FORM 2
THE PATENT ACT 1970
(39 of 1970)
&
The Patents Rules, 2003
COMPLETE SPECIFICATION
(See section 10 and rule l3)
1. TITLE OF THE INVENTION:
TASTE MASKED CHEWABLE COMPOSITIONS OF SILDENAFIL CITRATE
2. APPLICANT (S):
(a) NAME: AJANTA PHARMA LIMITED.
(b) NATIONALITY: INDIAN
(c) ADDRESS: Ajanta House, Charkop, Kandivali (West), Mumbai - 400 067.
The following specification particularly describes the invention and the manner in
which it is to be performed.


FIELD OF THE INVETION
The present invention provides novel chewable immediate release compositions comprising sildenafil citrate wherein the bitter taste of sildenafil has been masked by forming a sildenafil mask complex The masking agent comprises of a mixture of polyacrylic resin, carbomer and powdered microcrystalline cellulose. The sildenafil gets entrapped in the polyacrylic resin which has free exchange sites and a cationic exchange occurs. The carbomer serves as a binder to strengthen the complex formation whereas the powdered microcrystalline cellulose is a filler. The said composition further comprises other excipients like mannitol which serves as the base for a chewable tablet, disintegrants, binders, lubricants, glidants and flavours.
BACKGROUND AND PRIOR ART
Sildenafil citrate is a selective inhibitor of cyclic guanosine monophosphate (cGMP)-specific phosphodiesterase type 5 (PDE5), commercially developed by Pfizer, Inc. as VIAGRAR. Sildenafil citrate is designated chemically as l-[[3-(6,7-dihydro-l-methyl-7-oxo-3-propyl-l//-pyrazolo[4,3-c/]pyrimidin-5-yl)-4-ethoxyphenyl]sulfonyl]-4-methyl piperazine citrate, having a molecular weight of 666.7, and the following chemical structure:


Sildenafil citrate is a white to off-white crystalline powder with a solubility of 3.5 mg/ml in water. The physiologic mechanism of erection of the penis involves release of nitric oxide (NO) in the corpus cavernosum during sexual stimulation. NO then activates the enzyme guanylate cyclase, which results in increased levels of cyclic guanosine monophosphate (cGMP), producing smooth muscle relaxation in the corpus cavernosum and allowing the inflow of blood. Sildenafil has no direct relaxant effect on isolated human corpus cavernosum, but enhances the effect of nitric oxide by inhibiting phosphodiesterase type 5, which is responsible for degradation of cGMP in the corpus cavernosum. When sexual stimulation causes local release of NO, inhibition of PDES by sildenafil causes increased levels of cGMP in the corpus cavernosum, resulting in smooth muscle relaxation and inflow of blood to the corpus cavernosum. Sildenafil at recommended doses has no effect in the absence of sexual stimulation.
However sildenafil citrate has a very bitter taste and hence tablets such as ViagraR, which are commercially available are film coated. The film coating masks any bitter taste in the mouth and these tablets have to be taken with water. However in case of chewable tablets which are usually uncoated, there is a need to mask the bitter taste of sildenafil as they are chewed and remain in contact with the taste receptors in the mouth for a longer period of time. Several formulations relating to various processes used for taste masking of ingredients are known priori art. There are also reports relating to taste masking of sildenafil by coating them with polymers. For example, formulations relating to processes for taste masking of various drugs and some specifically related to bitter drugs have been reported. Examples of patents describing such formulations are as follows.


US Patent No. 6,197,348 describes a dosage form that utilizes encapsulated particles coated with polymers, such as Eudragit RS and Eudragit RL. Taste masking is achieved as a result of the polymer coatings and a liquid suspending medium having a pH that is adjusted to a point where the active ingredient is insoluble. However, the thickness and type of coating is not sufficient for taste masking.
EP 0458751 discloses compositions containing a core that includes a cyclic amino acid compound. The core is coated with polymeric film forming compounds and hydrophilic fats' fatty acids and waxes.
US Patent No. 4,800,087 discloses a taste masked composition in a chewable dosage form having a controlled release profile. The invention utilizes a combination of polymers to achieve a taste masking coating suitable for incorporation into a chewable dosage form. The composition contains microcapsules which are composed of an active ingredient and a polymer mixture coating having a sufficient elasticity to withstand chewing. The polymeric coating mixture includes one high temperature film forming copolymer and one low temperature film forming copolymer.
US Patent No. 6,139,865 discloses a taste masked microcapsule composition of water soluble active ingredients. The water soluble active ingredients are coacervated in the polymeric material. This technique suffers from several disadvantages. For example, the technique requires the use of hydrocarbons and other organic solvents, such as; cyclohexane. These solvents are explosive and present problems in large scale manufacturing.


US Application 2002/064563 discloses a taste masked composition of topiramate and a process for its preparation. The process includes preparing core particles which include the active ingredient topiramate, coating with a taste masked mixture to form coated particles, and drying the coated particles.
US Patent No. 6,106,861 discloses a multiparticulate disintegrating tablet which includes excipients and an active ingredient in the form of microcrystals. Only a limited number of active ingredients can be commercially made in the form of microcrystals, and specifically, amorphous powders cannot be utilized in this process.
WO 01/35930 discloses a process for taste masking by granulation of the active ingredient with an aqueous admixture that includes a neutral methacrylic acid ester copolymers and a binder. Taste masking can only be achieved for moderately bitter and poorly soluble active ingredients, but is ineffective for highly bitter and/or soluble active ingredients.
US Patent No. 5,084,278 describes a chewable taste masked pharmaceutical composition having a controlled release profile. The composition comprises microcapsules with are made up of an active ingredient core coated with a polymer mixture. The coating includes a blend of ethyl cellulose and polymethacrylic acid ester copolymers.
US Patent No. 6,136,347 describes a pharmaceutical composition which comprises microcapsules wherein the active ingredient is microencapsulated within the microcapsule wall. The active ingredient is present as an anhydrate or its free base fond. The composition further utilizes an oily suspension as a vehicle for suspending


microparticles coated with a combination of water soluble and water insoluble polymers' thus preventing the interaction of water. However, this dosage form suffers from the disadvantage of poor acceptability due to a sand/oily feel in the mouth. Additionally, it needs a vehicle for reconstitution to be supplied along with the microcapsules It is evident that there is a commercial need for a pharmaceutical dosage form that effectively provides taste masking, without alteration of the release profile. The prior art fails to describe a pharmaceutical composition with a taste masking coating that provides for immediate release of the encapsulated active ingredient in solution, without the problems of leaching or swelling when exposed to an aqueous media in suspension at the typical pH of saliva.
US Patent No. 6,221,402 assigned to Pfizer discloses a rapidly releasing and taste masking pharmaceutical dosage form for sildenafil and a process for the preparation of the same. However this product uses an inner and outer coating wherein the inner coating coats the granules of sildenafil citrate and comprises of Eudragit NE30D, the outer coating comprising of two layers one made up of Eudragit El00 and the other being a sugar coating layer.
WO 04/087111 assigned to Ranbaxy discloses oral taste masked pharmaceutical compositions that include a core having an active ingredient coated with a mixture of polymeric film forming binders and inorganic carriers. Also provided are processes for preparing the oral taste masked pharmaceutical composition.
WO 04/022037 assigned to Ranbaxy relates to taste masked dosage forms utilizing low amounts of taste masking polymer, and simple and economical processes for the


preparation of the taste masked dosage forms. The taste-masked dosage form includes one or more drugs and one or more cationic polymers synthesized from dimethylaminoethyl methacrylate and neutral methacrylic acid esters. The wt/wt ratio of the drug to polymer is less than about one to two.
US Application 2006/0159758 relates to coating compositions for taste masking and methods for applying the coating compositions to dosage forms to mask the taste of a medicinal substance. The taste masking coating compositions generally include a copolymer of acrylate and methacrylate with a quaternary ammonium group in combination with sodium carboxymethylcellulose and a polyvinyl alcohol-polyethylene glycol copolymer.
Summary of the Invention
In one general aspect there is provided a taste masked pharmaceutical composition of sildenafil citrate that includes use of a polyacrylic resin where in a cationic exchange occurs. There is a commercially available product by the name InstamaskR [IC-MK-9014 White] and sold by Ideal Cures Pvt. Ltd., India. The ready mix comprises of a polyacrylic resin which is cationic in nature. In addition it comprises carbomer and powdered cellulose. The polyacrylic resin does not belong to the class of methacrylic acid esters. It has free binding sites wherein the sildenafil citrate gets exchanged. Sildenafil Citrate forms a complex with polyacrylic resins by simple anion exchange mechanism resulting in Sildenafil complexing with Polyacrylic resin and in the process releasing sodium citrate in the filtrate. The pure Sildenafil - Resin complex is collected and dried and used in the process.


Embodiments of the composition may include one or more of the following features. For example, the active pharmaceutical ingredient may be one or more of antibiotics, antihistamines, antiarthritics, anti psychotics, tranquillizers, antidiabetics, antipyretics, antiulcerants, antiasthmatics, antihypertensives, antianxiety, nonsteroidal antiinflammatory active ingredients and salts thereof. The active pharmaceutical ingredient may be one or more of clarithromycin, ciprofloxacin, acetaminophen, bambuterol, olanzapine, ranitidine, sildenafil, cefodoxime, amoxycillin, erythromycin, chlorpheniramine, cefuroxime and salts thereof. The active pharmaceutical ingredient may be present in the range of from about 5% w/w to about 90% w/w. The cationic polyacrylic resin comprising the ready mix does not belong to the methacrylate class of polymers and may be present in a concentration ranging from about 10% w/w to about 9070 w/w.
The other excipients include mannitol which forms the base for chewable tablets. The concentration range for mannitol may vary from about 5% w/w to about 15% w/w. The composition may further include one or more pharmaceutically acceptable excipients which includes disintegrants like croscarmellose sodium, pH adjusters like citric acid monohydrate and sodium chloride, fillers like microcrystalline cellulose (Vivapur 102), sweetners like aspartame sucralose and sucrose, flavors like monoammonium glycerrhizinate, glidants and lubricants like magnesium stearate, talc and colloidal silicon dioxide (Aerosil), binders like PVP and colours.
In another general aspect there is provided a process for the preparation of an oral taste masked composition of sildenafil citrate using an ion-exchange mechanism to mask the


bitter taste of the drug. The process includes forming a mask complex of sildenafil citrate by using Instacoat MK 9014 by using an aqueous process to obtains taste masked granules which are suitably sized followed by aqueous granulation of the masked complex with various excipients and then lubrication of the final mass before compression into tablets using suitable tooling.
In another general aspect there is provided a method of treating a condition for which an active pharmaceutical ingredient is prescribed. The method includes administering a taste masked pharmaceutical composition that includes a taste masked chewable tablet formulation.
The details of various embodiments of the inventions are set forth in the accompanying description below. Other features and advantages of the inventions will be apparent from the description and the claims.
The present invention provides obvious benefits being simple and fast operational process for manufacturing said oral solid extended release pharmaceutical composition. While the present invention has been described in terms of its specific embodiments, certain modifications and equivalents will be apparent to those skilled in the art and are intended to be included within the scope of the present invention.
Detailed Description of the Invention:
The present invention provides taste masked chewable tablet compositions for bitter tasting drugs like sildenafil citrate. The said composition comprises the bitter drug sildenafil citrate in the form of a mask complex which is achieved by using a cationic


exchange resin. The drug gets exchanged with the free sites in the polyacrylic cationic resin to form a taste masked complex. This taste masked complex is then incorporated into a formulation. The other excipients used to arrive at the final composition include disintegrants like croscarmellose sodium, pH adjusters like citric acid monohydrate and sodium chloride, fillers like microcrystalline cellulose (Vivapur 102), sweetners like aspartame sucralose and sucrose, flavors like monoammonium glycerrhizinate, glidants and lubricants like magnesium stearate, talc and colloidal silicon dioxide (Aerosil), binders like PVP and colours.
The term "pharmaceutically acceptable derivative" means various pharmaceutical equivalent isomers, enantiomers, complexes, hydrates, polymorphs, and etc. of metoprolol succinate.
The term composition includes but not limited to solutions and/or suspensions, dispersions, concentrates, ready mix, powders, granules, tablets, micro-tablets, capsules, and pellets, comprising metoprolol succinate or pharmaceutically acceptable derivatives thereof.
The term "therapeutically effective amount" means an amount of the drug, which is capable of eliciting a physiological response in a human patient. More specifically, the term "therapeutically effective amount" means the amount of drug, which is capable of treating erectile dysfunction and related disorders.
The medicament according to the present invention comprises a formulation substantially as herein described, and in particular a capsule, a tablet, micro-tablets, granules or pellets


filled in capsule formulation, typically an extended or modified release tablet formulation substantially as hereinafter further described.
Suitably a formulation according to the present invention provides a taste masked chewable dosage form, preferably tablets comprising taste masked sildenafil citrate or pharmaceutically acceptable derivatives thereof along with other pharmaceutically acceptable excipients wherein the taste masking is achieved through an ion-exchange mechanism
A preferred embodiment of the present invention is a chewable tablet formulation comprising a pharmaceutically active agent (sildenafil citrate) along with suitable excipients. In particular, the present invention provides for taste masking the bitter taste of sildenafil citrate by using an ion-exchange mechanism.
The taste masked chewable tablet dosage form of sildenafil citrate according to the present invention may be formulated by mixing the drug with a polyacrylic cationic exchange resin that is commercially available as INSTAMASKR. This ready mix commercially available product comprises of a polyacrylic resin (cationic) ion-exchange resin, carbomer and powdered cellulose. In addition the composition of the present invention may also comprise some drug that is not taste masked and added directly. The other excipients used include disintegrants like croscarmellose sodium, pH adjusters like citric acid monohydrate and sodium chloride, fillers like microcrystalline cellulose (Vivapur 102), sweetners like aspartame sucralose and sucrose, flavors like monoammonium glycerrhizinate, glidants and lubricants like magnesium stearate, talc and colloidal silicon dioxide (Aerosil), binders like PVP and colours.


The present invention further comprises a process of preparing a pharmaceutical product, or a pharmaceutical composition, or a medicament substantially as herein before described.
The total dose of sildenafil citrate is divided into two halves with one half being taste masked. The remaining half dose is added as such directly into the composition. This is done by mixing sildenafil citrate and Instacoat MK 9014 in purified water for 30 minutes, followed by stirring for a period of about 4 hours. The suspension is then centrifuged and dried in a fluidized bed drier. The resulting sildenafil citrate - Instacoat MK 9014 masked complex is sifted through Sieve No. 40. This dried masked complex is then granulated in a Rotary Mixer Granulator along with the remaining 50% sildenafil citrate, mannitol, microcrystalline cellulose, citric acid monohydrate, sodium chloride, aspartame, monoammonium glycerrhizinate, sucralose, sucrose, croscarmellose sodium and colours for a period of 15 minutes. All excipients are passed through Sieve No. 40 before use. The binder solution comprising povidone (PVPK30) in isopropyl alcohol is added to the dry mix and the mass granulated to obtain suitable granules. The granules are dried in a fluidized bed drier and sifted through Sieve No. 20. The granules are then transferred to an octagonal blender and mixed for 2 minutes. The granules are lubricated by addition of croscarmellose sodium, colloidal silicon dioxide, purified talc and flavours are mixed in the octagonal blender for 15 minutes. All excipients added at the lubrication stage are passed through Sieve No. 60. After blending of lubricants is completed for 15 minutes, magnesium stearate passed through Sieve No. 60 is added to the octagonal blender and the resulting mass is further mixed for 5 minutes. The lubricated mass is then compressed into tablets using suitable tooling.

A flow chart depicting the process of manufacture is diagrammatically given below:
FLOW CHART

The present invention will now be illustrated with reference to the following examples, which does not limit the scope of the invention in any way. Further different strengths of the formulation may be achieved by proportionately using a dose weight scale-up or scale-down formula. The concentration of the excipients may also be varied or modified to achieve the desired dissolution profile by a skilled artisan.


Example 1:
Taste masked tablets of sildenafil citrate were prepared using the following excipients in the stated quantities:

Sr. No. Ingredients Quantity per Tab in mg % w/w
1 Sildenafil Citrate * 140.48 23.41
2 Mask IC-MK-9014 (Instacoat) 210.75 35.13
3 Purified Water - -
4 Mannitol 56.17 9.36
5 Croscarmellose sodium 10.00 1.67
6 Citric acid monohydrate 6.00 1.00
7 Sodium chloride 6.00 1.00
8 Aspartame 10.00 1.67
9 Monoammonium Glycerrhizinate 10.00 1.67
10 Sucralose 18.00 3.00
11 Sucrose (Pharma grade) 60.00 10.00
12 Colloidal Silicon Dioxide (Aerosil 200 ) 2.00 0.33
13 Microcrystalline cellulose (Vivapur 102) 20.00 3.33
14 Lake sunset yellow 20.00 3.33
15 P.V.P. K-30 10.00 1.67
16 Isopropyl alcohol ** — -
17 Trusil Orange ASV flavour 0.60 0.10
18 Croscarmellose sodium 10.00 1.67
19 Colloidal Silicon Dioxide (Aerosil 200 ) 1.00 0.17
20 Purified Talc 3.00 0.50
21 Magnesium Stearate 6.00 1.00
Total Weight of tablet 600.00 mg -
*100 mg Sildenafil equivalent to 140.480 mg of Sildenafil Citrate ** Not present in the final product.


Procedure:
Mix a part of sildenafil citrate with Instacoat MK 9014 in purified water to form a sildenafil citrate mask complex. The resultant complex is dried and sized. This complex is then mixed with the remaining 50% sildenafil citrate, mannitol, microcrystalline cellulose, citric acid monohydrate, sodium chloride, aspartame, monoammonium glycerrhizinate, sucralose, sucrose, croscarmellose sodium and colours for a period of 15 minutes. The dry mix is granulated with a binder solution of povidone (PVPK30) in isopropyl alcohol, dried in a fluidized bed drier and sifted. The granules are lubricated by addition of croscarmellose sodium, colloidal silicon dioxide, purified talc and flavours and mixed in the octagonal blender for 15 minutes, followed by addition of magnesium stearate and further mixing for 5 minutes. The lubricated mass is then compressed into tablets using suitable tooling.


Example 2:
Taste masked tablets of sildenafil citrate were prepared using the following excipients in
the stated quantities:

Sr. No. Ingredients Quantity per Tab in mg % w/w
1 Sildenafil Citrate * 140.48 23.41
2 Mask IC-MK-9014 (Instacoat) 210.75 35.13
3 Purified Water - -
4 Mannitol 55.72 9.29
5 Croscarmellose sodium 10.00 1.67
6 Citric acid monohydrate 6.00 1.00
7 Sodium chloride 6.00 1.00
8 Aspartame 10.00 1.67
9 Monoammonium Glycerrhizinate 10.00 1.67
10 Sucralose 18.00 3.00
11 Sucrose (Pharma grade) 70.00 11.67
12 Colloidal Silicon Dioxide (Aerosil 200 ) 2.00 0.33
13 Microcrystalline cellulose (Vivapur 102) 20.00 3.33
14 Quinoline yellow WS 6.00 1.00
15 Sunset yellow FCF 0.05 0.01
16 Purified Water - -
17 P.V.P. K-30 10.00 1.67
18 Isopropyl alcohol ** ~ -
19 Trusil Banana ASV flavour 5.000 0.83
20 Croscarmellose sodium 10.00 1.67
21 Colloidal Silicon Dioxide (Aerosil 200 ) 1.00 0.17
22 Purified Talc 3.00 0.50
23 Magnesium Stearate 6.00 1.00
Total Weight of tablet 600.00 mg -
*100 mg Sildenafil equivalent to 140.480 mg of Sildenafil Citrate ** Not present in the final product.
Procedure: Same as mentioned in Example 1.


Example 3:
Taste masked tablets of sildenafil citrate were prepared using the following excipients in
the stated quantities:

Sr. No. Ingredients Quantity per Tab in mg % w/w
1 Sildenafil Citrate * 140.48 23.41
2 Mask IC-MK-9014 (Instacoat) 210.75 35.13
3 Purified Water - -
4 Mannitol 70.57 11.76
5 Croscarmellose sodium 10.00 1.67
6 Citric acid monohydrate 6.00 1.00
7 Sodium chloride 6.00 1.00
8 Aspartame 10.00 1.67
9 Monoammonium Glycerrhizinate 10.00 1.67
10 Sucralose 18.00 3.00
11 Sucrose (Pharma grade) 60.00 10.00
12 Colloidal Silicon Dioxide (Aerosil 200 ) 2.00 0.33
13 Microcrystalline cellulose (Vivapur 102) 20.00 3.33
14 Colour- Allura Red 0.20 0.03
15 Purified Water - -
16 P.V.P. K-30 10.00 1.67
17 Isopropyl alcohol ** ~ -
18 Trusil Strawberry ASV flavour 6.000 1.00
19 Croscarmellose sodium 10.00 1.67
20 Colloidal Silicon Dioxide (Aerosil 200) 1.00 0.17
21 Purified Talc 3.00 0.50
22 Magnesium Stearate 6.00 1.00
Total Weight of tablet 600.00 mg -
*100 mg Sildenafil equivalent to 140.480 mg of Sildenafil Citrate ** Not present in the final product.
Procedure: Same as mentioned in Example 1.


Example 4:
Taste masked tablets of sildenafil citrate were prepared using the following excipients in
the stated quantities:

Sr. No. Ingredients Quantity per Tab in mg % w/w
1 Sildenafil Citrate * 140.48 23.41
2 Mask IC-MK-9014 (Instacoat) 210.75 35.13
3 Purified Water - -
4 Mannitol 42.77 7.13
5 Croscarmellose sodium 10.00 1.67
6 Citric acid monohydrate 6.00 1.00
7 Sodium chloride 6.00 1.00
8 Aspartame 10.00 1.67
9 Monoammonium Glycerrhizinate 10.00 1.67
10 Sucralose 18.00 3.00
11 Sucrose (Pharma grade) 70.00 11.67
12 Colloidal Silicon Dioxide (Aerosil 200 ) 2.00 0.33
13 Microcrystalline cellulose (Vivapur 102) 20.00 3.33
14 Lake Quinoline Yellow 18.00 3.00
15 P.V.P. K-30 10.00 1.67
16 Isopropyl alcohol ** — -
17 Trusil Pineapple ASV flavour 6.000 1.00
18 Croscarmellose sodium 10.00 1.67
19 Colloidal Silicon Dioxide (Aerosil 200 ) 1.00 0.17
20 Purified Talc 3.00 0.50
21 Magnesium Stearate 6.00 1.00
Total Weight of tablet 600.00 mg
*100 mg Sildenafil equivalent to 140.480 mg of Sildenafil Citrate ** Not present in the final product
Procedure: Same as mentioned in Example 1.


WE CLAIM:
1. An oral pharmaceutical taste masked chewable tablet composition comprising: a therapeutically effective amount of sildenafil citrate or a pharmaceutically acceptable derivative thereof in the form of a sildenafil mask complex alongwith pharmaceutically acceptable excipients.
2. The composition of claim 1, wherein the said mask complex is formed by sildenafil and a polyacrylic resin by a cationic exchange mechanism.
3. The composition of claim 2, wherein carbomer and powdered cellulose are additional excipients, which facilitate the formation of the sildenafil mask complex.
4. The composition of claim 1, wherein the pharmaceutically acceptable excipients include diluents, disintegrants, sweetners, binders, flavours, colours and lubricants.
5. The composition of claim 4, wherein mannitol is used as the diluents to form a base for the chewable tablet.
6. The composition of claim 4, wherein croscarmellose sodium is used as disintegrant.
7. The composition of claim 4, wherein sweeteners include aspartame, monoammonium glycerrhizinate, sucralose and sucrose.
8. The composition of claim 4, wherein povidone is used as a binder.
9. A process for masking the bitter taste of sildenafil citrate comprising the steps of:
i. Forming a sildenafil mask complex between sildenafil citrate and an ion-exchange
polyacrylic resin, ii. Granulating the taste masked complex with other pharmaceutically acceptable
excipients and sildenafil citrate drug using a binder solution iii.Lubricating the final mixture using pharmaceutically acceptable lubricants


iv. Compression of the lubricated blend using suitable tools to obtain chewable tablets.
10. The pharmaceutical composition of claim 1, wherein the said composition is used to treat patients with erectile dysfunction.

Abstract
The present invention relates to chewable solid pharmaceutical compositions comprising sildenafil citrate. Sildenafil citrate is a very bitter drug, hence the conventional tablets, comprise of a film coating for aesthetic appearance and acceptability. Chewable tablets are usually uncoated and hence there is a need to mask the bitter taste of sildenafil to ensure patient acceptability. The present invention achieves the taste masking of sildenafil citrate by using an ion-exchange resin which forms a complex and masks the bitter taste of sildenafil. The ion-exchange masked sildenafil complex is then incorporated with other excipients to formulate a chewable tablet using flavours and other ingredients.