QUETIAPINE COMPOSITION
FIELD OF THE INVENTION
The present invention relates to novel sustained-release pharmaceutical compositions comprising quetiapine and a nonswelling anionic polymer.
BACKGROUND OF THE INVENTION
Quetiapine is an atypical antipsychotic with established efficacy in the treatment of schizophrenia, shows efficacy in the treatment of acute mania and depression associated with bipolar disorder. Quetiapine, either as monotherapy or in combination with lithium or divalproex sodium (valproate semisodium), is generally well tolerated and effective in reducing manic symptoms in adult and adolescent patients with acute bipolar mania, and is approved for use in adults for this indication. As monotherapy, the drug is also effective in reducing depressive symptoms in patients with bipolar depression.
Quetiapine and its hemifumarate salt was first disclosed in EP240228. Later were published many more patent applications concerning quetiapine such as EP282236, EP907364, WO9906381, EP1218009, EP1448169, EP1482945, WO2005028457, WO2005041935, WO2007036599, EP1252151.
Anionic polymers are widely used in the manufacturing of pharmaceutical products. Some anionic polymers such as xanthan, carrageenans, alginate and carbomers do not dissolve in water but because of their chemical nature swell upon contact with water and/or physiological fluids. This phenomenon is used in the preparation of prolonged release solid dosage forms, where the drug's release rate is diminished by hindering the diffusion of dissolved drug molecules through the gel layer formed due to swelling of the polymer in the matrix. On the other hand anionic polymers which do not swell but whose solubility is pH dependent are used for preparation of delayed release solid dosage forms. Delayed release is based on the fact that anionic polymers are not soluble at low pH which is characteristic for the upper part of the gastro intestinal tract, but are soluble at higher pH, typically higher than 5.5.
WO 97/45124 describes a sustained-release formulation of quetiapine comprising a hydrophilic matrix comprising a gelling agent. The drawback of such a composition is the gelling level of the composition. Also, its dissolution rate is difficult to control as it also depends on physiological factors.
WO 03/039516 discloses a method of improving dissolution of a poorly dispersible medicament e.g. quetiapine fumarate, which comprises mixing the poorly dispersible medicament with a floating agent and granulating the mixture. As floating agents non-water soluble cellulose, sodium alginate, propylene glycol alginate, tragacanth powder or xanthan gum are mentioned.
Swellable matrix systems have disadvantages in case of high doses of soluble active pharmaceutical ingredient as it is difficult to control the release profile thereof. This is due to an increasing diffusion rate due to continuous dissolving of drug from the matrix which process accelerates the penetration of water into the matrix resulting in faster dissolution and release of active pharmaceutical ingredient. This drawback of such a swellable matrix is overcome by the present invention.
DETAILED DESCRIPTION OF THE INVENTION
The problem solved by the present invention is the provision of a pharmaceutical composition overcoming the above mentioned drawbacks. We have surprisingly found that a 24 hour release profile of quetiapine or its salt can be achieved by the preparation of a matrix solid pharmaceutical composition characterized by a homogenous mixture of drug and anionic polymer particles.
Preferred embodiments of the present invention are disclosed in the dependent claims attached to this description.
The present invention describes a pharmaceutical composition and processes for its preparation, said composition comprising a solid matrix system of quetiapine or its salt and a nonswellable anionic polymer. In particular, the compositions of the present invention consist of the active ingredient, a nonswellable anionic polymer and further excipients as described in detail hereinbelow.
Quetiapine is preferably present in the form of its salt such as quetiapine hemifumarate. The anionic polymer can be used as a pure polymer or as a blended ready to use product such as Sureteric, Acryl-EZE or the like. Sureteric is a blend of polyvinyl acetate phthalate, plasticizers and other ingredients in a completely optimized dry powder formulation, which should be dispersed in water before use. Acryl-EZE is a preblended product containing polymethacrylate ethylacrylate polymer (Eudragit L 100-55), plasticizer and pigments. The composition according to the present invention is capable of prolonging the release of quetiapine from the composition to at least 12 hours, preferably to at least 16 hours and most preferably to at least 24 hours.
The pharmaceutical composition according to the present invention can be formulated in different dosage forms such as tablets or capsules. Preferably, the composition according to the present invention is in the form of tablets which can be manufactured by direct compression or via wet or dry granulation.
The pharmaceutical composition can be present in the form of tablets or capsules, which can be optionally further coated with a functional film coating giving the dosage forms the required physical or biopharmaceutical properties, decreased permeability to moisture and other gases such as oxygen, taste or color masking and/or smoothening of the surface for easier swallowing in case of tablets.
The term "nonswellable" according to present invention means that it does not swell upon contact with water. Nonswellable anionic polymers can be selected from the group comprising cellulose acetate phthalate such as Eastman C-A-P Cellulose Ester; methacrylic acid copolymer such as Eudragit L, Eudragit S and Eudragit FS types; cellulose acetate succinate such as Hypromellose Acetate Succinate (HPMCAS, Aqoat); polyvinyl acetate phthalate such as Sureteric, shellac and/or hydroxypropylmethyl cellulose phthalate (HPMCP) such as HPMCP-50, HPMCP-55 and/or mixtures thereof. Ready-to-use compositions containing the mentioned polymers can contain other excipients selected from drug release rate modifiers, surfactants, pH modifiers, antitacking agents, plasticizers, pigments and colorants. Anionic polymers can be partially neutralized in-situ during manufacturing of solid compositions in order to control the extent of interaction with quetiapine or its salts.
More specifically, Eastman C-A-P Cellulose Ester is characterized by a content of 35% phthalyl, 24% acetyl and 0% hydroxyl with less than 2% moisture and about 0.5% free acid (as phthalic acid).
Eudragit L 100-55 is a copolymer of methacrylic acid and ethyl acrylate in the ratio 1 :1 , wherein the ratio of the free carboxyl groups to the ester groups is approximately 1 : 1. The average molecular weight is approximately 250,000.
Eudragit L is a copolymer of methacrylic acid and methyl methacrylate, wherein the ratio of the free carboxyl groups to the ester groups is approximately 1 : 1. Eudragit S, i.e. another suitable methacrylic acid copolymer, is based on methacrylic acid and methyl methacrylate wherein the ratio of the free carboxyl groups to the ester groups is approximately 1 :2. The average molecular weight is approximately 135,000. Eudragit FS is another example for a suitable methacrylic acid copolymer. It is based on methyl acrylate, methyl methacrylate and methacrylic acid as comonomers. The ratio of the free carboxyl groups to the ester groups is approximately 1 :10. The average molecular weight is approximately 220,000.
Aqoat NF is a commercially available form of hypromellose acetate succinate which is characterized by the following structure:
with R being -H5 -CH3, -CH2CH(CH3)OH, -COCH3, -COCH2CH2COOH, -CH2CH(CH3)OCOCH3, -CH2CH(CH3)OCOCH2CH2COOH. It has a molecular weight (weight average) of about 18,000 and the degree of polymerization is 70 (weight average, measured with SEC-MALLS).
Sureteric is a commercially available form of a suitable polyvinyl acetate phthalate (PVAP). It is characterized by a pH of 4.5 - 5.8 (15% dispersion in deionized water) and a Brookfield viscosity of 30 - 75 cP (15% dispersion in deionized water). The molecular structure of the polymer is as follows.
a and b may vary, c is constant. It contains not less than 55.0% and not more than 62.0% of phthalyl (o-carboxybenzoyl, C8H5O3) groups, calculated on an anhydrous acid-free basis.
Hydroxypropyl methyl cellulose phthalate (HPMCP) in the form of the two commercially available products HPMCP-50 and HPMCP-55 is another suitable nonswellable anionic polymer according to the present invention. It is also referred to as the 2-hydroxypropyl methyl ether, phthalic acid ester of cellulose. In HPMCP-50 the nominal phthalyl content is 24%. In HPMCP-55 the nominal phthalyl content is 31%.
According to one embodiment of the present invention, the pharmaceutical composition of the present invention comprises a homogeneous solid matrix system of quetiapine hemifumarate, polyvinyl acetate phthalate and at least one further excipient selected from the group consisting of PEG 20000, lactose, povidone, mannitol and sorbitol. The content of quetiapine hemifumarate is in particular from about 51 to 70% by weight, based on the total composition.
According to another embodiment, the pharmaceutical composition of the present invention comprises a solid matrix system comprising quetiapine hemifumarate, a methacrylic acid copolymer based on methacrylic acid and methyl methacrylate wherein the ratio of the free
carboxyl groups to the ester groups is approximately 1 :1, another methacrylic acid copolymer containing units derived from methyl acrylate, methyl methacrylate and methacrylic acid, wherein the ratio of free carboxyl groups to the ester groups is approximately 1 :10, and further comprising at least one excipient selected from the group consisting of microcrystalline cellulose, talc and hypromellose having viscosity of 6 cP (USP method) (Pharmacoat 603). The content of quetiapine hemifumarate is in particular about 40% by weight, based on the total composition
According to another embodiment, the pharmaceutical composition comprises a solid matrix system comprising quetiapine hemifumarate and HPMCAS containing about 9% acetyl and 1 1 % succinoyl and at least one further excipient selected from the group consisting of microcrystalline cellulose, magnesium stearate and Pharmacoat 603 or povidone. The content of quetiapine hemifumarate is in particular about 51% by weight, based on the total composition.
According to another embodiment of the present invention, the pharmaceutical composition comprises a solid matrix system comprising quetiapine hemifumarate and CAP and at least one further excipient selected from the group consisting of microcrystalline cellulose, magnesium stearate, and Pharmacoat 603 or povidone. The content of quetiapine hemifumarate is in particular about 48% by weight, based on the total composition.
According to another preferred embodiment, the pharmaceutical composition of the present invention comprises a solid matrix system comprising quetiapine hemifumarate and HPMCAS containing 12% acetyl and 7% succinoyl and at least one further excipient selected from the group consisting of tablettose, sodium citrate dihydrate, magnesium stearate, PEG 8000, citric acid, PEG 4000, mannitol, fumaric acid, anhydrous fumaric acid disodium salt. The content of quetiapine hemifumarate is in particular about 37% by weight, based on the total composition.
In particular, the embodiments described above may consist of the mentioned ingredients.
The content of quetiapine, in particular quetiapine hemifumarate, calculated as quetiapine hemifumarate, in the solid matrix system of the present invention generally ranges from 30 to
90% by weight. Preferably, it is in the range from 35 to 70 or 40 to 60%, such as 50 to 60%, based on the weight of the total composition.
In one embodiment of the invention, quetiapine or its salt is mixed or granulated with anionic polymer in powder form, with optional use of other nonswelling excipients, in an appropriate mixer such as a biconical mixer or high shear mixer. Optionally, other excipients are added to produce a homogenous powder mixture, which is compressed into tablets, which can optionally be coated with a film coating.
In another embodiment of the invention, quetiapine or its salt is mixed with anionic polymers and optionally other excipients and in a next step wet granulated with a dispersion containing one or more polymers selected from anionic and/or neutral polymers. Water, organic solvents miscible with water such as ethanol, isopropanol, methanol, acetone or mixtures thereof can be used for the preparation of the dispersion of anionic polymer. Anionic polymer can be used in one embodiment of the invention solely in a powder mixture. In another embodiment, it can be used only in granulation liquid. In still another embodiment, anionic polymers can be partially incorporated into powder mixture and partially into granulation liquid. With such solutions intimate contact of quetiapine or its salt with anionic polymer is achieved. The granulation liquid can contain besides solvent and optionally anionic polymer also other excipients selected from drug release rate modifiers, binders, stabilizers, micropH modifiers. Wet granulation can be performed by state of the art processes and equipment such as low or high shear mixer or fluid bed granulators (top spray, bottom spray or tangential spray).
In a special embodiment of present invention, the granulation can be performed by dry granulation of a mixture of quetiapine or its salt and anionic polymer and optionally further excipients selected from drug release rate modifiers, diluents, binders, micropH modifiers, stabilizers, lubricants.
Additional excipients selected from drug release rate modifiers, diluents, binders, drug release rate modifiers, micropH modifiers, stabilizers, buffering agents, surfactants, granulation aids, disintegrants, glidants and/or lubricants can be used in the composition of the present invention.
Drug release rate modifiers can be selected from cellulose ethers such as hydroxypropylmethyl cellulose of different viscosity and/or substitution grades having a viscosity of 2% solution in water (determined according to USP method) in the range of 50 to 250,000 mPas and having a methoxyl group content preferably in the range of 16 to 32 w/w%, more preferably in the range of 19-32 w/w% and most preferably in the range of 19-30 w/w% and a hydroxypropyl group content preferably in the range of 4 to 32 w/w%, more preferably in the range of 7-12 w/w%, hydroxypropyl cellulose e.g. Klucel HF, HXF, EF or MF types having a viscosity of 1% aqueous solution in the range of 1,000 to 4,000 mPas, hydroxyethyl cellulose, methyl cellulose, methylhydroxyethylcellulose, ethylcellulose, propylhydroxyethylcellulose, polyHEMA, methylcellulose povidone, copovidone, polyvinyl alcohol, poly(ethyleneoxide) of molecular weight in the range of 1,000,000 to 7,000,000 e.g. Polyox WSR303), polylactic acid, xanthan gum, alginates, such as alginic acid and sodium alginate sodium and calcium carboxymethylcellulose, polysaccharides such as alginates, tragacanth, ceratonia, xanthan gum, guar gum, carrageenan (Carrageenan Iota, Kappa, Lambda), carbomers (different product types e.g. Carbopol 97 IP, Carbopol 71G), methacrylic ester copolymers such as Eudragit® NE, ethyl cellulose, cellulose acetate propionate, cellulose acetate, poly(ethyl acrylate, methyl methacrylate, trimethylammonioethyl methacrylate chloride) 1 :2:0.1, sold as Eudragit® RS, poly(ethyl acrylate, methyl methacrylate, trimethylammonioethyl methacrylate chloride) 1 :2:0.2 copolymer, commercially available as Eudragit® RL5 poly(ethyl acrylate, methyl methacrylate) sold as Eudragit® NE and Eudragit® NM, polyvinylpyrrolidone acetate, polyvinyl chloride, polyvinyl acetate, mixture of polyvinyl acetate and polyvinylpyrrolidone, commercially available as Kollidon SR or Kollicoat SR and polyethylene, waxes and fats such as hydrogenated castor oil, hydrogenated vegetable oil, carnauba wax and microcrystalline wax, fatty acid derivatives such as glyceryl monostearate, glyceryl palmitostearate, glyceryl behenate, glyceryl tristearate, lauryl stearate or the like, fatty alcohols with 10-24 C atoms such as stearol, and palmitol, esters and ethers of fatty acids with alcohols such as glycerol, sucrose, or fatty alcohols with 10-24 C atoms in the fatty acid residue such as sucrose stearate/palmitate with HLB value of less than 6.
Carrageenan, used as a drug release rate modifier, can be used in pure form or as a mixture of different types of carrageenans. Also, it can be used as a mixture with carriers such as starch, lactose and/or glucose. Preferably, carragenan is lambda carrageenan and preferably it is at
least 30%, more preferably at least 50%, even more preferably at least 75% and most preferably at least 90% pure.
The release rate modifiers can be used in the concentration range 3 to 50% (w/w), preferably 10 to 30% (w/w) of the total weight of the composition.
A combination of the above mentioned release rate modifiers can also be used.
Diluents can be selected from water soluble diluents such as lactose, mannitol, sorbitol, dextran and/or from water insoluble diluents such as starch, starch derivatives like pregelatinized starch, crystalline cellulose such as microcrystalline cellulose, alkaline earth salts of phosphoric acid such as calcium hydrogen phosphate in an anhydrous or hydrated state etc.
Surfactants can be selected from nonionic or ionic surfactants having an HLB value of more than 8, preferably of more than 10, where nonionic surfactants can be selected from polyoxyethylated glycol monoethers, cetomacrogol, sorbitan esters (Spans) and polysorbates (Tweens), polyoxyethylene-polyoxypropylene copolymers such as poloxameres, sugar esters with fatty acids with 10 to 22 C atoms. Ionic surfactants can be selected from the group of anionic surfactants such as organic sulphonates (RSO3"), sulphates (ROSOβ') e.g. sodium lauryl sulphate CH3 (CI^)I iS(VNa+, potassium laurate CH^(CH2) ioCOO-K+ or cationic surfactants selected from the group consisting of organic quaternary ammonium halides, R4N+C1", cetrimide, a mixture consisting of tetradecyl (about 68%), dodecyl (about 22%), and hexadecyltrimethylammonium bromides (about 7%), as well as benzalkonium chloride, a mixture of alkylbenzyldimethylammonium chlorides of the general formula
[C6H5CH2N+(CH3)2R]C1-, where R represents a mixture of alkyls from CgHn to C18H37 or ampholytic surfactants selected from sulfobetaines RN+(CH3)2CH2CH2Sθ3~), or betains N-Dodecyl-N,N-Dimethylbetaine, Ci2H25N+(CH3)2CH2COO- .
Binders can be selected from povidone with a K value of 7 to 100, copovidone, polyvinyl alcohol, block copolymers of ethylene oxide and vinyl alcohol sold under trade name Kollicoat IR, microcrystalline cellulose, water soluble types of cellulose ethers such as
hydroxyethylcellulose, hydroxypropylcellulose, hydroxypropylmethylcellulose, starch, pregelatinised starch.
Disintegrants are in a preferred embodiment selected from the group consisting of crospovidone, starch, pregelatinised starch, sodium starch glycolate, microcrystalline cellulose, carboxymethylcellulose sodium (CMC-Na) or calcium (CMC-Ca), cross-linked CMC-Na, polacrilin potassium, low-substituted hydroxypropylcellulose or mixtures thereof.
Granulation aids can be selected from substances having large surface area such as silica, colloidal anhydrous, which can have hydrophilic or hydrophobic surface such as hydrophobic colloidal silica sold under trade name Aerosil R972.
Stabilizers can be selected from substances which when admixed with the quetiapine result in increased chemical stability of the active ingredient in the pharmaceutical composition. In one embodiment of the invention, the stabilizer can be selected from the group of pH modifiers such as moderately acidic or alkaline reacting compounds such as mono or dibasic alkali and alkaline earth metal phosphates such as disodium hydrogen phosphate in anhydrous or hydrated state, hydrated or anhydrous calcium hydrogenphosphate, alkali and alkaline earth metal hydrogencarbonates, alkaline earth carbonates and hydroxycarbonates such as magnesium carbonate heavy, alkaline earth oxides such as magnesium oxide, alkali and alkaline earth salts of polycarboxylic acids such as citric acid or mixture thereof. Stabilizers can be added either as dissolved in the granulation liquid or in a powder form to the rest of the dry components of the granulate. In another embodiment of the invention stabilizer can be selected from antioxidants such as butylhydroxyanizole, butylhydroxytoluene, ascorbic acid, salts of ascorbic acid, natural and synthetic kinons such rutin, coffee acid, quecetin, gallic acid.
Lubricants can be selected from metal stearates such as magnesium, calcium, zinc or aluminium stearate, sodium starch fumarate, hydrogenated vegetable oils, stearic acid.
MicropH modifiers can be selected from organic and/or anorganic acids and/or their metal salts such as sodium, potassium, magnesium, calcium. Preferably, acids such as citric, fumaric, succinic and tartaric acid, which are solid under room temperature conditions (25°C), are used.
In a special embodiment of the invention, the drug containing tablet core can optionally be coated with water soluble coatings based on water soluble polymers selected from cellulose ethers such as low viscosity grades of hydroxypropylmethyl cellulose, hydroxypropyl cellulose, hydroxyethyl cellulose, methyl cellulose, polyvinyl alcohol, graft copolymer of polyethyleneglycol and polyvinyl alcohol Kollicoat IR or Kollicoat Protect), sodium carboxymethylcellulose, aminoalkyl methacrylate copolymer (Eudragit EPO). Such coating can optionally contain further ingredients such as stabilizers, antitacking agents, plasticizers, pigments and colorants. Coating can improve physical appearance such as colour, smoothness of the surface, which is important for processability during packaging of tablets into primary packaging such as blisters of the coated tablet and easiness of swallowing of tablets by patients, it reduces sorption of water (moisture) and the diffusion of oxygen into the core. Coating can be performed by the state of the art equipment such as perforated and non- perforated coating pans and fluid bed coaters.
The release rate of quetiapine from the solid composition can be additionally slowed by coating the above described tablet core with modified release coating based on water unsoluble polymers and/or lipophilic substances having average molecular weight of less than 3000, preferably of less than 1000 and solubility in water at 250C of less than 0.1 mg/ml.
The pharmaceutical compositions of the present invention can be packed into packaging material known from the state of the art such as blisters, glass bottles, containers made of polymeric materials with suitable closure systems. Packing can be performed under normal atmosphere or optionally under reduced oxygen concentration, preferably in inert atmosphere with reduced oxygen concentration or under reduced relative humidity such as 40% RH, preferably 35% RH and most preferably below 30% RH. Reduced oxygen concentration means that the concentration of oxygen in the gas surrounding the solid composition in the primary packaging is below 18vol/vol%, preferably below 10 vol/vol% and most preferably below 5vol/vol%. It is preferred that the solid composition according to present invention has a loss on drying as determined by a halogen dryer such as Mettler HR 73 (20 min., 850C) below 5 weight%, even more preferably below 3.5 weight%.
Quetiapine or its hemifumarate salt used in the present application can be prepared by methods disclosed in prior art such as EP240228, EP282236, EP 1252151 , EP 1660468,
WO2005028457, WO2005028458, WO2005028459, EP1602650, WO200601619, WO2006027789, WO2006094549, WO2006113425, WO20061 17700 or IP137604.
The invention is illustrated by reference to the following examples. However, the examples are not intended to limit the scope of the claims in any way. It will be apparent to those skilled in the art that many modifications, both to materials and methods, may be practiced without departing from the purpose and interest of this invention.
EXAMPLES
Example 1
* ; in form of Quetiapine hemifumarate
Manufacturing procedure:
Active ingredient is mixed with excipients and compressed into tablets.
Example 2
* ; in form of Quetiapine hemifumarate
Manufacturing procedure:
Active ingredient is mixed with excipients and compressed into tablets.
Example 3
* in form of Quetiapine hemifumarate
Manufacturing procedure:
Active ingredient is mixed with excipients and compressed into tablets.
Example 4
* ; in form of Quetiapine hemifumarate
Manufacturing procedure:
Active ingredient is mixed with excipients and compressed into tablets.
Example 5
in form of Quetiapine hemifumarate
Manufacturing procedure:
Active ingredient is mixed with excipients and compressed into tablets.
Example 6
* ; in form of Quetiapine hemifumarate
Manufacturing procedure:
Active ingredient is mixed with Eudragit FS30D and microcrystalline cellulose and granulated in top spray fluid bed granulator Glatt GPCG-3 with aqueous dispersion of Eudragit FS, hypromellose and talc.
Example 7
in form of Quetiapine hemifumarate
Manufacturing procedure:
Active ingredient is mixed with HPMCAS and microcrystalline cellulose and granulated in top spray fluid bed granulator Glatt GPCG-3 with hypromellose. Magnesium stearate is added to the granules and compressed in to tablets.
Example 8
* in form of Quetiapine hemifumarate
Manufacturing procedure:
Active ingredient is mixed with CAP and microcrystalline cellulose and granulated in top spray fluid bed granulator Glatt GPCG-3 with hypromellose. Magnesium stearate is added to the granules and compressed in to tablets.
Quetiapine hemifumarate as used in Examples 1- 8 was in a crystalline form I according to WO03080065. Particle size distribution of quetiapine hemifumarate is depicted in table 1.
Table 1 :
The specific surface area of the samples was between 0.3 and 5 sq.m/g using 6 point BET method.
The average particle diameter was determined by laser light scattering method using a Malvern-Mastersizer Apparatus MS 2000 with Isopar L as dilution medium. Volume particle size distribution is determined by measuring the angular distribution of laser light scattered by a homogeneous suspension of particles.
Example 9
Example 10
Example 11
Example 12
Example 13
Example 14
Example 15
Example 16
Example 17
Example 18
Example 19
Example 20
Example 21
Example 22
Example 23
Example 24
PROCEDURE FOR EXAMPLES 9-24:
a) DIRECT COMPRESSION:
Excipients are mixed. Active ingredient is added and mixed with excipients. To the obtained mixture magnesium stearate is added, homogenous mixture is finally mixed and compressed on tabletting machine.
or
b) WET GRANULATION:
Excipients except magnesium stearate are mixed. Active ingredient is added and mixed with excipients and granulated with granulation liquid. To the obtained granulate magnesium
stearate is added, homogenous mixture is finally mixed and compressed on tabletting machine. Water, organic solvents miscible with water such as ethanol, isopropanol, methanol, acetone or mixtures thereof can be used as a granulation liquid, in which optional binder or other excipients can be dispersed
Particle size and crystal form of quetiapine hemifumarate used in examples 9-24 were the same as in examples 1-8.