extrusion and hot melt extrusion to prepare these compositions.

Detailed description of the invention:

Constipation and Irritable bowel syndrome is a chronic condition which the patient has to manage long term. Typically, based on symptoms, three types of IBS are found viz. constipation-predominant, diarrhea-predominant or mixed. Various medications are approved for IBS and include
i) Medication to relax the colon and slow the movement of waste through the lower bowel for e.g. Alosetron;
ii) Medication for reducing muscle contractions and fluid secretion in the intestine, and increasing muscle tone in the rectum for e.g. Eluxadoline;
iii) Medications for increasing fluid secretion in your small intestine to help with the passage of stool for e.g. Lubiprostone and Linaclotide.
Additionally, antibiotics such as Rifaximin can decrease bacterial overgrowth and diarrhea.
All these medications are small synthetic chemicals.

Natural medications such as certain herbs can manage IBS and provide side effects free treatment. However, there are many challenges. Herbs such as Boswellia Serrata when given orally would lose large dose before it reaches the site of action.
Curcumin from Curcumin Longa has exceptional natural healing properties and can produce synergistic action with IBS medication but again majority of the dose is lost before it reaches site of action because of less or no aqueous solubility.

The active ingredient of Boswellia Serrata viz. Boswellic acids specifically AKBA is generally low i.e up to 30 -35 % of the powder. Some experiments to increase AKBA up to or more than 60 % are being attempted.

Boswellia Serrate powder has gummy nature and therefore, solubilizing AKBA from the powder is highly challenging task. Several solubilizers and their combinations are sometimes needed to cause rapid release of AKBA if large dose is able to reach at its site of action.

Some Boswellia Powders and tablets which are available in the market do not seem to have included any agent or solubility modifier which can help to release until it reaches at the site of action and then ensure complete release.

The inventors of the present invention have come up with the novel formulations of Boswellia Serrata having therapeutically releasing AKBA and optionally Curcumin powder ensuring that both these natural herbs allow their respective natural actives to reach site of action in sufficient amounts and immediately and gradually releasing completely once they reach the site of action.

In one aspect, the present invention provides a composition comprising:
a) a core comprising boswellia serrata having therapeutically effective amount of AKBA, optionally curcumin and one or more solubilizing agents;
b) an enteric coating layer enclosing the core a).

In another aspect, the present invention provides a composition comprising:
a) a core comprising boswellia serrata having therapeutically effective amount of AKBA, and one or more solubilizing agent;
b) optionally, barrier or seal coating;
c) a gastroprotective coating layer enclosing the core a).
In yet another aspect, the present invention provides a composition comprising:
a) a core comprising boswellia and meglumine, an alkaline solublizer;
b) an enteric coating layer / gastro-resistant coating enclosing the core a).

In another aspect, the present invention provides a composition comprising:
a) a core comprising boswellia serrata and meglumine, an alkaline solublizer;;
b) optionally, barrier or seal coating;
c) an enteric coating layer / gastroresistant coating enclosing the core a).

The composition of the present invention may further comprise an additional active ingredient such as curcumin or therapeutically effective curcuminoids.
In one more aspect, the present invention provides a composition comprising:
a) a core comprising boswellia serrata having about 30 % AKBA and curcumin powder having about 20 % Curcumin and alkaline solublizer;
b) optionally, barrier or seal coating;
c) an enteric coating layer / gastroresistant coating enclosing the core a).

The amount of Boswellia Serrata powder in a composition will vary from 10 – 90 %, preferably from around 20 % to around 80 %. In an embodiment, amount of Boswellia Serrata Powder is 80.64. In another embodiment it is from 72-73 %. In yet another embodiment it is 59-60 %. One more embodiment has around 30 % of this powder. In yet another embodiment, the powder is 23 – 24 %. When AKBA content is higher than 30 %, lower amounts can be used. When AKBA content is 30 %, higher amounts such as more than 50 % is preferred.

The solubilizer or solubilizing agent plays a vital role in solubilizing active ingredient AKBA from the gummy powder of Boswellia Serrata. In the absence of a solubilizer, AKBA release is surprisingly reduced.

The solubilizing agent according to the present invention may be selected from but not limited to meglumine, Soluplus® [a polyethylene glycol, polyvinyl acetate and polyvinylcaprolactame-based graft copolymer (PVAc-PVCap- PEG)], SEPITRAP™ 80 [Polysorbate 80 (45-65%), Magnesium Aluminometasilicate (35-55%)], Nu-RICE® (rice extract or rice bran extract from RIBUS, Inc.), vitamin E acetate (tocopherol), vitamin E TPGS (D -a-Tocopherol polyethylene glycol 1000 succinate), natural polymer Pullulan, poloxamer.

Combination of solubilizers are tried and such compositions are found to be highly desired. In an embodiment, combination of poloxamer 188 and meglumine is used. In another embodiment, meglumine is combined with vitamin TPGS. In yet another embodiment, meglumine and Pullulan are used. In one more embodiment, Pullulan and Nu-RICE® have been employed.

The amount of solubilizer is from 5 – 35 %. In an embodiment, around 4 % meglumine and around 4 % Vitamin TPGS are used. In another embodiment, 12-13 % of meglumine and around 4 % of poloxamer 188 re used. In yet another embodiment 11-12 % meglumine and 5 % Pullulan are used. An embodiment contained three solubilizers namely meglumine 13 – 14 %, vitamin E TPGS around 3 % and Nu-Rice® in 1.5 – 2 %.

Nu-Rice® being a natural ingredient, higher amounts such as 15 – 25 % are also employed and found to provide excellent compositions. Nu-Rice® is a new natural emulsifier and solubilizer which is marketed by Ribus. It is a rice extract or rice bran extract prepared by a patented process to extract functional components of rice bran. It can be used even at a concentration from 0.25 %. Various concentrations such as from 1 - 2 % to 15 – 25 % have been tried.

The effect of a solubilizer is ascertained from the release of AKBA from the composition of Boswellia Serrata. Since the targeted drug delivery is designed, the tablets are coated with an enteric coat. Optionally, a barrier coat is applied on the tablets before subjecting to enteric coating. Enteric coated compositions are tested for release first in an acidic media of pH 1.2 followed by a buffer of alkaline pH such as preferably phosphate buffer of pH 6.8. Since targeted drug release is desired, it is ensured that not more than 10 % is released when tested in a medium of acidic pH. Thus, the desired release is not more than 10 % for first two hrs in a media of acidic pH and a complete release viz. at least 90 – 95 % over next 8 – 10 hrs, preferably over next 8 hrs.

The materials which may be incorporated in the barrier coating are natural or synthetic pharmaceutically acceptable materials such as sugar, sugar alcohols, polyethylene glycols, polyvinylpyrrolidones, polyvinyl alcohols, polyvinyl acetates, hydroxypropyl celluloses, methylcelluloses, ethylcelluloses, hydroxypropyl methylcelluloses, carboxymethyl cellulose sodium, water soluble salts of enteric coating polymers, and others, used alone or in mixtures. This barrier coating may comprise various other additives such as plasticizers, colorants, pigments, fillers, anti-tacking and antistatic agents (such as magnesium stearate, titanium dioxide, and talc), and other additives. Barrier coating may also comprise sodium, potassium, calcium or magnesium as their oxides, hydroxides, or salts.

Other ingredients include glidants such as colloidal silicon dioxide and a novel ingredient Nu-Sorb® having Rice bran, Oat Fiber and Sunflower lecithin marketed by Ribus.

The core a) of the composition according to the present invention is subjected to a process of coating, for example in a coating pan, with a dispersion of a substance capable of forming a film resistant to gastric juices, to obtain the gastro-protection.

Preferably, the enteric coating (b) comprises enteric polymer i.e. i) at least one or a combination of derivatives of methacrylic acid and methyl methacrylate with non-limiting examples including Eudragit™ L100, Eudragit™ L12,5, Eudragit™ S100, Eudragit™ S 12,5; ii) shellac (Shellac™) or iii) methyl cellulose derivatives such as HPMC phthalate / Cellulose acetate phthalate or HPMC succinate.

The gastroresistant coating typically comprises an enteric polymer such as one or more of cellulose derivatives, cellulose phthalates, succinates, methacrylic or polymethacrylic acid polymers, shellac or alginates, preferably of shellac and hydroxypropylmethylcellulose, or ethyl cellulose with alginic acid, or polymethacrylates (pH-dependent), ethylcellulose or hydroxypropylmethylcellulose (pH-independent), HPMC Acetate Succinate, EUDRAGUARD® (Evonik Industries AG).

The enteric coating may comprise various other additives such as plasticizers, colorants, pigments, fillers, anti-tacking and antistatic agents (such as magnesium stearate, titanium dioxide, and talc), and other additives.

Preferably, the composition according to the invention is in the form of an enteric coated granule / tablet/ microtablet/drug coated pellet or likes wherein the core a) is enclosed in the enteric film b), or of a gastro-resistant capsule wherein said core a) is enclosed in a hard or soft shell (layer b) that is enterically coated.
The amount of enteric coating varies from 3 – 12 %, preferably from 3 – 10 %. In an embodiment, around 8 % enteric coat containing around 6 % enteric polymer is employed. A preferred enteric polymer is 2:1 or 1:1 combination of Eudragit L 100 and Eudragit S 100.
Another preferred polymer is Shellac which is also preferred because it is natural polymer. Shellac from 3 – 12 %, preferably from 3 – 8 % can be employed. In few embodiments, shellac is employed at concentrations of 3.5 % , 4.5 % and 6 %.
Plasticizers are used in amounts from 10 – 40 % of the enteric polymer and from 1 – 3 % of the compositions. Suitable plasticizers include triethyl citrate, polyethylene glycols etc. Combination of these two in a ratio of 1:1 is most preferred. In few embodiments, 1.2 % , 1.4 % and 2 % plasticizers are used.
Talc is employed as anti-tacking agent from 0.5 – 2 % of the composition.
Batches F001 to F007 are manufactured in accordance with the present invention employing from around 60 % (59.55 %) – around 80 % (80.64 %) of Boswellia Serrata powder with 30 % AKBA and two solubilizers. The core tablets are coated with an enteric coating using either the combination of Eudragit L100 and Eudragit S 100 in 2:1 or 1:1 proportion or using Shellac natural polymer.
In an embodiment, Curcumin powder containing at least 20 % water soluble curcumin is used in addition to Boswellia Serrata. The two actives can be used in ratios from 1:5 to 5: 1 with a preferred ratio from 1:1 to 4:1. In a composition having 60 % of actives, 30 % of Boswellia Seratta and 30 % of Curcumin powder (having 20 % of Curcumin) have been employed. Another combination is 60 % of Boswellia Serrata and 15 % of Curcumin powder. Yet one more combnation is 60 % of Boswellia Seratta and 20 % of Curcumin powder.

A batch F008 with two actives viz. Boswellia Serrata (Containing 30 % AKBA) and Curcumin powder 30 % (containing about 20 % water soluble Curcumin) is manufactured in accordance with the present invention and tested for % Cumulative release to ensure compliance.
All these batches (provided under various examples) complied with the dissolution requirements i.e. the release is not more than 10 % in acidic media followed by at least 90 – 95 % release in next 8 – 10 hrs in a buffer of alkaline pH.
The dissolution conditions employed are as follows:
Dissolution media – Acidic media of pH 1.2, 900 ml for first two hrs followed by 900 ml of alkaline phosphate buffer of pH 6.8.
Dissolution apparatus : Type II
Speed – 100 RPM

In another embodiment, the present invention provides a method for the preparation of pharmaceutical composition comprising boswellia serrata and
wherein said composition comprising the steps of:
i. blending boswellia serrata and meglumine,
ii. granulating the blend to form granules and
iii. compressing the granules into tablet.
In another embodiment, the present invention provides a method for the preparation of pharmaceutical composition comprising boswellia serrata
wherein said composition comprising the steps of:
i. blending boswellia serrata and meglumine,
ii. granulating the blend to form granules and
iii. filing the granules into capsule.
In another embodiment, the present invention provides a method for the preparation of pharmaceutical composition comprising boswellia serrata
wherein said composition comprising the steps of:
i. blending boswellia serrata and meglumine,
ii. granulating the blend to form granules,
iii. compressing the granules into tablet and
iv. coating the tablet with enteric coating layer.

The process of preparation of the compositions of the present invention include -Granulation or Extrusion or Hot melt Extrusion.
When meglumine and poloxamer are used, they are generally blended with dry ingredients followed by granulation. Vitamin E TPGS and Pullulan are added to hot water and allowed to come to room temperature. After blending of dry ingrdients, the solution is used for granulation.
In hot melt extrusion, solubilizer is added to dry ingredients and blended to get a mass. The mass is passed through the twin scree extruder at Temp NMT 150 Deg C. and the extruded material is collected and milled into the fine granular particles.

Yet alternatively, a direct compression process is employed by mixing all dry ingredients and compressing the blend into tablets.

The compressed tablets are optionally barrier coated and further subjected to enteric coating.

As non-limiting examples, the composition of the present invention can be in one of the following forms: an enteric coated tablet, an enteric coated granule, an enteric coated pellets which are drug coated before applying the enteric coat, tablet comprising an enteric coated pellets which are drug coated before applying the enteric coat, a capsule comprising enteric-coated granules or microtablets, or pellets or a hard or soft capsule with a gastro-resistant coating comprising the core a) in the form of powder, granules, micropellets, solution or suspension.

In a preferred embodiment according to the present invention, the layer b) is an enteric film directly coating said core a), i.e. an enteric film enclosing the core and applied directly on the core.

In another preferred embodiment according to the present invention, the layer b) is an enteric film coating barrier coated core a), i.e. an enteric film enclosing the barrier coated core and applied on the barrier coated core.

The compositions according to the invention modulate the activity of bowsellia, reducing its frequency of administration and modulating its release in particular sites of the gastrointestinal tract.

The compositions according to the invention are useful in the treatment of inflammatory diseases, including chronic colitis, ulcerative colitis, arthritis, Crohn's disease and can be given as Once a Day Therapy.

The compositions according to the invention are useful in the treatment of intestinal disorders of inflammatory, immunological and/or systemic origin, in particular in the treatment of gastrointestinal disorders, irritable bowel syndrome, Crohn's disease and ulcerating colitis or in constipation.

The gastroresistant coating of the core prevents release in vitro for at least one hour under conditions of pH less than 6.0, preferably less than 5.5 and most preferably less than 5.

The gastroresistant coating of the core prevents release in vitro for at least 2 hours under conditions of pH < 1.2 - 4.5.

The core is coated with a quantity of polymer/resin sufficient to guarantee that it remains substantially intact in gastric for at least 2 hours before the release of the active ingredient from the core (lag time).

In this way the system prevents early release of boswellia serrata (AKBA) during the stomach-jejunum transit time, and help for the targeted and complete release the medicament in the intestine.

The compositions according to the invention therefore are delayed-release forms (gastroresistant with lag time), which can reach the distal part of the ileum and/or the initial part of the colon substantially unchanged and thereafter rapidly release the active constituents.

The compositions according to the invention contain a unit dose ranging between 50 to 1200 mg of active ingredient boswellia, preferably 100 to 1000 mg of active ingredient boswellia and most preferably 250 to 500 mg of active ingredient boswellia.

The weight ratio between boswellia and solubilizing agent ranges between 1:10 and 10:1. Preferably from 1:1 to 10:1. In an embodiment, it is 3:2, in another embodiment it is 2.4 :1. In yet another embodiment, it is from 1:3.2.

The compositions according to the invention can also contain other excipients, such as diluents, binders, wetting agents, ionic or non-ionic surfactants, disintegrating agents, super-disintegrating agents, crosslinked polymers, complexing agents and lubricants.

Examples of said excipients include phosphatides, lecithins, sodium lauryl sulphate, sorbitan esters, sucrose palmitate, sodium lauryl sarcosinate, cholic acids, poloxamer, cyclodextrins, starches, sodium starch glycolate, croscarmellose and crosslinked polyvinylpyrrolidones.

The compositions according to the invention maximise the pharmacological effect of Boswellia serrata or its constituents such as AKBA in the treatment of irritable bowel syndrome, due to their ability to carry the active ingredient and specifically release it in the colon.

The compositions according to the invention are therefore particularly useful for the treatment of acute and chronic gastrointestinal disorders such as irritable bowel syndrome, diarrhoea, constipation, Crohn's disease, ulcerating colitis, diverticulitis and inflammatory bowel disease in general.

Conventional techniques such as direct compression, wet granulation, and dry compacting /granulation and melt granulation can be used to prepare the compositions according to the invention.

The product, with the addition of excipients such as wetting agents, surfactants, disintegrating agents, super-disintegrating agents, glidants, non-stick agents or lubricants is then prepared using a suitable wet or dry granulation technique, direct division, direct compression, co-grinding, melt granulation or extrusion granulation.

The other ingredients include diluents up to 50%, lubricants (0.01-3%), glidants (0.01-3%), disintegrating and super-disintegrating agents (0 - 40%) and complexing agents (0 - 40%) may be added to this mixture.

The outer coating, essentially consisting of materials possessing gastroresistance properties is then applied to the core thus obtained. The said process of coating could be any of the process of applying a coat known in the art.

As used herein, the term “enteric coating or enteric coating layer” means a layer, forming a continuous barrier, that consists of substances that are resistant to the acidic gastric juices and dissolve in the upper intestinal tract. Said enteric coating layer may be applied directly on the core (e.g. to obtain a filmed tablet or granule) or may be in the form of a shell (e.g. an enteric-coated hard or soft capsule shell comprising the core a), which encloses said core in the form of powder or of one or more tablets, granules or micro-pellets.

In the context of the present invention, "enteric film" or “enteric coat” means a coat that is preferably applied directly on the core, i.e. it adheres to the core, and is capable of protecting the composition from the action of the gastric juices in the stomach and to release the active principle in the upper intestine. Alternatively, enteric coating is applied on the barrier coated cores.

In some embodiments, the compositions and methods comprise use of Boswellia (Boswellia serrata) extract or any components found in Boswellia extract, including but not limited to boswellic acid and pentacyclic triterpene acids. Examples of components include, but are not limited, to a-boswellic acid, ß-boswellic acid, 3-acetyl a-boswellic acid, 3-acetyl ß-boswellic acid, 11-keto-ß-boswellic acid (KBA) and acetyl-11-keto-ß-boswellic acid (AKBA). The preferred component is acetyl-11-keto-ß-boswellic acid (AKBA).

The following examples are provided to describe particular embodiments of the present invention, without intending to limit its scope.
Example 1 provides three core compositions according to the present invention under table I and dissolution profiles of the said three compositions under table II. Example 2 provides additional three core compositions according to the present invention under table III and dissolution profiles of the said three compositions under table IV.
Example 3 provides three more compositions of Boswellia Serrata for Colon Targeted Delivery under table V and corresponding dissolution profiles under table VI-A and VI-B using a buffer of pH 1.2 for 2 hrs followed by buffer of pH 6.8 for next 3 hrs.
It is noted that enteric coated compositions of the present invention for colon targeted delivery have achieved
i) release not more than 20 %, preferably not more than 15 % and more preferably not more than 10 % of Boswellia serrata active in buffer of pH 1.2.; and
ii) release of at least 80 %, preferably at least 90 % and more preferably at least 95 % in buffer of pH 6.8 over next 3 hours.

Example 1
Table I – Compositions 1, 2 and 3.
Sr. No. Ingredient Composition 1
Quantity/Batch Composition 2 Quantity /Batch Composition 3 Quantity /Batch
1 Boswellia serrata (AKBA-30) 80.64
80.64 80.64
2 Poloxamer 188 4.40 3.40 5.40
3 Meglumine 14.20 15.20 13.20
4 Collodial silicon dioxide 0.50 0.50 0.50
Extra-granular
5 Collodial silicon dioxide 0.26 0.26 0.26
Total 100 100 100

Process:
Boswellia serrata (AKBA-30) powder, meglumine, poloxamer and colloidal silicon oxide were mixed in a blender. The blend was granulated in a granulator. The granules were mixed with colloidal silicon oxide and compressed into tablet.

Table II : Dissolution profile of compositions 1, 2 and 3
Dissolution Conditions:
Medium and Volume: 900 ml water with 0.5 % SLS, 900 ml;
Apparatus: USP Type II
RPM: 100
Time points: 15, 30, 45 and 60 mins from start.
Time points
(In mins) Composition 1 Composition 2 Composition 3
15 81 79 90
30 91 94 96
45 95 102 98
60 96 104 102

Example 2
Table III: Compositions 4, 5 and 6.

Sr. No. Ingredient Composition 4
Quantity /Batch Composition 5
Quantity /Batch Composition 6
Quantity /Batch
1 Boswellia serrata (AKBA-90) 23.28
23.28
23.28

2 Poloxamer 188 21.91 20.91 22.91
3 Meglumine 52.81 53.81 51.81
4 Collodial silicon dioxide 0.50 0.50 0.50
Extra-granular
5 Collodial silicon dioxide 1.5 1.5 1.5
Total 100 100 100

Process:
Boswellia serrata (AKBA-90) powder, meglumine, poloxamer and colloidal silicon oxide were mixed in a blender. The blend was granulated in a granulator. The granules were mixed with colloidal silicon oxide and compressed into tablet.

Table IV: Dissolution profiles of compositions 4, 5 and 6.
Dissolution Conditions:
Medium and Volume: 900 ml water with 0.5 % SLS, 900 ml;
Apparatus: USP Type II
RPM: 100
Time points: 15, 30, 45 and 60 mins from start.

Time points
(In mins) Composition 4 Composition 5 Composition 6
15 105 91 102
30 105 99 103
45 106 101 104
60 107 104 105

Example 3
Table V: Compositions of Boswellia Serrata for Colon Targeted Delivery

Sr. No. Ingredient Composition 7
Quantity /Batch Composition 8
Quantity /Batch Composition 9
Quantity /Batch
1 Boswellia serrata (AKBA-30) 72.57 72.576 72.576
2 Poloxamer 188 3.96 3.06 4.86
3 Meglumine 13.89 14.68 12.88
4 Collodial silicon dioxide 0.45 0.45 0.45
Extra-granular
5 Collodial silicon dioxide 0.234 0.234 0.234
Coating
6 Eudragit L 100 3.996 3.996 3.996
7 Eudragit S 100 1.998 1.998 1.998
8 Triethyl Citrate 0.999 0.999 0.999
9 Polyethylene glycol 6000 (PEG 6000) 0.999 0.999 0.999
10 Talc 1.008 1.008 1.008
Coated Tablet 100.00 100.00 100.00

Process:
Boswellia serrata (AKBA-30) powder, meglumine, poloxamer and colloidal silicon oxide were mixed in a blender. The blend was granulated in a granulator. The granules were mixed with colloidal silicon oxide and compressed into tablet. Polyethylene glycol 6000, Eudragit L 100, Eudragit S 100 and talc were dispersed in purified water to form a coating solution. The compressed tablets were coated with coating solution at Bed temperature NMT 40° C in coating pan.

Table VI-A – Dissolution profiles of Colon Targeted Delivery Compositions 7, 8 and 9 in pH 1.2 buffer for first 2 hrs.
Dissolution Conditions:
Medium and Volume: Buffer of pH 1.2, 900 ml;
Apparatus: USP Type II
RPM: 100
Time points: Only 120 mins from start.

Time points
(In mins) Release in pH 1.2 buffer

Composition 7 Composition 8 Composition 9
120 8 7 7

Table VI-B - Dissolution profiles of Colon Targeted Delivery Compositions 7, 8 and 9 in pH 6.8 buffer for next 3 hrs.
Dissolution Conditions:
Medium and Volume: Buffer of pH 6.8, 900 ml;
Apparatus: USP Type II
RPM: 100
Time points: 30, 60, 90, 120 and 180 minutes from start.

Time points
(In mins) Composition 7 Composition 8 Composition 9
30 20 25 24
60 45 48 48
90 68 70 70
120 88 89 90
180 100 100 101

Example 4 : Table VI : Compositions of Boswellia Serrata for Colon Targeted Delivery and % Cumulative release in a media of acidic pH for 2 hrs followed by release in an alkaline phosphate buffer of pH 6.8.
Batch Numbers F001 F002 F003 F004 F005 F006 F007
Core Tablets %w/w %w/w %w/w %w/w %w/w %w/w %w/w
Boswellia serrata (AKBA-30) 72.57 72.58 72.58 80.64 80.64 72.58 59.55
Curcumin 20% - - - - - - -
Poloxamer 188 3.96 - - - - - -
Meglumine 12.78 13.67 11.88 4.03 4.03 11.88 -
Vitamin E TPGS - 3.06 - 4.03 4.03 - -
Pullunan - - 5.00 - - 5.00 11.18
NuRice - 1.69 - - - - 23.67
Collodial silicon dioxide 1.69 - 1.54 0.90 0.90 1.54 -
Nu-Sorb - - - - 2.60 - -
Coating
Eudragit L 100 4.00 4.00 4.00 4.00 - - -
Eudragit S 100 2.00 2.00 2.00 4.00 - - -
Shellac - - - - 6.00 6.00 3.50
Triethyl Citrate 1.00 1.00 1.00 0.80 0.60 1.00 0.70
PEG 6000 1.00 1.00 1.00 0.80 0.60 1.00 0.70
Talc 1.01 1.01 1.01 0.80 0.60 1.01 0.70
Total 100.00 100.00 100.00 100.00 100.00 100.00 100.00
Avg Wt of Tablets 690 mg 690 mg 1000 mg 900 mg 900 mg 1000 mg 840 mg

Dissolution in 900 ml, Type II
% Release % Release % Release % Release % Release % Release % Release
pH 1.2 (2 Hrs) 0 0 2 1 0 3 1
pH 6.8 Phosphate Buffer (hrs)
1 30 35 55 17 20 30 22
2 45 55 65 36 39 44 38
4 78 85 78 55 58 63 57
6 95 99 88 72 78 84 79
8 99 100 101 94 96 99 99
Manufacturing process:

Batch F001: Wet granulation

1. Pass Boswellia Serrata Powder through 30 mesh.
2. Pass Poloxamer 188 and Meglumine through 40 mesh and mix with step 1 material.
3. Granulate the Step 2 material in RMG or twin-screw granulation and collect the wet mass.
4. Dry the granules in fluid bed dryer till LOD reaches to NMT 2%
5. Pass the dried granules through mill and subsequently pass through 30 mesh.
6. Lubricate the blend with Colloidal Silicon dioxide pass previously through 30 mesh.
7. Compress the tablets using suitable tooling.
8. Dissolve the Triethyl citrate and Polyethylene glycol 6000 in Purified Water and add Eudragit L 100 and S 100 Powder to the same solution under stirring.
9. Add Talc to the step 8 dispersion and stir for 15 min.
10. Coat the step 7 compress tablets using the dispersion from step 9.
11. Post coating dry the tablets for 30 min at NMT 40Deg C.

Batch F002: Wet granulation

1. Pass Boswellia Serrata Powder through 30 mesh.
2. Pass Meglumine through 40 mesh and mix with step 1 material.
3. Add the Vitamin E TPGS in hot water and keep aside till it reaches room Temperature.
4. Granulate the Step 2 material in RMG or twin-screw granulation using step 3 solution and collect the wet mass.
5. Dry the granules in fluid bed dryer till LOD reaches to NMT 2%
6. Pass the dried granules through mill and subsequently pass through 30 mesh.
7. Lubricate the blend with NuRice pass previously through 30 mesh.
8. Mix the blend for 10 min in suitable blender.
9. Compress the tablets using suitable tooling from the step 8 blend.
10. Dissolve the Triethyl citrate and Polyethylene glycol 6000 in Purified Water and add Eudragit L 100 and S 100 Powder to the same solution under stirring.
11. Add Talc to the step 10 dispersion and stir for 15 min.
12. Coat the step 9 compress tablets using the dispersion from step 11.
13. Post coating dry the tablets for 30 min at NMT 40Deg C.

Batch F003: Wet granulation
1. Pass Boswellia Serrata Powder through 30 mesh.
2. Pass Meglumine through 40 mesh and mix with step 1 material.
3. Add the Pullulan in hot water and keep aside till it reaches room Temperature.
4. Granulate the Step 2 material in RMG or twin-screw granulation using step 3 solution and collect the wet mass.
5. Dry the granules in fluid bed dryer till LOD reaches to NMT 2%
6. Pass the dried granules through mill and subsequently pass through 30 mesh.
7. Lubricate the blend with Colloidal Silicon Dioxide pass previously through 30 mesh.
8. Mix the blend for 10 min in suitable blender.
9. Compress the tablets using suitable tooling from the step 8 blend.
10. Dissolve the Triethyl citrate and Polyethylene glycol 6000 in Purified Water and add Eudragit L 100 and S 100 Powder to the same solution under stirring.
11. Add Talc to the step 10 dispersion and stir for 15 min.
12. Coat the step 9 compress tablets using the dispersion from step 11.
13. Post coating dry the tablets for 30 min at NMT 40Deg C.

Batch F004: Hot Melt extrusion

1. Pass Boswellia Serrata Powder through 30 mesh.
2. Pass Meglumine through 40 mesh and mix with step 1 material.
3. Add the Vitamin E TPGS to the step 2 premix.
4. Pass the mass through the twin scree extruder at Temp NMT 150 Deg C.
5. Collect the extruded material and mill into the fine granular particles.
6. Pass the granules from step 5 through 30 mesh.
7. Lubricate the blend with Colloidal Silicon Dioxide pass previously through 30 mesh.
8. Mix the blend for 10 min in suitable blender.
9. Compress the tablets using suitable tooling from the step 8 blend.
10. Dissolve the Triethyl citrate and Polyethylene glycol 6000 in Purified Water and add Eudragit L 100 and S 100 Powder to the same solution under stirring.
11. Add Talc to the step 10 dispersion and stir for 15 min.
12. Coat the step 9 compress tablets using the dispersion from step 11.
13. Post coating dry the tablets for 30 min at NMT 40 Deg C.

Batch F005: Hot Melt extrusion

1. Pass Boswellia Serrata Powder through 30 mesh.
2. Pass Meglumine through 40 mesh and mix with step 1 material.
3. Add the Vitamin E TPGS to the step 2 premix.
4. Pass the mass through the twin scree extruder at Temp NMT 150 Deg C.
5. Collect the extruded material and mill into the fine granular particles.
6. Pass the granules from step 5 through 30 mesh.
7. Lubricate the blend with NuRice and Colloidal Silicon Dioxide pass previously through 30 mesh.
8. Mix the blend for 10 min in suitable blender.
9. Compress the tablets using suitable tooling from the step 8 blend.
10. Dissolve the Triethyl citrate and Polyethylene glycol 6000 in Purified Water
11. Add Shellac in Isopropyl Alcohol under stirring and dissolve it completely.
12. Add Talc to the step 11 dispersion and stir for 15 min.
13. Coat the step 9 compress tablets using the dispersion from step 12.
14. Post coating dry the tablets for 30 min at NMT 40Deg C.

Batch F006: Hot Melt extrusion
1. Pass Boswellia Serrata Powder through 30 mesh.
2. Pass Meglumine through 40 mesh and mix with step 1 material.
3. Pass the mass through the twin scree extruder at Temp NMT 150 Deg C.
4. Collect the extruded material and mill into the fine granular particles.
5. Pass the granules from step 5 through 30 mesh.
6. Mix the granular blend with Pullulan and Colloidal Silicon Dioxide pass previously through 30 mesh.
7. Mix the blend for 10 min in suitable blender.
8. Compress the tablets using suitable tooling from the step 8 blend.
9. Dissolve the Triethyl citrate and Polyethylene glycol 6000 in Purified Water
10. Add Shellac in Isopropyl Alcohol under stirring and dissolve it completely.
11. Add Talc to the step 10 dispersion and stir for 15 min.
12. Coat the step 8 compress tablets using the dispersion from step 11.
13. Post coating dry the tablets for 30 min at NMT 40Deg C.

Batch F007: Direct Compression
1. Pass Boswellia Serrata Powder through 30 mesh.
2. Pass Pullulan and NuRice through 40 mesh and mix with step 1 material.
3. Mix the blend for 10 min in suitable blender.
4. Compress the tablets using suitable tooling from the step 4 blend.
5. Dissolve the Triethyl citrate and Polyethylene glycol 6000 in Purified Water
6. Add Shellac in Isopropyl Alcohol under stirring and dissolve it completely.
7. Add Talc to the step 6 dispersion and stir for 15 min.
8. Coat the step 4 compress tablets using the dispersion from step 8.
9. Post coating dry the tablets for 30 min at NMT 40Deg C.

Example 5: Table VI : Compositions of Boswellia Serrata with all natural ingredients for Colon Targeted Delivery (Less than 5 % synthetic chemicals)

Batch Number F008
Core Tablets % w/w
Boswellia serrata (AKBA-30) 30.00
Curcumin 20% 30.00
Poloxamer 188 -
Meglumine -
Vitamin E TPGS -
Pullunan 9.80
NuRice 15.00
Collodial silicon dioxide -
Nu-Sorb 8.00
Coating
Eudragit L 100 -
Eudragit S 100 -
Shellac 4.50
Triethyl Citrate 0.90
PEG 6000 0.90
Talc 0.90
Total 100.00
Avg Wt of Tablets 750 mg

Process: Direct Compression
Batch F008:
1. Pass Boswellia Serrata Powder through 30 mesh.
2. Pass Pullulan through 40 mesh and mix with step 1 material.
3. Pass the Curcumin 20% through 40 mesh and mix with the NuRice, previously passed through 40 mesh.
4. Mix the step 2 and step 3 material in blender and blend for 30 min in suitable blender.
5. Add Nu-Sorb to the step 4 blend and mix for 10 min in blender.
6. Compress the tablets using suitable tooling from the step 5 blend.
7. Dissolve the Triethyl citrate and Polyethylene glycol 6000 in Purified Water
8. Add Shellac in above step 7 solution under stirring and dissolve it completely.
9. Add Talc to the step 8 dispersion and stir for 15 min.
10. Coat the step 6 compress tablets using the dispersion from step 9.
11. Post coating dry the tablets for 30 min at NMT 40Deg C.

Example 6: Table VII : % Cumulative release of AKBA and Curcumin in a media of acidic pH for 2 hrs followed by release in an alkaline phosphate buffer of pH 6.8.
Dissolution Conditions: Dissolution in 900 ml media with Type II apparatus.
Time in hrs % Release for AKBA % Release For Curcumin

pH 1.2 (2 Hrs) 8 4
pH 6.8 Phosphate Buffer (hrs)
1 24 33
2 45 55
4 64 72
6 83 89
8 98 101

,CLAIMS:Claims

We claim

1. A composition of Boswellia Serrata characterized in having
i) from 10 % – 90 % w/w of Boswellia Serrata powder; and
ii) from 5 % - 35 % w/w one or more solubilizer.
2. The composition in accordance with claim 1 wherein the solubilizer is selected from meglumine, pullulan, poloxamer, Nu-Rice®, Vitamin E TPGS and combinations thereof.
3. A Gastro resistant and / or colon targeted delivery composition of Boswellia Serrata characterized in having composition of claim 1.
4. The Gastro resistant and / or colon targeted delivery composition of Boswellia Serrata of claim 3 characterized in having from
i) from 10 % –90 % w/w of Boswellia Serrata powder;
ii) from 5 % –35 % w/w of one or more solubilizers;
iii) from 3 % - 12 % w/w enteric coat comprising an enteric polymer.
5. The Gastro resistant and / or colon targeted delivery composition of Boswellia Serrata of claim 4 characterized in having enteric polymer selected from one or more of cellulose derivatives, cellulose phthalates, succinates, methacrylic or polymethacrylic acid polymers, shellac or alginates.
6. The Gastro resistant and / or colon targeted delivery composition of Boswellia Serrata of claim 3 characterized in having weight ratio of boswellia and solubilizing agent from 1:1 to 10:1.
7. The Gastro resistant and / or colon targeted delivery composition of Boswellia Serrata of claim 3 characterized in having following release
i) Not more than 10 % in first two hrs when tested in media of pH 1.2; and
ii) At least 90 – 95 % over next 8 – 10 hrs when tested in phosphate buffer of pH 6.8.
8. The Gastro resistant and / or colon targeted delivery composition of Boswellia Serrata of claim 3 further characterized in having Curcumin powder wherein weight ratio of Boswellia Serrata powder to Curcumin powder is from 1:1 to 4:1.
9. A process of preparing a Gastro resistant and / or colon targeted delivery composition of Boswellia Serrata characterized in having at least one process selected from direct compression, wet granulation, extrusion and hot melt extrusion.
10. A process of preparing a Gastro resistant and / or colon targeted delivery composition of Boswellia Serrata characterized in having
i) blending Boswellia serrata powder with one or more solubilizer and extragranular ingredients to produce blend and compressing the blend into tablets;
OR
i) blending Boswellia serrata powder with one or more solubilizer to obtain mixture and granulating mixture to produce granules and mixing granules with extra-granular ingredients to produce blend and compressing the blend into tablets;
or
i) granulating Boswellia serrata powder optionally blended with a solubilizer with solution of a solubilizer to produce granules and mixing granules with extragranular ingredients to produce blend and compressing the blend into tablets;
or
i) blending Boswellia serrata powder with one or more solubilizer to obtain mixture and passing the mixture through the twin scree extruder at Temp NMT 150 Deg C; collecting the extruded material, milling extruded material into the fine granular particles, blending granules with extragranular ingredients to produce blend and compressing the blend into tablets
wherein
boswellia serrata powder is used from 10 – 90 % w/w and solubilizer is used from 5 – 35 % w/w; and
ii) optionally coating the tablets with a barrier coat;
iii) and coating the tablets from step i or ii with an enteric coating material having an enteric polymer wherein enteric coat weight build up is from 3 – 12 % w/w of the enteric coated tablet.

___________________________________
Ms. Kharkar Pallavi Shashikant
Patent Agent Registration No.: IN/PA-1138
(Agent for Applicant)