DESC:FIELD OF THE INVENTION
[0001] The present disclosure pertains to the field of solid pellet formulations, in particular, formulations of hyaluronic acid in pellet form.

BACKGROUND OF THE INVENTION
[0002] Hyaluronic acid (HA) is a natural and linear carbohydrate polymer belonging to the class of non-sulfated glycosaminoglycans. Hyaluronic acid, also referred to as hyaluronan or hyaluronate or HA, is an anionic, nonsulfated glycosaminoglycan polymer of disaccharides, composed of D-glucuronic acid and D-N-acetylglucosamine, linked via alternating ß-1,4 and ß-1,3 glycosidic bonds. It is present in hyaline cartilage, synovial joint fluid, and skin tissue, both dermis and epidermis. HA is employed in a wide range of current and developing applications due to the unique physical and biological properties.
[0003] Hyaluronic acid is a natural substance found in the fluids in the eyes and joints. It acts as a cushion and lubricant in the joints and other tissues. Different forms of hyaluronic acid are used for cosmetic purposes. Hyaluronic acid might also affect the way the body responds to injury and help to decrease swelling. HA is an important component of articular cartilage, where it is present as a coat around each chondrocyte and is a major component of the synovial fluid providing essential lubrication in joints. HA has been used for human and veterinary purposes such as for treatment of articular disorders in horses. It is indicated for carpal and fetlock joint dysfunctions and also used as a treatment for knee osteoarthritis by injecting HA into the joint thereby providing substantial pain relief. Injectable HA has some significant drawbacks, as it is an invasive procedure that involves pain and a chance of introducing an infection in the joint.
[0004] Hyaluronic acid is also available in dietary supplement form. Oral HA dietary supplement pills and capsules have been marketed for reducing inflammation, relieve pain, restore joint fluids, protect against cartilage breakdown in osteoarthritis patients as well as for treating chronic fatigue syndrome, chronic pain, fibromyalgia and insomnia. However, HA is difficult to formulate as an effective supplement for oral administration. While most effective in liquid form, HA breaks down over time into lower molecular weight components which are less effective (effectiveness being proportional to the molecular weight) and has a short shelf-life, often less than 9 months from preparation.
[0005] In order to maximize stability, and therefore shelf-life, dry solid formulations of HA have been made. However, these formulations have demonstrated low oral bioavailability. During hydration HA swells, becoming viscous and sticky, making it poorly soluble.
[0006] Accordingly, it would be desirable to provide an HA formulation suitable for oral ingestion in which the HA is stable (substantially maintains its high molecular weight) and is readily dissolved having the high bioavailability of a liquid HA formulation.
SUMMARY OF THE INVENTION
[0007] Accordingly, the present invention in one aspect provides a hyaluronic acid formulation. In one aspect, the present disclosure discloses a hyaluronic acid formulation comprising non-pareil seed in an amount in the range of 33 to 50 % w/w, hyaluronic acid in an amount in the range of 28 to 42 % w/w, at least one additive in an amount in the range of 3 to 4 % w/w, at least one polymer in an amount in the range of 14 to 21 % w/w, at least one plasticizer in an amount in the range of 14 to 21 % w/w, at least one solvent in an amount in the range of 150 to 226 % w/w and , at least one pharmaceutically acceptable excipient in an amount in the range of 1 to 2 % w/w. Typically, the formulation is prepared in the dosage forms selected from the group of a semi-solid mass, a pellet and tablet. Further, the dosage form is selected from the group of immediate release, sustained release, and delayed release.
[0008] The present invention in another aspect also discloses a method for preparing the hyaluronic acid formulation.

DETAILED DESCRIPTION OF THE INVENTION
[0009] The following is a detailed description of embodiments of the present disclosure. The embodiments are in such detail as to clearly communicate the disclosure. However, the amount of detail offered is not intended to limit the anticipated variations of embodiments; on the contrary, the intention is to cover all modifications, equivalents, and alternatives falling within the spirit and scope of the present disclosure as defined by the appended claims.
[00010] Unless the context requires otherwise, throughout the specification which follow, the word “comprise” and variations thereof, such as, “comprises” and “comprising” are to be construed in an open, inclusive sense that is as “including, but not limited to.”
[00011] Reference throughout this specification to “one embodiment” or “an embodiment” means that a particular feature, structure or characteristic described in connection with the embodiment is included in at least one embodiment. Thus, the appearances of the phrases “in one embodiment” or “in an embodiment” in various places throughout this specification are not necessarily all referring to the same embodiment. Furthermore, the particular features, structures, or characteristics may be combined in any suitable manner in one or more embodiments.
[00012] As used in the description herein and throughout the claims that follow, the meaning of “a,” “an,” and “the” includes plural reference unless the context clearly dictates otherwise. Also, as used in the description herein, the meaning of “in” includes “in” and “on” unless the context clearly dictates otherwise.
[00013] In some embodiments, the numbers expressing quantities of ingredients, properties such as concentration, and so forth, used to describe and claim certain embodiments of the invention are to be understood as being modified in some instances by the term “about.” Accordingly, in some embodiments, the numerical parameters set forth in the written description are approximations that can vary depending upon the desired properties sought to be obtained by a particular embodiment. In some embodiments, the numerical parameters should be construed in light of the number of reported significant digits and by applying ordinary rounding techniques. Notwithstanding that the numerical ranges and parameters setting forth the broad scope of some embodiments of the invention are approximations, the numerical values set forth in the specific examples are reported as precisely as practicable.
[00014] The recitation of ranges of values herein is merely intended to serve as a shorthand method of referring individually to each separate value falling within the range. Unless otherwise indicated herein, each individual value is incorporated into the specification as if it were individually recited herein.
[00015] All methods described herein can be performed in suitable order unless otherwise indicated herein or otherwise clearly contradicted by context. The use of any and all examples, or exemplary language (e.g., “such as”) provided with respect to certain embodiments herein is intended merely to better illuminate the invention and does not pose a limitation on the scope of the invention otherwise claimed. No language in the specification should be construed as indicating any non-claimed element essential to the practice of the invention.
[00016] The headings and abstract of the invention provided herein are for convenience only and do not interpret the scope or meaning of the embodiments.
[00017] Various terms are used herein. To the extent a term used in a claim is not defined below, it should be given the broadest definition persons in the pertinent art have given that term as reflected in printed publications and issued patents at the time of filing.
[00018] The present invention discloses a hyaluronic acid formulation and a method for preparation thereof. In one aspect, the present disclosure discloses a hyaluronic acid formulation. The formulation comprises pre-determined amounts of non-pareil seed, hyaluronic acid, at least one additive, at least one polymer, at least one plasticizer, at least one solvent and at least one pharmaceutically acceptable excipient.
[00019] In an embodiment of the present invention, the at least one additive is selected from the group consisting of, but not related to, magnesium stearate, stearic acid, microcrystalline cellulose powder, carrageenan, sodium carboxymethyl cellulose (CMC), carboxymethylcellulose; HPMC, hydroxypropyl methylcellulose. In another embodiment of the present invention, the at least one polymer is a water-soluble polymer. In an exemplary embodiment of the present invention, the at least one water-soluble polymer is selected from the group consisting of, but not related to, polyvinylpyrrolidone, Hypromellose (HPMC), Hydroxypropyl cellulose (HPC), Starch, Modified starch and Cellulosic polymer.
[00020] In yet another embodiment of the present invention, the at least one plasticizer is selected from the group consisting of, but not related to, polyethylene glycol (PEG), glycerine, Triethyl citrate (TEC), Polysobads, Sodium laureth sulfate (SLS) and Polyvinylpyrrolidone (PVP). In still another embodiment of the present invention, the at least one solvent is selected from the group consisting of, but not related to, water, alcohol, organic solvent and a combination thereof. In an exemplary embodiment of the present invention, the at least one solvent is selected from the group consisting of, but not related to, hydroalcoholic solvent, organic solvent, polar solvent, non-polar solvent and aqueous solvent.
[00021] In an embodiment of the present invention, at least one pharmaceutically acceptable excipient is selected from the group consisting of at least one diluent, at least one disintegrant, at least one binder, at least one lubricant, at least one glidant, at least one filler, at least one vitamin, at least one mineral, at least one phytochemical, at least one antioxidant and combinations thereof.
[00022] Typically, at least one diluent is selected from the group consisting of, but not limited to, lactose, microcrystalline cellulose (mcc), calcium carbonate, sugar and alcohols such as sorbitol, xylitol and mannitol.
[00023] Typically, at least one disintegrant is selected from the group consisting of, but not limited to, HPMC, hydroxypropyl methylcellulose, cross-linked carboxymethyl cellulose (croscarmellose), sodium starch glycolate, polyvinyl pyrrolidone and sago starch.
[00024] Typically, at least one binder is selected from the group consisting of, but not limited to, cellulose, gelatin, cellulose derivatives, polyvinyl pyrrolidone, starch, sucrose, mannitol, polyethylene glycol, and liquid glucose.
[00025] Typically, at least one lubricant is selected from the group consisting of, but not limited to, talc, silica and fats such as vegetable stearin, magnesium stearate or stearic acid.
[00026] Typically, at least one glidant is selected from the group consisting of, but not limited to, talc, silica and fats such as vegetable stearin, magnesium stearate or stearic acid.
[00027] Typically, at least one filler is selected from the group consisting of, but not limited to, magnesium stearate, stearic acid, microcrystalline cellulose powder, carrageenan, sodium carboxymethyl cellulose (CMC), carboxymethylcellulose; HPMC, hydroxypropyl methylcellulose
[00028] Typically, at least one vitamin is selected from the group consisting of, but not limited to, Vitamin K, Vitamin E, and Vitamin A.
[00029] Typically, at least one mineral is selected from the group consisting of, but not limited to, zinc, magnesium and ferrous.
[00030] Typically, at least one phytochemical is selected from the group consisting of, but not limited to, flavonoids, phenolic acids, isoflavones, curcumin, isothiocyanates, and carotenoids.
[00031] Typically, at least one antioxidant is selected from the group consisting of, but not limited to, vitamin C, vitamin E, selenium, and carotenoids such as beta-carotene, lycopene, lutein, and zeaxanthin.
[00032] In an exemplary embodiment of the present invention, the formulation comprises:
• Non-Pareil seed in an amount in the range of 33 to 50 % w/w;
• Hyaluronic acid (HA) in an amount in the range of 28 to 42 % w/w;
• Magnesium stearate in an amount in the range of 3 to 4 % w/w;
• Polyvinylpyrrolidone in an amount in the range of 14 to 21 % w/w;
• Polyethylene glycol in an amount in the range of 1 to 2 % w/w; and
• Hydroalcoholic solvent in an amount in the range of 0.5 to 259 % w/w.
[00033] In an embodiment of the present invention, the formulation is prepared in the dosage forms selected from the group of a semi-solid mass, a pellet, tablet and the like. In another embodiment, the dosage form is further selected from the group of immediate release, sustained release, and delayed release. Depending upon the dosage the formulation may comprise further excipients necessary for the manufacture of the preferred dosage form and its breakdown following ingestion and may be chosen by those skilled in the art.
[00034] In another aspect of the present invention, disclosed is a method for preparing the hyaluronic acid formulation. The method comprises initially preparing a blend by blending in predetermined amounts, hyaluronic acid and at least one additive. Further, predetermined amounts of Non-Pareil seeds are loaded into a pan coater followed by periodic spraying with at least one solvent and dusting with the blend to obtain a mixture. Lastly, the mixture is dried to obtain the pellets.
[00035] Alternatively, the hyaluronic acid formulation can also be prepared by initially preparing a blend by blending in predetermined amounts, hyaluronic acid and at least one additive. Further, predetermined amounts of Non-Pareil seeds are loaded into a rotary pan followed by periodic tangentially spraying with at least one solvent using spray nozzle and loading the blend using powder feeder in rotary pan to obtain a mixture. Lastly, the mixture is dried to obtain the pellets.
[00036] EXAMPLES:
[00037] Hyaluronic Acid pellet Development by Rotor Pan Technology:
The hyaluronic acid formulation was prepared by coating with polymer powders. Fluid bed rotor technology was used which incorporates the use of high centrifugal motion of rotor disc to compress layers of powder and binder spray on to pellet surface. This process is faster because as we sprayed/layered direct powder API/excipients in contrast to layering of API/excipients from solution in case of bottom spray pellet coating. The powder (API/Polymer/excipients) and binder solution was sprayed through nozzle in tangential direction with the direction rotor disc and flow of pellet bed. It was a simultaneous phenomenon wherein moistening of pellet surface and layering of powder and drying takes place, further layered powder gets strength with high centrifugal force. Both binder spraying and layering of powder are concurrent processes.
Trial-1
Sr.no Ingredients %w/w
1 Non-Pareil seed 75-80%
2 Hyaluronic acid (HA) 20-30%
3 Hydroxypropyl methylcellulose 2-5%
4 Hydroalcoholic solvent 120-250%

Reason: After Pelletization we found the pellets not having adequate strength, we have to modify the formula on strength direction.
Trial-2
Sr.no Ingredients %w/w
1 Non-Pareil seed 70-75%
2 Hyaluronic acid (HA) 20-30%
3 Hydroxypropyl methylcellulose 2-5%
4 Polyvinylpyrrolidone 1-6%
5 Hydroalcoholic solvent 150-350%
Reason: After modification pellets found pellets process sticking of pellets to each other has been increased, modification in trial with lubricants consideration.
Trial-3
Sr.no Ingredients %w/w
1 Non-Pareil seed 70-73%
2 Hyaluronic acid (HA) 20-30%
3 Hydroxypropyl methylcellulose 2-5%
4 Plasdone 1-6%
5 Magnesium stearate 0.5-1%
6 Hydroalcoholic solvent 150-350%
Reason: After modification pellets found to be rough in nature and fines are also there during development stage.

Trial-4
Sr.no Ingredients %w/w
1 Non-Pareil seed 70-73%
2 Hyaluronic acid (HA) 25-35%
3 Hydroxypropyl methylcellulose 1-5%
4 Polyvinylpyrrolidone 1-3%
5 Magnesium stearate 0.5-1%
6 Hydroalcoholic solvent 150-350%
Reason: After modification pellets found to be rough and not adequate spherical.

Trial -5
Sr.no Ingredients %w/w
1 Non-Pareil seed 33-50%
2 Hyaluronic acid (HA) 28-42%
3 Polyvinylpyrrolidone 14-21%
4 Polyethylene glycol 1-2%
5 Magnesium stearate 0.5-1%
6 Hydroalcoholic solvent 150-226%
Reason: After modification we found the pellets are fit in desirable range of all the parameter.
[00038] STABILITY STUDIES
Accelerated stability studies were conducted at 40 °C and 75% relative humidity for a period of 6 months.
Physical Analysis Results
Test Specification Method Initial 1 Month 2 Months 3 Months 6 Months
Appearance White to off-white free flowing spherical shaped pellets Visual White to off-white free flowing spherical shaped pellets No significant difference No significant difference No significant difference No significant difference
Loss on Drying Not more than 5 % IH complies complies complies complies complies
Pellets size Range of 16 mesh ASTM to 25 mesh ASTM IH complies complies complies complies complies
Disintegration Test (in minutes) NMT 30 IH 14 to 15 13 to 16 14 to 16 15 to 16 15 to 17

Accelerated stability results were complying to the laid down specifications. Based on the above stability studies it was determined that the composition has 24 months shelf life for the said product.

[00039] While the foregoing description discloses various embodiments of the disclosure, other and further embodiments of the invention may be devised without departing from the basic scope of the disclosure.
,CLAIMS:1.) A hyaluronic acid formulation comprising:
? non-pareil seed in an amount in the range of 33 to 50 % w/w;
? hyaluronic acid in an amount in the range of 28 to 42 % w/w;
? at least one additive in an amount in the range of 3 to 4 % w/w;
? at least one polymer in an amount in the range of 14 to 21 % w/w;
? at least one plasticizer in an amount in the range of 14 to 21 % w/w;
? at least one solvent in an amount in the range of 150 to 226 % w/w; and
? at least one pharmaceutically acceptable excipient in an amount in the range of 1 to 2 % w/w.
2.) The formulation as claimed in claim 1, wherein said at least one additive is selected from the group consisting of magnesium stearate, stearic acid, microcrystalline cellulose powder, carrageenan, sodium carboxymethyl cellulose (CMC), carboxymethylcellulose and Hypromellose (HPMC).
3.) The formulation as claimed in claim 1, wherein said at least one polymer is a water-soluble polymer;
wherein said at least one water-soluble polymer is selected from the group consisting of polyvinylpyrrolidone, Hypromellose (HPMC), Hydroxypropyl cellulose (HPC), Starch, Modified starch and Cellulosic polymer.
4.) The formulation as claimed in claim 1, wherein said at least one plasticizer is selected from the group consisting of polyethylene glycol (PEG), glycerine, Triethyl citrate (TEC), Polysobads, Sodium laureth sulfate (SLS) and Polyvinylpyrrolidone (PVP).
5.) The formulation as claimed in claim 1, wherein said at least one solvent is selected from the group consisting of water, alcohol, organic solvent and a combination thereof;
wherein said at least one solvent is selected from the group consisting of hydroalcoholic solvent, organic solvent, polar solvent, non-polar solvent and aqueous solvent.
6.) The formulation as claimed in claim 1, wherein said at least one pharmaceutically acceptable excipient is selected from the group consisting of at least one diluent, at least one disintegrant, at least one binder, at least one lubricant, at least one glidant, at least one filler, at least one vitamin, at least one mineral, at least one phytochemical, at least one antioxidant and combinations thereof.
7.) The formulation as claimed in claim 6, wherein said at least one diluent is selected from the group consisting of lactose, microcrystalline cellulose (mcc), calcium carbonate, sugar and alcohols such as sorbitol, xylitol and mannitol.
8.) The formulation as claimed in claim 6, wherein said at least one disintegrant is selected from the group consisting of hydroxypropyl methylcellulose, cross-linked carboxymethyl cellulose (croscarmellose), sodium starch glycolate, polyvinyl pyrrolidone and sago starch.
9.) The formulation as claimed in claim 6, wherein said binder is selected from the group consisting of cellulose, gelatin, cellulose derivatives, polyvinyl pyrrolidone, starch, sucrose, mannitol, polyethylene glycol and liquid glucose.
10.) The formulation as claimed in claim 6, wherein said at least one lubricant and glidant are selected from the group consisting of talc, silica and fats;
wherein said fats are selected from the group of vegetable stearin, magnesium stearate and stearic acid.
11.) The formulation as claimed in claim 6, wherein said at least one filler is selected from the group consisting of magnesium stearate, stearic acid, microcrystalline cellulose powder, carrageenan, sodium carboxymethyl cellulose (CMC), carboxymethylcellulose and hydroxypropyl methylcellulose (HPMC).
12.) The formulation as claimed in claim 6, wherein said at least one vitamin is selected from the group consisting of Vitamin K, Vitamin E, and Vitamin A.
13.) The formulation as claimed in claim 6, wherein said at least one mineral is selected from the group consisting of zinc, magnesium and ferrous.
14.) The formulation as claimed in claim 6, wherein said at least one phytochemical is selected from the group consisting of flavonoids, phenolic acids, isoflavones, curcumin, isothiocyanates, and carotenoids.
15.) The formulation as claimed in claim 6, wherein said at least one antioxidant is selected from the group consisting of vitamin C, vitamin E, selenium, and carotenoids such as beta-carotene, lycopene, lutein, and zeaxanthin.
16.) The formulation as claimed in claim 1, wherein said formulation is prepared in the dosage forms selected from the group of a semi-solid mass, a pellet and tablet, wherein the dosage form is selected from the group of immediate release, sustained release, and delayed release