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(51)  Int.CLS:  A 61K 35n8, 9/06   
               
(21)  Application Number:    KE/P/2005/ 000452   
              
(22)  Filing Date:    13/05/2005 
          
(31) Priority Number:    (32) Date:  (33) Country:   

(73)  Owner(s):    DR MWETHERA PETER GICUHI of P 0  BOX 11706 TOM MBOYA  STREET NAIROBI KENYA, Kenya   

(72)  Inventor(s)    DR MWETHERA PETER GICUHI   

(74)  Agent/address for correspondence:                        

(54) Tide: DEVELOPMENT OF A VAGINAL SPERMICIDE AND MICROBICIDE TO PREVENT PREGNANCY AND TRANSMISSIONN OF HIV/AIDS

(57) Abstract: 
A safe and easy to use substance that would reliably protect the vagina from HIV infection and prevent pregnancy would be a great empowerment to women. Historical evidence from the Mediterranean region shows that lemon juice was once widely used as a contraceptive in the vagina. In addition, it is reported that Casanova advocated the use of half a lemon as a contraceptive which many people believe led to today's cervical caps and diaphragms. We have canied out preliminary studies which show that administration of neat lemon juice into the baboon vagina lowers the vaginal pH with the resultant adverse effects on ejaculated baboon sperm. Inorder to evaluate the safety, efficacy and acceptability oflemonnjuice as a conntraceptive (Spermicide) and/or Viruside to HIV, we have developed a vaginal gel which incorporates neat lemon juice. We shaH examine the effect of this vaginal gel on HIV infectionn and fertility in preclinical studies using baboon model and in clinical studies in human composion and pharmaceutical excipients from 30%  to 60% w/w of the composition.

DETAILED DESCRIPTION OF INVENTION

In accordance with the present Invention there Is disclosed a controlled release composition of Nimesulide.

The c:Orriposition in accordance with present invention comprises a controlled release phannaceutical composition of Nimesulide which comprises nimesulide as an active drug fmm 5% to 95% w1w of the composiUon, one or more sustaining materials from 2% to 95% w1w of the composition and pharmaceutical excipients from 0% to 90% w/w of the composition. In another aspect, such compositions contain nimesullde in micronized form having average particle size below 5 microns.

Preferably the composition in accordance with the present Invention comprises nimesulide as en active drug fmm 20% to 70% w/w of the composition, one or more sustaining materials from 5% to 65% w/w of the composRion and pharmaceutical exciplents fmm 10% to 70% wlw of the composition.

More preferably the composition in eccordence with the present Invention comprises  nimesulide  as  en  active  drug  from  40%  to  60%  w/w  of  the composition, one or more sustaining materials from 8% to 20% w/w of the composiUon and pharmaceutical exciplents from 30% to 60% w/w of the composition.

In a preferred embodimant of the invention the composition consists of bilayer tablets wherein the active agent may be present in one or both layers. The bilayer  tablets  may be coated  or  uncoated.  Tha  coating . may  be  semi-

permeable type membrane. Further, the seml-permaebta coat may have an orifice drilled through it on the drug layer side to provide passage for constant release of drug.

In another aspect of the invention the coating may be of microporous type through which the drug release takas place at constant rata.

In another aspect of the invention the bilayer tablet dosage form may have a first layer which gives fast release of the drug, and a second layer which gives extended release of the drug.

The first fast release layer comprises materials like dislntagrants, fillers, rapidly soluble/dispersible excipients and wetting agents. The second extended release layer comprises sustaining polymers binders wetting agents and fillers.

Tha sustaining polymers preferably ere hydrophilic In nature and present In a blend of fast and slow hydrating polymers.
 

The sustaining materiels ere selected from the group cellulose and cellulose derivatives, waxes, carbomers, polyalkylane polyols, polycarbophils, melhaaylete acid derivatives, gelatins, gums, polyethylene O>Cides.

The sustaining materials comprise materials which are non-toxic and phannaceutically acceptable. These may be natural, sfllllkynlhatic, synthetic or man-modified. Suitable materials include cellulose and cellulose derivatives like microaystalline cellulose, methyl cellulose, ethyl cellulose, hydroXypropylmethyl cellulose, hydroxypropyl cellulose, cellulose acetate phthalate, cellulose acetate, cellulose ilcetata butyrate, cellulose acetate propionate, cellulose acetate tlimellitata, cellulose carboxymethyl ethers and !hair salts, hydroxypropyl melhylcellulose phthalate , hydroxypropyl methylcellulose acetate succinate.

Polyethylene; Polyquatemium-1; Polyvinyl acetate (homopolymer); Polyvinyl acetate phthalate; Propylene glycol alginate; PVMIMA copolymer; PVP/ dimethiconylaaylate/polycarbamyUpolyglycolester;PVP/dimethylaminoethylm athaaylate copolymer; PVP/dimathylaminoethylmalhaaylateipolycari:>amyl polyglycol ester; PVP/polycarbamyl polyglycol ester; PVP/ VA copolymer

Lanolin and lanolin derivatives, glyceryl monostearete, stearic acid, paraffins,

beeswax, camauba wax. Tribehenlri.

Polyalkylene polyols like polyethylene glycols.

Gelatin and gelatin derivatives.

Alginates. Carbomers. Polycarbophils.

Melhaayllc acid copolymers.
 
Carragaenans, pectins, chRosens, cyctodexlrlns, lecithins.

Natufal end synthetic gums_ containing galectomannens like xanlhan gum,

tragacanth, acacia, agar, guar gum, etc.

Pharmaceutical axcipients as used In lhe composiUon are selected from lhe

group of excipients generally used by persons skilled In lhe art e.g. fillers,

bulking agen~ colourants, stabilizers, preservatives, lubricants, glidants, chelating agents and lhe like.

Preferably lhe composRion also comprises release modifiers. Such release modifiers are selected from lhe groups wetting agenls, solubilizers, surfactants, plasticizers, solvents, pore formers, pH modifiers and tonlclty adjusting agents.

SuRable example of such ingredients include :

Reaction products of natural end hydrogenated vegetable oils end elhylena glycol e.g. polyoxyethylene glycolated natural or hydrogenated castor oil such as those available under the trade name Cremophor.

Other suitable products include polyoxyethylene sorbRan fatty acid esters e.g.

of the type available under the trade name TWEEN.

Polyoxyethylene fatty acid esters e.g. MYRJ end CETIOL HE.

Polyoxyethylene polyoxypropylene oopolymn e.g. PLURONIC and Polyoxyethylene polyoxypropylene block copolymers e.g. POLOXAMER. Dioctylsodiumsulfosuccinate, sodium laurylsulphale.

Propylene glyool mono- and di•tally acid eslers e.g. MIGLYOL 840. Bile satts e.g alkali metals salls e.g. sodium taurocholate.

Polyethylene glycols, propylene glyool, triacelin, diacetin, dielhyl phlhalate, dibutyl phthalate, castor oil, triethyl citrate dibutyl sebacete.

Sodium chloride, potassium chloride, lactose, mannRol, sucrose, scirbitol. Sodium nydroxide, potassium hydroxide, sodium bicarbonale, sodium cllrate, citric acid, hydrochloric acid, lacllc acid, tartaric acid, malic acid.
The calculation of dose of nimesulida for onca-a-<lay oontrollad release dosage form was done on the basis of its pharmaooklnetic parameters using the following equation :

Dqsa =c. xv, x K,x T

c. Effective plasma ooncentration, 3.0. mgll v, Apparent Volume of distribution, 15.6 L

1
K, Elimination Rate conslent, 0.166 h' T Desired Duration of aclion, 24 hrs

Based on the above equation the dose was calculated to be 207.0 mg.

The oompositions of the present invention have another added advantage that once - a - day dosage form of Nlmasulide may be oombinad with another suitable long - acting drug to have. synergistic activity. The other drug may be presant in ncin-controlled releasa folm.  Such drugs may be selected from following categories :

(i)    Antihistaminics e.g. Cetirizine Dihydrochloride.

(ii)    Antispasmodics e.g. Pitofenone Hydrochloride, Hyoscine Hydrobromide.

(iii)    Antiasthmatics e.g. Ketotifen, Salbutamol.

The foregoing examples ere illustrative embodiments of the invention and are merely exemplary. A person skilled in the art may make variations and modifications without depending from the spirit and scope of the Invention. Ali
such modifications and variation are intended to be included within the scope of the invention as discuss in this specifications.

Example 1  Controlled release matrix tablet type   
(i) Nimesulide (micronized)    200 mg
(ii) Lactose    73 mg
(iii) Hydroxypropylmethyl Cellulose    70 mg
(iv) Magnesium Stearate    3.5 mg
(v) Purified Talc    3.5 mg

Blend (i), (ii), (iii), (lv) and {v) after sifting through mesh no. 30 (BSS). Compress into tablets.

The results of Dissolution Release Profile of Nimasulide CR Tablets based on example 1 are given below :

Time    Mean    so
30mins.    •4.2    ±1.36
1 hr    7.9    ±1.02
2hrs    16.4    ±1.74
3hrs    25.8    ±1.28
4hrs    34.2    ±1.71
Bhrs    50.8    ±2.44
8hrs    65.9    ±1.66
10hrs    74.9    ±0.97
12hrs    85.8    ±2.34
14 hrs'    93.5    ±2.49
16hrs    96.7    ±2.16
18hrs    97.1    ±1.06
19 hrs    98.8    ±1.32

The dissolution profile as given in table 1 of the nlmesulide sustained release

tablet should not ba construed to limit the scope of the invention. Variations

to  the• dissolution  profile  can  be  possible  depending  upon  the  dosage

requirements without departing from the spirit of the invention.

Example 2   Extended release membrane diffusion controlled tablet type

(i) Nimesulide (micronized)    200mg
(ii) Miaocrystalline Cellulose    60mg
(iii) Lactose    60mg
(iv) Maize Starch    10mg
(v) Purified Talc    3.5mg
(vi) Ethyl Cellulose    10mg
(As Aqueous Dispersion)   

(vii) Polyethylene Glycol

Blend (i), (ii) and (iii) and granulate with starch paste and dry the granules. Silllhrcugh mesh no. 22 (BSS). Lubricate with Talc. Comprass into !ablate. Coat the !ablate with Elhyt Cellulose using Polyethylene Glycol as a channel former.

Example 3   Suslained release bead type

(i) NQn - Parail Beads    347mg
(ii) Nimesulide    200mg
(lii)MaMitol    30mg
(iv) Lactose    30mg
(v) Polyvinyl Pyrrolidone    20mg
(vi) Purified Talc    15mg
(vii) Ethyl Cellulose    7mg
(viii) Diethyl Phthalate    1.4mg

Coat the non-pareil beads with blend of .(ii), (iii) and (iv) using (v) as a binder in a conventional or fluidized bed coater. Talc may be dusted onto the beads. Final coating is given with Ethyl Cellulose using (viii) as plastiCizer.

Example 4  Osmotically controlled constant release type device

Upper layer   
(i) Nimesulide (miaonized)    200mg.
(ii) Sodium Hydroxide    15mg
(iii) Lactose    34mg
(iv) Sodium Chloride    30mg
(v) Polyvinyl Pyrrolidone    6mg

(vi) Polyethylene Oxide    1.5mg

Lowerwer

(vii) Polyethylene Oxide    22mg

(viii) Hydroxypropylmelhyl Cellulose    1.Bmg

(ix) Sodium Chloride    20mg

(x) Dichloromelhane    q.s (Lost in processing)

Semi-permeable Coat
 

(XI) Cellulose Acetate (xii)Triacetin
(xiii)    Acetone

(xiv)    Water

Blend finely powdered (i), (il),  (iii), (iv) and (vi).
 

30mg

1mg

q.s (Lost In proceslng) q.s (Lost in processing) Granulate with aqueous
 

solution of (v). Granulate the blend of (vii) and (ix) with dispersion of (viii) in

(x).  Compress the two granulates  into bilayer tablets and coat with the

dispersion of (xii) and (xiii) In aqueous acetone. Anally, drill a hole in tha

drug layer (Upper layer) through which the drug is released In a controlled fashion due to osmotic pressure.

The results of Dissolution Release Profile of Nimesullde CR Tablets based on example 4 are given below :

Table 2       
Time    Mean    so
2 hours    5.16    :1:0.53
4 hours    16.75    :1:1.68
Shours    34.90    :1:2.26
8 hours    45.75    :1:2.26

IS
10h0urs    56.00    :t4.36   
12 hOurs    67.85    :t4.40   
14h0urs    79.:i6    :t5.03   
14 hours    90.25    :t3.68   
18 hours    101.16    :t3.53   
Example 5    Coated capsule type       
(i) Nimesulide (micronized)        200mg
(ii) Microaystalline Cellulose        SS.4mg
(iii) Lactose        7Dmg
(iv) Polyvinyl Pyrrolidone        7mg
(v) Magnesium Stearate        3.9mg
(vi) Ethyl Cellulose        20mg
(vii) Polyethylene Glycol        0.7mg
(viii) Alcohol: Dichloromethane (1 : 2)    q.s (Losi in processing)
(lx) Empty Gelatin Capsule (Size '1')   

Blend (i), (ii), (iii), (iv) and (v) and fill into empty gelatin capsule size '1'.Coal the capsules with dispersion of (vi) and (vii) in (viii).

Example 6  pH dependent delayed release type   
(i} Nimesulide (micronized)    100 mg
(li) Microaystalline Cellulose    150 mg
(iii) Lactose    76 mg
(iv) Polyoxyl 40 Hydrogenated Castor Oil •    7 mg
(v) Polyvinyl Pyrrolidone    10 mg
(vi) Magnesium Stearate    3.5 mg

(vii) Purified Tale    3.5mg

(viii) Cellulose Al:elate Phthalate    28mg

(lx) Oiethyl Phthalate    2mg

(x)Water    q.s (Lost In processing)

(xi) Alcohol: Dichloromethane (1 :2)    q.s (Lost In processing)

Granulate the blend of (i). (ii) and (iii) with solution of (iv) and (v) In water. Blend the granules with (vi) and (vii). Compress rnto tablets. Coat with the
dispersiCin of (viii) and (ix) in (xi).

Exampte7   Timed release bead type           
(i) Nimesullde (miaonized)    100mg    100mg    100mg
(ii) MicrccrysJaiDne Cellulose    200mg    200mg    200mg
(ill) Lactose    50mg    42mg    35mg
(iv) Polyvinyl Pyrrolldone    1Dmg    10mg    10mg
(v)Water    q.s    q.s    q.s
(vi) AmmonioMethacrylate           
Copolymer Type B    10mg    1Bmg    25mg
(Eudragit RS)           
(vii) Oiacetin    O.Smg    O.Smg    O.Smg
(viii) Water: Al:etone (1:9)    q.s    q.s    q.s

Procedure:

In lhis composRion 3 types of beads are prepared which are coated with

different amounts of (vi) to give a timed prcllle of lhe drug.  Beads are

prepared  by  blending  and  spheranizing (1),  (ii)  and  (ill) jusing  aqueous

solution of (iv). The dried beads are coated with dispersion of (vi) and (vii) in

(viii). The 3 different beads are blended togelher in a fixed ratio to obtain lhe required release profile.

Example 8   Nimesulide CR + Cetirizine Bilayered Tablets

Nimesulide Layer

(I) Nimesulide (micronized)    200mg
(ii) Ladose    106.5mg
(iii) Polyaxyl 40 Hydrogenated Castor 011    2.0mg
(iv) Hydraxypropylmelhylcellulose    31.5mg
(v) Magnesium Stearate    2.0mg
(vi) Colloidal Silicon Dioxide    2.0mg
Cetirizine laver   
(vi) Colloidal Silicon Dioxid~    2.0mg
(vii) Cetirizine Dihydrachloride    10.0mg
(viii) Ladose    105.0mg
(ix) Microaystalllna Cellulose    25.0mg
(x) Starch    S.Omg
(xi) Croscannellose Sodium    3.0mg
(xii) Magnesium Stearate    2.0mg

Blend lha components of lhe two layers separately and compress Into bilayer

tablets.

Example 8  OsmoUcally controlled constant release syetem

Ad:jve Laver

(I)    Nimesulide (micronized)    200.0mg
(ii)    Polyethylene oxide    116.5mg
(iii)    Hydroxypropylmethy cellulose    10.0mg
(iv)    Sodium chloride    10.0mg
(v)    Magnesium stearate    2.5mg

fY!!!..!ml:

(vi)    •f>'olyelhyleneoxide    140.0mg
(vii)    Sodium chloride    SO.Omg
(viii)    Hydroxypropylmethy cellulose    9.5mg
(ix)    Magnesium stearate    O.Smg
(X)    Iron oxide red    1.0mg
Functional coaling   
(xi)    Cellulose acetate    45.0mg
(xii)    Polyethylene glycol    S.Omg
(xiii)    Acetone    Lost in processing
Non-fundiona! coating   
(xiv)    Titanium dioxide    2.0mg
(xv)    Hydroxypropylmethyi cellulose    6.0mg
(xvi)    Purified Talc    2.0mg
(xvii)    Polyethylene glycol - 400    2.0mg
(xviii)    lsopr:opyl Alcohol    Lost in processing
(xlx)    Dichloromethane    Lost In processing

Prac:edura  :  Blend  (1),  (ii),  (Iii),  (iv)  and  (v)  In a double  cone  blender.

Separately blend (vi),  (vii),  (viii) (lx) and (x). Compress into bilayer lablet

using a suitable oo~pression machine. Coat the tablets with the dispersion of

(xl) and (xli) in (xili). The lablets are further ooeted with the dispersion of (xiv),

(xv), (xvi), (xvii) In mixture of (xvili) and (xlx).


Example 10 : Bilayer tablets having one fast release layer and one extended release layer
 
fast Release laver

(i)    Nimesulide (micronized)

(iij    Lactose

(Ill)    Starch

(iv)    Colloidal silicon Dioxide

(v)    Povidone K-30

(vi)    Docusate Sodium

(vii)    Polysorbate 80

(viii)    Magnesium Stearate

(lx)    Croscannellose Sodium

(x)    Water

Extended Release Layer

(xi)    Nimesulide (miaonized)

(xli)    Lactose

(xlii)    Hydroxypropylmelhyl cellulose K100LV •

(xlv)    Hydroxypropylmethyl cellulose K4MCR  •

(xv)    Povidone K-30
 

100.0mg

151.5mg

37.6mg

11.0mg

B.Smg

6.Bmg

1.0g

1.6mg

22.0mg

Lost in processing


100.0mg

200.0mg

23.0mg

100.0mg

9.0mg
 

zo
 (xvi)    Docusate Sodium    4.5mg
(xvii) Magnesium Stearate    4.5mg
(xvili)Colloidal Silicon Dioxide    4.5mg
(xix)    Sodium LaUiyl Sulphate    4.5mg
(xx)    Isopropyl Alcohol    Lost in processing

Procedure:

Blend 1.: Blend (1), (ii), (iii) and (iv) and granulale with solution of(v) and (vi) in (x).

Dry the granules and blend with (viii) and (ix).

Blend 2: Blend (ix), (xii), (xiii) and (xiv) and granulate with solution of(xv) and (xvi) in (xx). Dry the granules and mix with (xvii), (xvili) and (xix).

Compress into bilayer tablets using a suitable compression machine.

Example II : Bilayer tablets having one fast release layer containing drug in complexed fonn and one oxtended release layer

A    Fast Release layer   
(i)    Nimesulido (micronized)    IOO.Omg
(iJ)    B- cyclodextrin    400.0mg
(iii)    Starch    70.0mg
(vi)    Povidone K-30    7.5mg
(v)    CroSCIIIIIlellose Sodimn    20.0mg
(vi)    Magnesimn Stearate    2.5mg
B    Extended Release Layer   
(vii)    Nimesulide (micronized)    IOO.Omg

(vili)    Lactose    200.0mg
(ix)    Hydtoxypropymethyl celluloses Kl OOLV    230.0mg
(x)    Hydroxypropylmctbyl cellulose K4MCR    IOO.Omg
(xi)    Povidone K-30    9.0mg
(xii)    Magnesium Steamte    4.Smg
(xiii)    Colloidal Silicon Dioxide    .4.5mg
(xiv)    Docusate Sodium    4.5mg

Procedure:

Layer- I

I.    Mix (i) and (xii), co-mill under specific conditions favouring complexation using ball mill to prepare a complex.

2.    Mix complex of step I with (iii) and granulale with a solution of(iv) in WBil:r

3.    Diy the granules at 40° S0°C.

4.    Size the granules & mix with (v) and (vi)

Layer-11

l.    Mix (vii), (viii), (ix) and 9x). Granulale with a solution of(xi) and (xiv).

2.    Diy the granules at 40°- so0 c.

3.    Size the granules & mix with (xii) and (xiii).

4.    Compress the two layers into bilayered tablets using suitable compression macbine.

We claim:

I.    A Controlled release plunmaceutical composition of Nimesulide which comprises Nimesulide as an active diqg upto 99% w/w of the composition, one or more release controlling materials from 0.1% to 99 % w/w of the composition and plunmaceutical excipients from 0% to 90% w/w .of the

composition.

2.    A comrolled release plunmaceutical composition ofNimcsulide as claimed in claim 1. which comprises Nimesulide as an active drug from 20% to 70% w/w of the composition, one or more sustaining ma!erlals from 5% to 65% w/w of the composition and phmmaccutical excipients from •10% to 70% w/w of the composition.

3.    A comrolled release plunmaceutical composition of Nimcsulide as claimed in claim I which comprises Nimesulide as an active drug from40% to 60% w/w of the composition, one or more sustaining ma!erlals from 8% to 20% w/w of the composition and plunmaceutical cxcipients from 30 % 60"/o w/w of the composition.

4.    A comrolled release plunmaceutical composition ofNimesulidc as claimed in claim I to 3 wherein the sustaining ma!erlals are selected from the group ccllulose and cellulose derivatives, waxes, cmbornors, polyalkylenc polyols, polyCIIIbophils, methacrylate acid derivatives, gelatins, gmns, polyethylene

oxides and alike.

S.    The composition as claimed in claim I which further comprises release modifiers.
6.    A process for the manufacture of controlled release compositions of Nimcsulide which comprises mixing together under conventional conditions of temperature and pressure- Nimesulido as an active drug upto 99% w/w of the composition, one or more release controlling sustsining materials from 0.1% to

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