Claims:CLAIMS
We claim,
1. A vegetarian capsule formulation of butterbur extract comprising butterbur extract, riboflavin, feverfew and magnesium citrate and one or more inactive ingredient.

2. The vegetarian capsule formulation of butterbur extract as claimed in claim 1, wherein butterbur extract is present in the range from 30 mg to 60 mg, more preferably is in the range from 40 mg to 60 mg.

3. The vegetarian capsule formulation of butterbur extract as claimed in claim 1, comprising 10 to 500 mg of riboflavin, 60 to 200 mg of feverfew and 10 to 500 mg of magnesium citrate.

4. The vegetarian capsule formulation of butterbur extract as claimed in claim 1, wherein inactive ingredient is selected from filler, binding agent, lubricant, anti-adherent, glidant and preservatives.

5. The vegetarian capsule formulation of butterbur extract as claimed in claim 1, wherein capsule shell is of HPMC or carrageenan.

6. The vegetarian capsule formulation of butterbur extract as claimed in claim 1, wherein the formulation is prepared by sifting, mixing, milling and blending process.

7. A vegetarian capsule formulation of butterbur extract comprising 40 to 60 mg of butterbur extract , 50 to 150 mg of riboflavin, 60 to 80 mg of feverfew, and 100 to 200 mg of magnesium citrate and one or more inactive ingredients.

8. The vegetarian capsule formulation of butterbur extract as claimed in any preceding claims, wherein the formulation is used for the prophylactic and treatment of migraine, including reduction in the mean number and severity of migraine attacks, correcting the magnesium deficiency and low brain magnesium levels, corrects the depleted mitochondrial energy reserves between migraine attacks and influences inflammatory cascades associated with migraine.
, Description:
FORM 2
THE PATENTS ACT, 1970
(39 OF 1970)
&
The Patents Rules, 2003
COMPLETE SPECIFICATION
(See section 10; rule 13)

1. Title of the invention – A VEGETARIAN CAPSULE FORMULATION OF BUTTERBUR EXTRACT
2. Applicant(s)
NAME: TRION PHARMA INDIA LLP
NATIONALITY: INDIAN
ADDRESS: B/19 FIRST FLOOR, BARCELLONA MULTIPLE BUSINESS, SP RING ROAD CIRCLE, ODHAV, AHMEDABAD 382415 GUJARAT
3. Preamble to the description
The following specification particularly describes the invention and the manner in which it is to be performed.

A VEGETARIAN CAPSULE FORMULATION OF BUTTERBUR EXTRACT

FIELD OF THE INVENTION
The present invention provides a vegetarian capsule formulation. The present invention in particular provides a vegetarian capsule formulation comprising butterbur extract, one or more ingredient filled in vegetarian capsule. The present invention also provides the process for preparing a vegetarian capsule formulation.

BACKGROUND OF THE INVENTION
Petasites hybridus (butterbur) leaves have been used in the traditional Austrian and Czech medicine internally (as tea or cold maceration in ethanol) and externally (as compresses or maceration in vinegar) for treatment of infections, fever, flu, colds, hay-fever, and allergies. Currently, butterbur extracts are used for migraine prevention, as well as alleviate allergic rhinitis.

WO2017213306A1 describes composition for memory improvement comprising Petasites japonicus leaf extract. Most importantly, it relates to a method for producing Petasites japonicus leaf extract effective for memory improvement, and to a composition for memory improvement comprising the Petasites japonicus leaf extract. The Petasites japonicus leaf extract obtained by the production method of the patent application has an effect on nerve cell protection and regeneration.

US8197871BS discloses a nutritional composition for treating severe headaches and comprising a plurality of vitamins and a plurality of minerals that together represent at least a portion of required daily allowance thereof. The plurality of vitamins include at least vitamins A, C, D, E, K, B1, B2, B6, and B12, niacin, folic acid, biotin, pantothenic acid, and mixtures thereof, while the plurality of minerals include at least selenium, zinc, magnesium, calcium, iron, manganese, copper, chromium, cobalt, phosphorous, iodine, potassium and molybdenum. The composition further includes at least one or both of 125-175 mg of co-enzyme Q-10 and 25-150 mg of purified Butterbur root extract.

However there is still a need for the development to have an effective formulation of nutraceutical ingredients mainly of Butterbur extract with other nutraceutical ingredient like riboflavin, feverfew and magnesium in vegetarian capsule form to provide synergistic effect.

Inventors of present invention have surprisingly developed and found that formulation of butterbur extract with other nutraceutical ingredient like riboflavin, feverfew and magnesium can be formulated with specific formulation, concertation and process as described herein.

OBJECTIVE OF THE INVENTION
The main objective of the invention is to provide a stable vegetarian capsule formulation butterbur extract.

The other objective of the invention is to provide a vegetarian capsule formulation of butterbur extract which is having good bioavailability.

Yet another objective of the invention is to provide a vegetarian capsule formulation of butterbur extract which is easy to manufacture.

Yet another objective of the invention is to provide a vegetarian capsule formulation of butterbur extract which is showing synergistic effect.

SUMMARY OF THE INVENTION
The present invention is related to a vegetarian capsule formulation.

The main aspect of the invention is to provide a vegetarian capsule formulation of butterbur extract comprising butterbur extract, one or more nutraceutical ingredient selected from the group consisting of Riboflavin, Feverfew and magnesium citrate and one or more inactive ingredient.

Another aspect of the invention is to provide the process for preparing vegetarian capsule formulation of butterbur extract.

Yet another aspect of the present invention is to provide a vegetarian capsule formulation of butterbur extract with less disintegration time of 13 mins and 28 secs.

DESCRIPTION OF THE INVENTION
Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which the invention belongs. Although any methods and materials similar or equivalent to those described herein can be used in the practice or testing of the present invention, the preferred methods and materials are now described.

As used herein, the term "formulation" or “composition” unless otherwise defined refers to capsule formulation.

As used herein, whether in a transitional phrase or in the body of a claim, the terms “comprise(s)” and “comprising” are to be interpreted as having an open-ended meaning. That is, the terms are to be interpreted synonymously with the phrases “having at least” or “including at least”. When used in the context of a process, the term “comprising” means that the process includes at least the recited steps, but may include additional steps. When used in the context of a composition, the term “comprising” means that the composition includes at least the recited features or components, but may also include additional features or components.

As used herein, the singular forms “a,” “an” and “the” specifically also encompass the plural forms of the terms to which they refer, unless the content clearly dictates otherwise.

The term “about” is used herein to means approximately, in the region of, roughly, or around. When the term “about” is used in conjunction with a numerical range, it modifies that range by extending the boundaries above and below the numerical values set forth. In general, the term “about” or “approximately” is used herein to modify a numerical value above and below the stated value by a variance of 20%.

As used herein the term “Nutraceutical” is defined as any substance that is a food or part of a food and provides medical or health benefits, including the prevention and treatment of disease (DeFelice, 1994).

As used herein the term “vegetarian capsule” means the capsule shell made up of non-animal origin.

The present invention is described about the vegetarian capsule formulation of butterbur extract.

As per one main embodiment of the present invention, it provides a vegetarian capsule formulation comprising butterbur extract, one or more nutraceutical ingredient selected from the group consisting of butterbur, magnesium citrate, riboflavin and Feverfew and one or more inactive ingredient.

Butterbur (Petasites hybridus)
Petasites hybridus, the butterbur, is an herbaceous perennial flowering plant in the daisy family Asteraceae, native to Europe and northern Asia. Preliminary trials have shown a preparation of butterbur root to be possibly effective in reducing the frequency and severity of migraine attacks.

Petasites hybridus contains the sesquiterpene esters petasin, isopetasin, and neopetasin, which are believed to help alleviate migraine symptoms. Petasin may inhibit inflammatory functions through regulation of phospholipase Cß. Petasin has also been shown to block eosinophil cationic protein, an important step in the adaptive immune response system. Isopetasin operates by blocking intracellular signaling molecules in pathways involving Arachidonate 5-lipoxygenase in turn leading to the reduction of leukotriene synthesis.

Petasin's structure

The anti-allergic effects of butterbur are believed to come from Bakkenolide B a terpenoids found in the leaves of the plant. Bakkenolide was shown to have efficacy in mast cell degranulation and inhibiting gene inductions of inducible nitric oxide synthase and cyclooxygenase.

As per one embodiment of the present invention, the butterbur extract is in the range from 10-200 mg, preferably 10-150 mg, more preferably 20 -100 mg, more preferably 20-80 mg, more preferably 30-60 mg and most preferably 40-60 mg.

Riboflavin

Riboflavin’s structure

Riboflavin, also known as vitamin B2, is a vitamin found in food and consumed as a dietary supplement. It is essential to the formation of two major coenzymes, flavin mononucleotide and flavin adenine dinucleotide. These coenzymes are involved in energy metabolism, cellular respiration, antibody production and normal growth and development. The coenzymes are also involved in the metabolism of other vitamins – niacin, vitamin B6, and folate. Riboflavin is used medicinally as a prescription drug to treat corneal thinning and may reduce the incidence of migraine headaches in adults.

In its 2012 guidelines, the American Academy of Neurology included high-dose riboflavin (400 mg) as "probably effective and should be considered for migraine prevention," a recommendation also provided by the UK National Migraine Centre. A 2017 review reported that daily riboflavin taken at 400 mg per day for at least three months may reduce the frequency of migraine headaches in adults. Research on high-dose riboflavin for migraine prevention or treatment in children and adolescents is inconclusive, and not recommended.

As per one embodiment of the present invention, the riboflavin is in the range of 10-500 mg, preferably 10- 400 mg, more preferably 50-300 mg, more preferably 50-200 mg and most preferably 50-150 mg.

Feverfew (Tanacetum parthenium L.)
Feverfew (Tanacetum parthenium L.) (Asteraceae) is a medicinal plant traditionally used for the treatment of fevers, migraine headaches, rheumatoid arthritis, stomach aches, toothaches, insect bites, infertility, and problems with menstruation and labor during childbirth. Feverfew has also been used for psoriasis, allergies, asthma, tinnitus, dizziness, nausea, and vomiting. Feverfew action does not appear to be limited to a single mechanism. Plant extracts affect a wide variety of physiologic pathways. Some of these mechanisms have been discussed previously, including inhibition of prostaglandin synthesis, decrease of vascular smooth muscle spasm, and blockage of platelet granule secretion. The plant contains a large number of natural products, but the active principles probably include one or more of the sesquiterpene lactones known to be present, including parthenolide. Other potentially active constituents include flavonoid glycosides and pinenes.

The most important biologically active principles are the sesquiterpene lactones, the principal one being parthenolide. Parthenolide is found in the superficial leaf glands (0.2%–0.5%), but not in the stems, and comprises up to 85% of the total sesquiterpene content.

As per one embodiment of the present invention, the feverfew is in the range of 10-200 mg, preferably 10- 150 mg, more preferably 50-150 mg, more preferably 50-100 mg and most preferably 60-80 mg.

Magnesium citrate

Magnesium citrate’s structure

Magnesium citrate is a laxative used in bowel preparation for colonoscopy or as a magnesium supplement with migraine as associated condition. It is a low volume and osmotic cathartic agent. The cathartic action works primarily through the high osmolarity of the solution which draws large amounts of fluid into space where is used. Magnesium citrate is considered by the FDA as an approved inactive ingredient for approved drug products under the specifications of oral administration of a maximum concentration of 237 mg. It is also considered as an active ingredient in over-the-counter products.

As per one embodiment of the present invention, the magnesium citrate is in the range of 10-500 mg, preferably 10- 400 mg, more preferably 50-300 mg, more preferably 80-200 mg and most preferably 100-200 mg.

As per one embodiment, the present formulation also require one or more inactive ingredients which can be selected from filler, binding agent, lubricant, anti-adherent, glidant and preservatives.

Filler
They are also known as diluents or carriers; fillers are mainly used as bulking agents, to add substance so that the size of a capsule or tablet is filled to the correct proportions. This helps make very small active ingredients easier for consumption. Fillers are added to pharmaceuticals to help with the manufacturing and stabilization of these products. Fillers bind and stabilize a supplement. They do not alter or impact the effectiveness of the active pharmaceutical ingredient (API).

Filler is selected form but not limited to lactose, sucrose, magnesium stearate, starch, glucose, plant cellulose, calcium carbonate, microcrystalline cellulose, carrageenan, resins, citric acid and cellulose.

As per one embodiment of the present invention, filler is starch used in the range of 1 to 200 mg, preferably 10 to 150 mg, preferably 20 to 130 mg, more preferably 30 to 120 mg, more preferably 50 to 120 mg and most preferably 100 to 120 mg.

Binding agent
Binding agent impart cohesive properties to the powdered material. Examples of binders suitable for use in the present invention include: starch (e.g., paste, pregelatinized, mucilage), gelatin, sugars (e.g., sucrose, glucose, dextrose, molasses, lactose, dextrin, xylitol, sorbitol), polymethacrylates, natural and synthetic gums (e.g., acacia, alginic acids and salts thereof such as sodium alginate, gum tragacanth, Irish moss extract, panwar gum, ghatti gum, guar gum, zein), cellulose derivatives [such as carboxymethyl cellulose and salts thereof, methyl cellulose (MC), hydroxypropyl methyl cellulose (HPMC), hydroxypropyl cellulose (HPC), hydroxy ethyl cellulose (HEC) and ethyl cellulose (EC)], polyvinylpyrrolidone (PVP), Veegum, larch arabogalactan, polyethylene glycol, waxes, water, alcohol, magnesium aluminum silicate, and bentonites.

As per one embodiment of the present invention, the binding agents are gelatin and polyvinylpyrrolidone used both in the range of 1 to 20 mg, preferably 1 to 16 mg, preferably 2 to 18 mg, more preferably 2 to 15 mg, more preferably 3 to 10 mg and most preferably 3 to 8 mg.

Lubricant
Lubricants are generally used to enhance processing, for example, to prevent adhesion of the formulation material to manufacturing equipment, reduce interparticle friction, improve rate of flow of the formulation, and/or assist ejection of the formulations from the manufacturing equipment.

Examples of lubricants suitable for use in the present invention include: talc, stearates (e.g., magnesium stearate, calcium stearate, zinc stearate, palmitostearate), stearic acid, hydrogenated vegetable oils, glyceryl behanate, polyethylene glycol, ethylene oxide polymers, liquid paraffin, sodium lauryl sulfate, magnesium lauryl sulfate, sodium oleate, sodium stearyl fumarate, DL-leucine, and silica derivatives (e.g., colloidal silicon dioxide, colloidal silica, pyrogenic silica, and hydrated sodium silicoaluminate).

Anti-adherent
Anti-adherents functions to prevent tablet granulations from sticking to the faces of the punches and the die walls, but most importantly, prevent adherence of tablet granules from adhering to one another, a phenomenon known a-s blocking. Anti-adherents may be added to the tablet composition while the composition is in the hopper, or subsequent to grinding.

The anti-adherent is selected from the group consisting of silicates, silicon dioxide, talc, alkali metal phosphates and mixtures thereof.

As per one embodiment of the present invention, anti-adherent is colloidal silicon dioxide used in the range of 1 to 10 mg, preferably 1 to 6 mg, preferably 1 to 8 mg, more preferably 1 to 5 mg, more preferably 1 to 3 mg and most preferably 1 to 2 mg.

Glidant
Glidant for the present invention include, but are not limited to, colloidal silica, magnesium trisilicate, starches, talc, tribasic calcium phosphate, magnesium stearate, aluminum stearate, calcium stearate, magnesium carbonate, magnesium oxide, polyethylene glycol, powdered cellulose and microcrystalline cellulose.

As per one embodiment of the present invention, glidant is talc used in the range of 1 to 20 mg, preferably 1 to 16 mg, preferably 2 to 18 mg, more preferably 2 to 15 mg, more preferably 3 to 10 mg and most preferably 3 to 5 mg.

Preservatives
Preservatives are substances (natural or chemical) that are added to pharmaceutical products to prevent any kind of physical, chemical or biological changes. The preservatives are selected from and not limited to methyl paraben, ethyl paraben, propyl paraben, butyl paraben, benzyl paraben, chlorobutanol, phenol, Meta cresol, chloro cresol, benzoic acid, Sorbic acid, thiomersal, phenylmercuric nitrate, bronopol, propylene glycol, benzylkonium chloride and benzethonium chloride.

As per one embodiment of the present invention, the preservative are sodium methyl paraben and sodium propyl paraben used both in the range of 0.1 to 10 mg, preferably 0.1 to 6 mg, preferably 0.1 to 8 mg, more preferably 0.1 to 5 mg, more preferably 0.1 to 0.9 mg and most preferably 0.1 to 0.7 mg.
Capsule shell
The vegetarian capsule shells are mostly prepared from HPMC or Carrageenan.

HPMC capsules are types of drugs with Hydroxypropyl Methylcellulose as the main ingredient for the capsule body and cap. It is a safe drug for human consumption and a good alternative for gelatin capsules because of the vegetable source.

Hydroxypropyl Methylcellulose is an ingredient which you can also identify as hypromellose. It is a soluble methylcellulose ether that you can easily extract by chemically manufacturing polymer cellulose. Cellulose is the most significant constituent and polysaccharide of all the plant structures. Hydroxypropyl Methylcellulose has a better appearance and comes from a vegetable source thus making it a perfect alternative for gelatin. HPMC can be used as a binder, thickening agent, hydrophilic matrix material, and a film former. Apart from that, it can also be used for controlling the release of hydrophobic and hydrophilic drugs. Such properties make it a very good ingredient for making capsules.

Carrageenan is used as a gelling agent in products, such as frozen foods, jellies and yogurt. Commercially, carrageenan has been produced in six different types based on their structures. Among the six polymers, ?-carrageenan is the most produced due to its high gelling ability caused by the C4 conformation on the 3,6-anhydro-D-galactopyranosyl that forms a helix-like structure. The formation of the helix structure is supported by the enormous number of –OH groups that form many hydrogen bonds.

As per one preferred embodiment, the formulation of present invention is prepared by mixing, milling and blending process.

Sifting
Vibratory sifter is used in Sifting of materials in Pharmaceutical manufacturing with different mesh of Sieves and it is widely used equipment in pharmaceuticals and in food industries. Sifting is done to remove lumps or growth that might have formed on the materials after being stored for a longer period and materials are passed through a mesh that opens, which leads to fine the materials. It also removes the unrequired foreign particles and separate the materials according to size. Types of Vibratory Sifter:
1. One layer, Vibro sifter.
2. Double layer Vibro sifter, which has two layers.
3. Triple-layer Vibro sifter that has three layers.
4. Industrial Vibro sifter which is commonly used in food processing industries.
5. L-shaped sieve frame Vibro sifter.

Different parts of Vibratory Sifter:
1. Hopper Lid
2. Filter Screen
3. Wire Mesh Screen Ring
4. Oversize Material Outlet
5. Screen Material Outlet
6. Springs
7. Control Panel
8. Motor

Wet mixing (wet granulation)
Granulation is a unit operation in which small powder particles are gathered together to form agglomerates called granules. To achieve cohesion between the powders, it is necessary to include adhesive substances called binders or granulating agents within the formulation. It is a common practice to make use of a granulation solution since it is more effective in comparison with the same quantum of the dry powder binder. Powder mixing, in conjunction with the cohesive properties of the binder, enables the formation of granules which when duly compressed using tablet press forms tablets with the desired properties.

There are several reasons for converting powders or blends of powders into granules and they include:-
1. To enhance the flow properties of powder mix.
2. To prevent segregation of powder components during tableting or storage.
3. To reduce the incidence of dust production.
4. To reduce cross-contamination and hazard associated with the generation of toxic dust that may arise during manufacturing processes.
5. To improve the compression characteristics of drug substances.
6. To improve the appearance of the final product.

Dry mixing (dry granulation)
Dry granulation also referred to as precompression or double compression is a size enlargement process designed to improve the flow and compression characteristics of powders that would otherwise be unsuitable for compression. The process involves compaction of powder particles into large pieces or compacts which are subsequently broken down into granules to produce granules that can be further processed into dosage forms.

Dry granulation is typically used in the manufacture of tablets if the formulation ingredients are too fluffy or too susceptible to flowability problems for direct compression to be a viable processing option and/or too susceptible to degradation from heat and/or moisture for wet granulation to be a viable processing option for densification. The process is sometimes chosen as an alternative to wet granulation when direct compression is not feasible not because wet granulation is not feasible but because the manufacturer is more experienced with dry granulation or to reduce processing time and/or equipment requirements to reduce costs.

Method of dry granulation:-
1. Slugging technique
2. Roller compaction

Milling
Milling involves the application of mechanical energy to physically break down coarse particles to finer ones and is regarded as a “top–down” approach in the production of fine particles. Fine drug particulates are especially desired in formulations designed for parenteral, respiratory and transdermal use. Most drugs after crystallization may have to be comminuted and this physical transformation is required to various extents, often to enhance processability or solubility especially for drugs with limited aqueous solubility.

The mechanisms by which milling enhances drug dissolution and solubility include alterations in the size, specific surface area and shape of the drug particles as well as milling-induced amorphization and/or structural disordering of the drug crystal (mechanochemical activation). Technology advancements in milling now enable the production of drug micro- and nano-particles on a commercial scale with relative ease. This review will provide a background on milling followed by the introduction of common milling techniques employed for the micronization and nanonization of drugs. Salient information contained in the cited examples are further extracted and summarized for ease of reference by researchers keen on employing these techniques for drug solubility and bioavailability enhancement.

Blending/ lubrication
Blending is a critical unit operation in pharmaceutical manufacturing, as it is a prerequisite for the homogenous distribution of a drug’s components. Clearly, the content of the active pharmaceutical ingredients (API) in the final solid dosage form is particularly important. Tablets out of specifications lead to expensive rework or even recalls, and even more important, dosage forms not compliant with the therapeutic window may cause harm to patients. Another crucial feature affected by powder homogeneity is downstream processability (i.e., compaction of tablets may lead to problems, if certain components are distributed unevenly, e.g., during lubrication with magnesium stearate.

As per one embodiment, the process comprising is mixing process and more preferably the dry mixing and wet mixing in two different portion followed by mixing it with each other.

As per one embodiment, the vegetarian capsule of present invention is used for the prophylactic and treatment of migraine, including reduction in the mean number and severity of migraine attacks, correcting the magnesium deficiency and low brain magnesium levels, corrects the depleted mitochondrial energy reserves between migraine attacks and influences inflammatory cascades associated with migraine.

The examples are presented to illustrate the invention, parts and percentages being used by weight, unless and otherwise indicated.

EXAMPLE 1: FORMULATION

Ingredients Quantity (mg/Capsule)
Magnesium citrate 150 mg
Riboflavin 100 mg
Feverfew 75 mg
PA free butterbur root extract
(Petasites hybridus 12% extract) 50 mg
Starch 118 mg
Sodium methyl paraben 0.6 mg
Sodium propyl paraben 0.15 mg
Purified talc 3 mg
Colloidal silicon dioxide 1.2 mg
Polyvinylpyrrolidone K - 30 7.2 mg
Gelatin 0.6 mg
Magnesium stearate 150 mg
Vegetarian capsule shell 0.59 mg (± 5%)
Table 1: composition of the vegetarian capsule
The whole procedure is performed in a controlled temperature environment of 10-25? with relative humidity of NMT 30%

Procedure:
The procedure is divided into following stages:
1.1 Sifting
a) The sieve integrity was checked;
b) All the ingredients were shifted to obtain uniform texture for further processessing.

1.2 Mixing
1.2.1 Dry mixing:
a) Shifted magnesium citrate and starch were transferred into a rapid mixer granulator and were mixed for 5 min until dry mix blend was obtained.

1.2.2 Binder preparation
a) Purified water was boiled in paste kettle;
b) Gelatin and polyvinylpyrrolidone K – 30, methyl paraben sodium, propyl paraben sodium were added into step (a) and stirred continuously until clear binder solution is obtained.

1.2.3 Wet Mixing
a) Binder solution was added over the dry mix blend both obtained from 1.2.1 and 1.2.2;
b) Impeller was run at medium speed and chopper off with paste added continuously over it for 2-3 mins;
c) Granule consistency was checked from step (b) and extra purified water was added if required and noted down;
d) Impeller and chopper was run at medium speed for granule preparation of step (c) for 1-2 mins. Material was raked;
e) Impeller and chopper was run at high speed for 2-3 mins for consistent granules;
f) Wet granules from step (e) were unloaded by the discharge valve in FBD bowl.

1.3 Drying
a) Sieve integrity of FBD bowl was checked before use;
b) Granulated mass obtained from 1.2.3 was unloaded into the FBD bowls and air dried for 10 mins;
c) Material from step (b) was raked and the process of drying was repeated with the inlet temperature at 65-70? and outlet temperature upto 40-50? or until LOD of granules limit NMT 1-3% at 105?.

1.4 Sifting and Milling
a) Sieve integrity was checked before use;
b) The dried material obtained from 1.3 was sifted through 16# sieve and milled the retention using 2.0 mm screen;
c) The size of the granules and appearance was checked from step (b) and the granules were collected in poly-bags in container;
d) The observations from step (c) were recorded of sizing in respective annexure, weight and recorded each container.

1.5 Blending/ Lubrication
a) All material’s weight were counter checked and recorded before processing.
b) Riboflavin, feverfew, butter root extract, purified talc and colloidal silicon dioxide were added along with the dried granules obtained from 1.4 into the blender bin and blended for 13 mins;
c) Magnesium stearate was blended into step (b) for 5 mins;
d) The lubricated blend from step (c) was transferred in double polybag lined HDPE drum/ bin, status and under test label were affixed as per required SOP and transferred to granules quarantine area, weighed and recorded the details;
e) Sampling of lubricated granules was performed as per required SOP.

EXAMPLE 2: CAPSULE FILLING
Capsule filling machine used: SA-9
Capsule filling machine Capsule filling data
Capsule Size: Theoretical average fill weight: 500.0 mg

Actual weight of 20 capsule: 11.960 gm ± 5%

Individual Capsule weight variation limit: ± 5%
Capsule size: “0” Locking length of filled capsule 21.00 mm
(limit: 20.50 to 21.50 mm)
Table 2: Analysis of capsules

EXAMPLE 3: INPROCESS TEST PARAMETERS:
In-process quality control Limits
Weight of 20 filled capsules 11.9600 gm ± 5%
Average weight 598 mg
Individual weight variation 598
Locking length of filled capsule 21.00 mm
(Limit: 20.50 to 21.50 mm)
Disintegration time NMT 30.0 mins
Table 3: In-process test parameters

EXAMPLE 4: POLISH & VISUAL INSPECTION
a) The capsules were inspected and polished;
b) The capsules from step (a) were stored in double polythene fine drums in quarantine room;
c) The rejected capsule material from step (a) that cannot be recovered were destroyed at the earliest;
d) The approved capsules form the step (a) were allowed for ALU ALU packaging.

EXAMPLE 5: PACKAGING
Sr. No. Name of packaging Material Std. Qty. Unit
1. Printed foil 10.000 Kg
2. Base foil 40.000 Kg
3. Printed carton 1000.0 No
4. Corrugated printed shipper 10.0 No
5. BOPP tape 1.00 No
6. Cello tape 1/2" IH 2.00 No
Table 4: Packaging material used for ALU ALU packaging

Packing Procedure:
a) 10.0 strip of 10.0 capsule was packed in a master carton in shipper box;
b) The box from step (a) was sealed with 4” BOPP tape in H-type;
c) The packing operations were completed and the yield was reconcilliated;
d) The package from step (c) was transferred to finished goods store after QA release.

EXAMPLE 6: ANALYTICAL DATA
Sr. No. Test Specification Results
1. Average fill weight 530.00 mg ± 7.5%
(490.25 mg to 569.75 mg) 526.52 mg
2. Uniformity of weight As per IP, two capsules may deviate by ± 7.5% of avg. wt. but none capsule should not deviate twice that percentage i.e. ± 15% Complies
3. Disintegration Time Not more than 30 mins. 13 mins and 28 secs
4. Estimation of:-

Magnesium citrate
Riboflavin
Feverfew
PA free butterbur root extract Each vegetable cellulose purports to contain:-

150 mg [90.0-110.0%]
100 mg [90.0-110.0%]
75 mg [NLT-90.0%]

50 mg [NLT-90.0%] Each vegetable cellulose of average net content is found to contain:-

149.28 mg [99.52%]
99.20 mg [99.20%]
75.15 mg [100.20%]

52.18 mg [104.36%]
Table 5: Analysis of the prepared capsule