A method of preparation of optically pure isomers of hydroxyitraconazole, in particular the two cis dioxolane diastereomers of the sec-butyl (S,S)-isomer, and to phosphate and sulfate derivatives thereof is disclosed. Pharmaceutical compositions containing these compounds and to their use for the treatment of fungal infection are also disclosed.

The present invention relates to a method of preparation of optically pure isomers of hydroxyitraconazole, in particular the two cis dioxolane diastereomers of the sec-butyl (S,S)-isomer, and to phosphate and sulfate derivatives thereof The invention also relates to pharmaceutical compositions containing these compounds and to their use for the treatment of fungal infection.
Itraconazole, a well-known antifungal agent, is defined in the USAN and USP Dictionary of Drug Names as 4-[4-[4-[4-[[2-(2,4-dichlorophenyl)-2-(1H-1,2,4-triazol-1-ylmethyl)-1,3-dioxolan-4-yl]methoxy]phenyl]-1-piperazinyl]phenyl]-2,4dihydro-2-(1-methylpropyl)-3H-1,2,4triazol-3-one or alternatively as (xc2x1)-1-sec-butyl-4[p-[4-[p-[[(2R*,4S *)-2-(2,4-dichlorophenyl)-2-(1H-1,2,4triazol-1-ylmethyl)-1,3-dioxolan-4-yl]methoxy]phenyl]-1-piperazinyl]phenyl]-xcex942-1,2,4-triazolin-5-one. The commercially available material is the cis isomer in the dioxolane ring and is represented by the structural formula I:
It will be noted that there are three asymmetric carbons in formula I (denoted by asterisks): two in the dioxolane ring and one in the sec-butyl side chain on the triazolone. There are eight possible isomers of a structure having three asymmetric carbons: (ROAR), (R,R,S), (R,S,S), (S,S,S), (R,S,R), (S,R,S), (S,R,R) and (S,S,R). Because the commercially available itraconazole is a cis isomer, it comprises a mixture of only those isomers that describe a cis relationship in the dioxolane ring. Adopting the convention that the first denoted chiral center is at C-2 of the dioxolane ring, the second is at C-4 of the dioxolane and the third is in the sec-butyl group, commercial itraconazole is a mixture of (R,S,S), (R,S,R), (S,R,S) and (S,R,R) isomers. Compounds of this invention have the (2R,4S) and (2S,4R) configurations in the dioxolane ring.
The hydroxylation of the methylene carbon of the sec-butyl side chain creates an additional chiral center and gives rise to eight additional possible enantiomers. The compounds of the present invention are those in which the two asymmetric centers in the butyl chain are S (at the a: carbon) and S (at the xcex2 carbon).
The graphic representations of racemic, ambiscalemic and scalemic or enantiomerically pure compounds used herein are taken from Maehr J. Chem. Ed. 62, 114-120 (1985): solid and broken wedges are used to denote the absolute configuration of a chiral element; wavy lines indicate disavowal of any stereochemical implication which the bond it represents could generate; solid and broken bold lines are geometric descriptors indicating the relative configuration shown but denoting racemic character; and wedge outlines and dotted or broken lines denote enantiomerically pure compounds of indeterminate absolute configuration. Thus, among the structures below, those having open wedges are intended to encompass both of the pure enantiomers of that pair, those having solid wedges are intended to encompass the single, pure enantiomer having the absolute stereochemistry shown.
Itraconazole is an orally active, broad-spectrum anti-fungal agent and is structurally related to miconazole and clotrimazole. It impairs the synthesis of ergosterol, which is the principal sterol of fungal cell membranes. This presumably results in an increased permeability and leakage of intracellular content. At high concentration, cellular internal organelles involute, peroxisomes increase, and necrotic changes occur.
Following oral administration, itraconazole is slowly absorbed. Peak plasma levels are attained after 15 days of daily administration, and the pharrnacokinetic behavior of itraconazole is nonlinear. The compound is eventually metabolized through the biologically active hydroxyitraconazole to several inactive metabolites. Metabolism is apparently through hepatic mechanisms, and in most subjects no metabolites are excreted in the urine [see, Hardin et al., Antimicro. Agents and Chemotherapy 32, 1310-1313 (1983)].
The racemic mixture of itraconazole has been approved for use as an antifungal agent for blastomycosis and histoplasmosis. The compound is also being investigated for use in aspergillosis, coccidioidomycosis, cryptococcosis, onychomycosis, dermatophyte and candidiasis infections.
Systemic fungal diseases (systemic mycoses) are usually chronic, very slowly developing conditions induced by opportunistic causative fungi which may not normally be pathogenic. However when they enter a host compromised by HIV, ionizing irradiation, corticosteroids, immunosuppressives, etc. or by such conditions as emphysema, bronchiectasis, diabetes mellitus, leukemia, burns and the like, they may become pathogenic. Symptoms in such fungal diseases are generally not intense, and may include fever, chills, anorexia and weight loss, malaise, and depression. Fungal diseases are often confined to typical anatomic distributions, and many involve a primary focus in the lung, with more characteristic manifestations of specific fungal infections when the fungus disseminates from a primary focus. For example, coccidioidomycosis occurs in a primary form as an acute, benign, self-limiting respiratory disease, with progressive disease developing from the primary form as a chronic, often fatal infection of the skin, lymph glands, spleen and liver. Similarly, blastomycosis primarily involves the lungs, and occasionally spreads to the skin. Other infectious diseases such as paracoccidioidomycosis and candidiasis offer a different course, and depending on the etiology may exhibit several forms involving the skin, mucous membranes, lymph nodes, and internal organs.
Superficial fungal infections are caused by dermatophytes or fungi that involve the outer layers of the skin, hair or nails. The infections may result in a mild inflammation, and cause intermittent remissions and exacerbations of a gradually extending, scaling, raised lesion. Yeast infections including candidiasis, and oral candidiasis (thrush) are usually restricted to the skin, and mucous membranes, and the symptoms vary with the site of infection.
Adverse effects associated with the administration of itraconazole include hepatotoxicity and inhibition of drug metabolism in the liver, leading to numerous, clinically significant, adverse drug interactions. [See, Gascon and Dayer Eur. J. Clin. Pharmacol. 41, 573-578 (1991) (interaction with midazolam); Honig et al. J. Clin. Pharmacol. 33, 1201-1206 (1993) (interaction with terfenadine); and Neuvonen et al. Clin. Pharmacol. Therap. 60, 54-61 (1996) (interaction with lovastatin).] Hypersensitivity reactions including urticaria and elevations in serum liver enzymes are also associated with the administration of the drug. Hepatoxicity is a less common but more serious adverse effect. Indeed, the use of oral conazoles as first line antifungals is usually discouraged because of the potentially serious consequences of the low incidence of hepatotoxicity [See, e.g., Lavrijsen et al. Lancet 340, 251-252 (1992)].
We have found evidence in our own studies in isolated guinea pig and rabbit hearts that the administration of racemic conazoles may be associated with an increased risk of cardiac arrhythmia. Arrhythmia has not been heretofore reported as a side effect of systemic itraconazole, although a particular subtype of arrhythmia, Torsades de Pointes, has been reported when racemic itraconazole was administered concurrently with terfenadine [Pohjola et al. Eur. J. Clin. Pharmacol. 45, 191-193 (1993)]. The lack of clinical reports of arrhythmia or QT anomalies may simply be a reflection of the fact that there is to date a relatively small subject population.
The relative non-polarity and insolubility of itraconazole give rise to two other drawbacks: it cannot be readily formulated in parenteral solution and it does not penetrate the blood-brain barrier. As a result, numerous therapeutic indications which require rapid achievement of efficacious blood levels or access to the CNS are beyond treatment with itraconazole. In particular, central candidiasis, which may be responsible for AIDS related dementia, cannot be treated with itraconazole.
Thus it would be particularly desirable to find a compound with the advantages of itraconazole which would not have the aforementioned disadvantages.
The compounds and compositions of the invention possess potent activity in treating local and systemic fungal, yeast and dermatophyte infections while avoiding adverse effects associated with the administration of itraconazole. The compounds and compositions of the invention also enjoy the particular advantage of being much more soluble in physiologically compatible solutions than is itraconazole. The preparation, for the first time, of the individual enantiomers of hydroxyitraconazole permits the preparation of unusually soluble single enantiomers and derivatives thereof.
In one aspect the invention relates to substantially pure single enantiomers of a compound of formula:
wherein X1 and X2 are independently chlorine or fluorine and R is hydrogen, xe2x80x94P(O)(OH)2 or xe2x80x94SO3H, or a salt thereof There are two such possible single enantiomers, represented by the formulae A and B:
In another aspect the invention relates to pharmaceutical compositions comprising the compounds above and a pharmaceutically acceptable carrier. The compositions contain less than 10% by weight of other enantiomers or diastereomers having the same structural formula. Preferably, the compositions contain a single enantiomer A or B.
In another aspect, the invention relates to a method for treating or preventing fungal infection comprising administering to a mammal suffering from (or at risk from) a fungal infection a therapeutically effective amount of the above compounds.
In another aspect, the invention relates to a process for preparing a 2,4-disubstituted 3H-1,2,4triazol-3-one of formula
wherein R1 is aryl or substituted aryl. The process comprises reacting a 2-aryl-3H-1,2,4-triazol-3-one of formula
with a cis 4,5-dimethyl-1,2,3-dioxathiolane 2,2-dioxide of formula
by forming the potassium salt of said 2-aryl-3H-1,2,4triazol-3-one with an excess of potassium hydride in an inert solvent in the presence of at least one equivalent of 1,4,7,10,13,16-hexaoxocyclooctadecane (18-crown-6) and adding said dioxathiolane at xe2x88x925xc2x0 C. to 25xc2x0 C. For the synthesis of itraconazole enantiomers, R1 is preferably
wherein R2 is methyl or benzyl.
In another aspect, the invention relates to a process for preparing a dioxolane tosylate of formula
wherein Ph is phenyl or substituted phenyl, Tos is toluenesulfonyl and R3 is heterocyclylmethyl. The process comprises the sequential steps of (a) dissolving a ketone of formula R3C(O) Ph and about one equivalent of an optically active 1,2-dihydroxypropyl toluenesulfonate in an inert solvent; (b) cooling to a temperature below 15xc2x0 C.; (c) adding an excess of trifluoromethanesulfonic acid at  less than 15xc2x0 C.; (d) allowing the foregoing materials to react to form a ketal; and (e) introducing said ketal in solution into an excess of alkali metal carbonate or bicarbonate in water at 0 to 10xc2x0 C.
The compounds of the invention are synthesized by the general route shown in Schemes 1, 2, 3 and 4:
As shown in Scheme 1, the chiral dioxolane DTTT (3) is prepared by a literature method from threo-tosyloxy-1,2-propanediol by acid-catalyzed ketalization to provide DTT.
As shown in Scheme 2, the dioxothiolane 5 is prepared from a butanediol of appropriate configuration by treatment with thionyl chloride, followed by in situ oxidation of the resulting cyclic sulfite with sodium periodate in the presence of ruthenium trichloride.
As shown in Scheme 3,2,4-dihydro-4-[4-[4-(4-methoxyphenyl)-piperazinyl]phenyl]-3H-1,2,4-triazol-3-one (6), prepared by the method of example XVII in U.S. Pat. No. 4,267,179, is reacted with the dioxothiolane 5, prepared by the procedure of Gao and Sharpless [J. Am. Chem. Soc. 110, 7538 (1988)], using potassium hydride in DMF in the presence of crown ether. The resulting methoxy-sulfate salt is cleaved to the phenol-alcohol 8 by heating with 48% HBr at 100-110xc2x0 C.
As shown in Scheme 4, the tosyl ester 3 from Scheme 1 and the phenol-alcohol 8 from Scheme 3 are reacted in the presence of potassium hydroxide in DMF to provide the product 9.
When it is desired that R in A or B be sulfate, the order of steps in Schemes 3 and 4 can be rearranged so that the methoxyl of 6 is cleaved before the addition of the residue of the sec-butyl side chain, and instead, 3 is added first, then 5.
When it is desired that R in A or B be phosphate, 8 is treated first with t-butyldimethylsilyl chloride and diisopropylethylamine to protect the phenol, then with dibenzyl diisopropylphosphoramidite and t-butylhydroperooxide according to the procedure of PCT application WO94/17407, which is incorporated herein by reference, to phosphorylate the alcohol. The silyl protecting group is removed with anhydrous tetrabutylammonium fluoride and the benzyl-protected phosphate is coupled with the doxolane tosylate as in Scheme 3. The benzyl protecting groups are cleaved by hydrogenolysis in the presence of a palladium catalyst to provide the phosphate product.
It will be noted that in the above Scheme 3 a racemic mixture of the RR and SS enantiomers of 8 is formed. The racemic mixture can be readily separated by chromatography on a chiral medium by methods well known in the art. Alternatively, single enantiomers can be produced by two different modifications of Scheme 3, shown in Schemes 5, 6 and 7:
2,4-Dihydro-4-[4-[4-(4-methoxyphenyl)-piperazinyl]phenyl]-3H-1,2,4-triazol-3-one (6) is reacted with the dioxothiolane 5a as described for Scheme 3, but the sulfate ester of the resulting methoxy-sulfate salt is hydrolyzed without cleaving the methyl from the phenol by heating with 48% HBr at 45-50xc2x0 C. to produce alcohol 11. As shown in Scheme 6, alcohol 11 may be treated with diisopropylazodicarboxylate, triphenylphosphine and benzoic acid according to the method of Mitsunobu [Synthesis 1981, 1-27], hydrolysed with potassium hydroxide in methanol, and cleaved with 48% HBr at reflux to provide 17, the single enantiomer of 8. Alternatively, as shown in Scheme 7, the alcohol 11 may be treated with methanesulfonyl chloride in the presence of dimethylaminopyridine and diisopropylethylamine and the resulting mesylate ester of 14 inverted by treatment with cesium propionate according to the method of Senanyake et al. [Tet. Lett. 34, 2425 (1993)] to provide the propionate ester 16. The methoxy-ester 16 may be cleaved as before with potassium hydroxide and then HBr to give 17.

A suspension of (R)-tosyloxy-1,2-propanediol (10.0 g, 40 mmol) and 1-(2,4-dichlorophenyl)-2-(1H-1,2,4-triazol-1-yl)ethanone (10.0 g, 39 mmol) in toluene (50 mL) is cooled to 5xc2x0 C., Triflic acid (15 mL, 4 eq) is slowly added so that the temperature stays below 15xc2x0 C. After complete addition the reaction mixture (2 phases) is stirred at 25xc2x0 C. for 60 h. The mixture is diluted with ethyl acetate (EtOAc) (200 mL) and slowly dropped into a solution of K2CO3 (50 g) in water (400 mL) at 5xc2x0 C. The organic layer is separated and the aqueous layer washed with EtOAc (150 mL). The combined organic extracts are dried over Na2SO4 (10 g) and filtered. A solution of toluenesulfonic acid (TsOH) (7.6 g monohydrate in EtOAc (50 mL) is slowly added at 25xc2x0 C. The white solid product is filtered after 30 min, washed and dried to give cis DTTT containing 5% trans. Two crystallizations from CH3CN (400 mL) gives 13.5 g pure (2R,4S)-DTTT (50% yield) [a]D25=+16.6xc2x0 (c=1, MeOH); ee=99.6%.

A suspension of (S)-tosyloxy-1,2-propanediol (14.8 g, 60 mmol) and 1-(2,4-dichlorophenyl)-2-(1H-1,2,4-triazol-1-yl)ethanone (15.2 g, 58 mmol) in toluene (80 mL) is cooled to 5xc2x0 C. Triflic acid (18 mL) is slowly added so that the temperature stays below 15xc2x0 C. After complete addition the reaction mixture (2 phases) is stirred at 25xc2x0 C. for 60 h. The mixture is diluted with CH2Cl2 (300 mL) and slowly dropped in a solution of K2CO3 (30 g) in water (300 mL) at 5xc2x0 C. the organic layer is separated and concentrated to about 100 mL. The residue is diluted with methyl isobutylketone (MIBK) (300 mL) and a solution of TsOH (11.0 g monohydrate) in MIBK (100 mL) is slowly added at 25xc2x0 C. The white solid product is filtered after 30 min., washed and dried to give cis DTTT containing 6% trans. Two crystallizations from CH3CN (600 mL) gives 16.6 g pure (2S,4R)-DTIT (44% yield).
[xcex1]D25=xe2x88x9216.6xc2x0 (c=1, MeOH) ee=99.6%
A three-necked 500 mL round-bottom flask fitted with a reflux condenser and a calcium chloride drying tube was charged with meso-2,3-butanediol (10.0 g, 10.1 mL, 0.11 mol) and carbon tetrachloride (20 mL). Thionyl chloride (15.98 g, 9.8 mL, 0.134 mol) was added dropwise at room temperature. Rapid gas evolution began. The reaction mixture was stirred at room temperature for 10 min, then warmed to reflux for 30 min to insure complete removal of HCl gas. The reaction mixture was cooled to 0xc2x0 C. in an ice-water bath and acetonitrile (120 mL), RuCl3 H2O (14 mg, 0.07 mmol), NaIO4 (35.6, 0.166 mol) and water (180 mL) were added, respectively. The reaction mixture was allowed to warm to room temperature and stirred for 1.5 hr. The mixture was poured into methyl t-butyl ether (900 mL) and water was added to dissolve the remaining NaIO4 (ea. 600 mL). The phases were separated and the aqueous phase was extracted with methyl t-butyl ether (2xc3x97100 mL). The combined organic phases were washed with water (1xc3x9750 mL), saturated aqueous sodium bicarbonate (2xc3x9750 mL) and saturated aqueous sodium chloride (1xc3x9750 mL). The organic solution was dried over anhydrous magnesium sulfate and filtered through a bed of silica gel to give a clear and colorless solution. the solvent was removed in vacuo to give 16.20 g (96% yield) of the title compound.
A three-necked 500 mL round-bottom flask fitted with a reflux condenser and a calcium chloride drying tube was charged with (2R,3R)-(+)-2,3-butanediol (10.0 g, 10.1 ml, 0.11 mol) and carbon tetrachloride (120 mL). Thionyl chloride (16.0 g, 9.8 mL, 0.13 mol) was added dropwise at room temperature. Rapid gas evolution began. The reaction mixture was stirred at room temperature for 10 min, then warmed to reflux for 30 min to insure complete removal of HCl gas. The reaction mixture was cooled to 0xc2x0 C. in an ice-water bath and acetonitrile (120 mL), RuCl3 H2O (14 mg, 0.07 mmol), NaIO4 (35.6 g, 0.17 mol) and water (180 mL) were added, respectively. The reaction mixture was allowed to warm to room temperature and stirred for 1.5 hr. The mixture was poured into methyl t-butyl ether (900 mL), and water was added to dissolve the remaining NaIO4 (ca. 600 mL). The phases were separated and the aqueous phase was extracted with methyl t-butyl ether (2xc3x97100 mL). The combined organic phases were washed with water (1xc3x9750 mL), saturated aqueous sodium bicarbonate (2xc3x9750 mL) and saturated aqueous bicarbonate (2xc3x9750 mL) and saturated aqueous sodium chloride (1xc3x9750 mL). The organic solution was dried over anhydrous magnesium sulfate and filtered through a bed of silica gel to give a clear and colorless solution. The solvent was removed in vacuo to give 16.01 g (95% yield) of the title compound.
To a suspension of potassium hydride (8.53 g, 74.4 mmol, 35% dispersion in oil), prewashed with hexane (2xc3x9750 mL) in N,N-dimethylformamide (120 mL) at room temperature was added 18-crown-6 (15.73 g, 59.5 mmol) and 2,4dihydro-4-[4-[4-(4-methoxyphenyl)-1-piperazinyl]phenyl]-3-H-1,2,4-triazol-3-one (6)(17.43 g, 49.6 mmol). The solution was warmed to 80-85xc2x0 C. for 1.5 hr, then cooled in an ice-water bath to 9xc2x0 C. To this solution was added (4R*,5S*)-4,5-dimethyl-1,2,3-dioxathiolane 2,2-dioxide (5) (8.00 g, 52.6 mmol). The reaction mixture exothermed to 13xc2x0 C. After recooling to 0xc2x0 C., the reaction mixture was warmed to room temperature and stirred for 18 hr. The mixture was poured into 2.5 L of methyl t-butyl ether, and the solid product was filtered from the solution. Water (1 L) was added to the crude solid, and the mixture was warmed to 80xc2x0 C. and the solid by-product was removed by filtration. The solid was rinsed with water (400 mL), and the filtrate was allowed to cool to room temperature. Saturated aqueous potassium chloride (50 mL) was added and the product precipitated from the solution immediately. After filtration, the solid was dried in vacuo to give 13.46 a (47% yield) of the title compound.
To potassium (2R*,3R*)-3-[2,4-Dihydro-4-[4-[4(4-methoxyphenyl)-1-piperazinyl]phenyl]-3H-1,2,4triazol-3-on-2-yl]but-2-yl sulfate (7) (7.00 g, 12.9 mmol) and sodium sulfite (480 mg, 3.80 mmol) was added 48% HBr (40 mL). The solution was heated to reflux for 6 hr, then cooled to room temperature. The reaction mixture was poured into water (100 mL) and the pH raised to 7-8 with saturated aqueous potassium carbonate solution. The product was collected by filtration and dried in vacua. The filtrate was extracted with chloroform (3xc3x9720 mL), and the combined organic fractions were dried over anhydrous magnesium sulfate, filtered and the solvent removed in vacuo to give a white solid. The solids were combined to give 3.89 g (62% yield) of the title compound as an adduct with SO3.
To 2,4-dihydro-4[4-[4-(4-hydroxyphenyl)-1-piperazinyl]phenyl]-2[(1R*,2R*)-(2-hydroxyl-1-methylpropyl)]-3H-1,2,4-triazol-3-one SO3 adduct (8) (1.00 g, 2.04 mmol) and (xe2x88x92)-(2R4S)-2-(2,4-dichlorophenyl)-2-(1H-1,2,4-triazol-1-ylmethyl)-4-tosylocxymethyl-1,3-dioxolane tosylate (3a tosylate) (1.52 g, 2.32 mmol) was added powdered potassium hydroxide (658 mg, 11.7 mmol) and N,N-dimethylformamide (30 mL). The reaction mixture was warmed to 50-55xc2x0 C. for 8 hr and cooled to room temperature. Water was added (300 mL), and the mixture was stirred for 30 min. Saturated aqueous sodium chloride (50 mL) was added to the mixture, the mixture was stirred for 1 hr and the crude product was collected by filtration and dried in vacuo. Purification by flash chromatography, eluting with ethyl acetate, followed by chloroform, 98:2 chloroform:methanol, then 95:5 chloroform:methanol gave 420 mg (29% yield) of the title compound; [xcex1]D25=19.7xc2x0 (c=0.1, MeOH).
To 2,4 -dihydro-4-[4-[4(4-hydroxyphenyl)-1-piperazinyl]phenyl]-2-[(1R*,2R*)-2-hydroxy-1-methylpropyl)]-3H-1,2,4-triazol-3-one (8) (1.00 g, 2.04 mmol) and (xe2x88x92)-(2S,4R)-2-(2,4dichlorophenyl)-2-(1H-1,2,4triazol-1-ylmethyl)-4-tosyloxymethyl-1,3-dioxolane tosylate (3b tosylate) (1.02 g, 1.56 mmol) was added powdered potassium hydroxide (428 mg, 7.63 mmol) and N,N-dimethylformamide (22 mL). The reaction mixture was warmed to 50-55xc2x0 C. for 7 hr and cooled to room temperature. Water was added (220 mL) and the crude product was collected by filtration and dried in vacuo. Purification by flash chromatography, eluting with 98:2 chloroform:methanol, and recrystallization from methanol gave 388 mg (23% yield) of the title compound; [xcex1]D≅=xe2x88x9218.5xc2x0 (c=0.1, MeOH).
The compounds in which X1 and X2 are fluorine may be made in analogous fashion from the appropriate 3, which is available by condensation as shown in Scheme 1 from the appropriate 2,4-dihalophenylethanone.
The term xe2x80x9csubstantially pure single enantiomerxe2x80x9d as used herein means that less than 10% by weight of other enantiomers is present. The compositions contain hydroxyitraconazole or a derivative thereof, in which at least 90% by weight of the hydroxyitraconazole has a cis dioxolane and a sec-butyl side chain of the stereochemistry shown above.
Microbiological and pharmacologic studies can be used to determine the relative potency and the profile of specificity of the optically pure enantiomers, and the racemic mixture of itraconazole as antimycotic agents with a broad spectrum of activity against many fungi, yeast, and dermatophytes.
With respect to antimicrobial activity of the aforementioned compounds, selected experiments are illustrated to profile useful antimicrobial activity, and not to limit this invention in any way, including the scope of susceptible microorganisms. Antifungal conazoles may be evaluated in vitro at several concentrations (in xcexcg/mL) against a number of fungi and bacteria. [See, Van Cutsem Chemotherapy 38 Suppl 1, 3-11 (1992) and Van Cutsem et al. Rev. Infec. Dis. 9 Suppl1, S15-S32 (1987)]. The fungistatic assay is carried out in Sabouraud""s liquid (1 g of neopeptone Difco and 2 g of glucose Difco per 100 mL of distilled water) in 16xc3x97160 mm test tubes, each containing 4.5 mL of liquid medium which has been autoclaved at 120xc2x0 for 5 min. The compounds to be tested are dissolved in 50% alcohol at initial concentration of 20 mg/mL. The solutions are subsequently diluted with sterile distilled water to give a concentration of 10 mg/mL. Successive decimal dilutions are made in distilled water. To tubes containing 4.5 mL of Sabouraud""s liquid medium 0.5 mL of the solution of the drug is added, thereby obtaining concentrations of 1000, 500, 100, 10, and 1 xcexcg/mL of medium. Control tubes are prepared by adding 0.5 mL of distilled water to 4.5 of mL medium, alcohol being added to give concentrations identical with the tubes containing 1000 and 500 xcexcg of the drug. The filamentous fuingi are incubated in Sabouraud""s agar at 25xc2x0 for 2-3 weeks. A block of 2xc3x972xc3x972 mm is then inoculated into the medium. All cultures are made in duplicate and are incubated at 25xc2x0 for 14 days. Itraconazole antifungal activity is enhanced in vitro in Sabouraud broth containing 10% inactivated bovine serum, and depends on the test medium used. Complete or marked inhibition of growth in Sabouraud broth after 14 days of incubation may be observed with Microsporum canis, Trichophyton mentagrophytes, Candida albicans, Sporothrix schenckii, Paracoccidioides brasiliensis, Blastomyces dermatitides, Histoplasma spp., Aspergillus spp. and other fungi and bacteria.
A 10 mL tube containing 4 mL of Sabourauds dextrose broth was inoculated with 1 colony of Candida albicans picked from a plate of pure culture. The strain was ordered from the American Type Culture Collection (ATCC). The organism was grown for 4 hours at 30xc2x0 C. while shaking at 150 RPM. While the organism was growing, samples of the diastereomeric mixtures 9 containing hydroxy-itraconazoles A and B were solubilized to a concentration of 10 mg/mL in DMSO. Each sample was then diluted 1:10 to make 1 mg/mL samples or 1000 xcexcg/mL. These samples were then diluted by serial 2-fold dilutions to produce samples now containing 1000, 500, 250, 125, 62.5, 31.25, 15.6 xcexcg/mL. A 96-well microtiter dish was set up with 98 xcexcL of liquid growth media in each test well, along with 1 xcexcL of hydroxy-itraconazole solution. At 4 hours of growth time the Candida albicans was diluted to a 0.5 McFarland standard representing about 105-106 cells/mL and 1 xcexcL of this inoculum placed into each test well of the microtiter dish. The dish was then covered and incubated at 30xc2x0 C. for 16 hours. The MIC""s for both mixtures containing A and B were below 0.156 xcexcg/mL.
Actively growing cultures of Candida albicans, Cryptococcus neoformens and Saccharomnyces cerevisiae were prepared as described above. The cultures were diluted to a 0.5 McFarland standard and swabbed onto a 150 mm Sabouraud Dextrose agar plates. Paper disks (7 mm) were placed onto the agar plates using a disk dispenser. Next 10 xcexcl of 10 mg/mL solutions of each sample hydroxy-itraconazole was pipetted onto separate paper disks. The plates were then incubated at 30xc2x0 C. for 16 hours. Zones of inhibition were then measured in mm.
The data are summarized below.
Data Represent Zones of Inhibition in mm.
In vivo activity of hydroxyitraconazole and derivatives may be compared against experimental cutaneous candidosis in guinea pigs, and vaginal candidosis in rats. The in vivo activity of the compounds in vaginal candidosis is evaluated by inducing vaginal infection with C. albicans in ovariectomized and hysterectomized Wistar rats (100 g) which are treated weekly with 100 xcexcg of estradiol undecanoate in sesame oil, subcutaneously. Animals in pseudooestrus are infected intravaginally with a fixed concentration of C. albicans in saline. Control of infection or cure is estimated by taking vaginal smears at fixed days after infection. Drugs to be evaluated, and compared on a mg/kg basis, may be given prophylactically, or therapeutically and their efficacy judged by comparison the ratio of negative animals to the total number in each drug group. In similar studies, the activity against cutaneous candidosis in guinea pigs [(Van Cutsem et al. Chemotherapy 17, 392, (1972)] provides the basis of comparison.
The compounds of the present invention allow the treatment of fungal infections while avoiding the adverse effects associated with itraconazole. The term xe2x80x9cadverse effectsxe2x80x9d includes, but is not limited to, arrhythmogenicity, hepatotoxicity and elevations in serum liver enzymes, drug interactions, hypersensitivity reactions including urticaria, nausea, vomiting, abdominal pain, headache, dizziness and the like.
The potential for promoting arrhythmia is evaluated by examining the effects of the isomers of hydroxyitraconazole on cardiac action potential and contractility in human, canine and rabbit hearts. Torsades de Pointes is a well known side effect of antiarrhythmic drugs, such as quinidine, sotalol and acetyl-procainamide, which cause a prolongation of cardiac repolarization. All of these drugs have in common the ability to block a cellular potassium channel called the delayed rectifier (IK), and it is generally assumed that this is mechanistically linked to their ability to induce the syndrome of Torsades de Pointes. [See, Zehender et al. Cardiovascular Drugs Ther., 5 515-530 (1991).] Increases in QT duration and action potential duration in isolated guinea pig or rabbit hearts can therefore be used to indicate an arrhythmogenic effect. Hearts are perfused with an oxygenated Tyrode""s solution, containing 0.0; 1.0; 5.0; 10.0 or 30.0 xcexcM of racemic itraconazole. QT duration and action potential duration (APD) are measured from cardiac electrodes.
To observe the effects in viv, mongrel dogs of either sex weighing 5-20 kg are anesthetized and instrumented by standard techniques for blood pressure and EKG. A solid state transducer for dP/dT is placed in the left cardiac ventricle, and an epicardial electrode is put into place. The test compound is infused at progressively higher doses, beginning at 1 xcexcg/kg/min for 15 to 30 minutes and increased incrementally until a cardiovascular collapse ensues. Parameters measured are: blood pressure, heart rate, dP/dT, and the QT-interval. Measurements of hemodynamics and electrical activity, including QTc interval, are made in response to the test compound and compared.
The potential for promoting hepatotoxicity is assessed in vitro in human hepatic microsomes, human lymphocytes or other cell culture systems. Hepatic microsomes are prepared from human liver. Tissue is thawed and then homogenized in 0.15 M KCl in a Polytron homogenizer. The homogenate is centrifuged and the pellet is resuspended and homogenized in 0.15 M KCl. Aliquots are frozen and stored at xe2x88x9270xc2x0 C. Human lymphocytes are aseptically isolated from fresh, heparinized human blood. Blood is diluted with Eagle""s minimal essential medium and layered on Ficoll-Paque. The samples are centrifuged, and lymphocytes are then removed from the aqueous-Ficoll interface and suspended in medium (15 Mm HEPES, pH, 7.4). The cells are then centrifuged, washed once in the HEPES medium, and resuspended.
Cytotoxicity is assessed by the conversion of 3-(4,5 dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MMT) to a purple formazan. The conversion of MTT to dye is done in multiwell plates. After preparation, hepatic microsomes or lymphocytes are incubated alone or with the test compound in a concentration range from 1 to 400 xcexcM at 37xc2x0 C. in a humidified incubator. After incubation, the microsomes/cells are washed with 5% albumin in HEPES-buffered medium and resuspended. The microsomes/cells are then incubated at 37xc2x0 C. in a humidified incubator. After the incubation, 125 xcexcg of MTT is added to each well. The plates are incubated at 37xc2x0 C. and centrifuged. After centrifugation, 100 xcexcL of isopropanot is added and, after incubation, the optical density is determined using an automated plate-reader.
The magnitude of a prophylactic or therapeutic dose of hydroxyitraconazole or derivative in the acute or chronic management of disease will vary with the severity of the condition to be treated, and the route of administration. The dose, and perhaps the dose frequency, will also vary according to the age, body weight, and response of the individual patient. In general, the total daily dose range, for hydroxyitraconazole or a derivative, for the conditions described herein, is from about 50 m to about 1200 mg, in single or divided doses. Preferably, a daily dose range should be between about 100 mg to about 800 mg, in single or divided doses, while most preferably, a daily dose range should be between about 200 mg and 400 mg, in divided doses. In managing the patient, the therapy should be initiated at a lower dose, perhaps about 100 mg to about 200 mg, and increased up to about 400 mg or higher depending on the patient""s global response. It is further recommended that children, and patients over 65 years, and those with impaired renal, or hepatic function, initially receive low doses, and that they be titrated based on individual response(s) and blood level(s). It may be necessary to use dosages outside these ranges in some cases as will be apparent to those skilled in the art. Further, it is noted that the clinician or treating physician will know how and when to interrupt, adjust, or terminate therapy in conjunction with individual patient response. An amount sufficient to alleviate or prevent infections but insufficient to cause adverse effects is encompassed by the above-described dosage amounts and dose frequency schedule.
Any suitable route of administration may be employed for providing the patient with an effective dosage of hydroxyitraconazole or derivative. For example, oral, rectal, parenteral (subcutaneous, intramuscular, intravenous), transdermal, topical and like forms of administration may be employed. Dosage forms include tablets, troches, dispersions, suspensions, solutions, capsules, patches, ointments, creams, shampoos and the like.
The pharmaceutical compositions of the present invention comprise hydroxyitraconazole or derivative as the active ingredient, or a pharmaceutically acceptable salt thereof, and may also contain a pharmaceutically acceptable carrier, and optionally, other therapeutic ingredients.
The terms xe2x80x9cpharmaceutically acceptable saltsxe2x80x9d or xe2x80x9ca pharmaceutically acceptable salt thereofxe2x80x9d refer to salts prepared from pharmaceutically acceptable non-toxic acids or bases including inorganic acids and bases and organic acids and bases. Since the hydroxy compound of the present invention is basic, salts may be prepared from pharmaceutically acceptable non-toxic acids including inorganic and organic acids. Suitable pharmaceutically acceptable acid addition salts for the compound of the present invention include acetic, benzenesulfonic (besylate), benzoic, camphorsulfonic, citric, ethenesulfonic, fumaric, gluconic, glutamic, hydrobromic, hydrochloric, isethionic, lactic, maleic, malic, mandelic, methanesulfonic (mesylate), mucic, nitric, pamoic, pantothenic, phosphoric, succinic, sulfuric, tartaric, p-toluenesulfonic, and the like. The phosphate and sulfate, being acidic, allow for the preparation of salts of bases as well as internal salts. Suitable pharmaceutically acceptable base addition salts for the compounds of the present invention include metallic salts made from aluminum, calcium, lithium, magnesium, potassium, sodium and zinc or organic salts made from lysine, N,Nxe2x80x2-dibenzylethylenediamine, chloroprocaine, choline, diethanolamine, ethylenediamine, meglumine (N-methylglucamine) and procaine.
The compositions of the present invention include compositions such as suspensions, solutions, elixirs, aerosols, and solid dosage forms. Carriers such as starches, sugars, microcrystalline cellulose, diluents, granulating agents, lubricants, binders, disintegrating agents, and the like, are commonly used in the case of oral solid preparations (such as powders, capsules, and tablets), with the oral solid preparations being preferred over the oral liquid preparations. The most preferred oral solid preparation is tablets.
Because of their ease of administration, tablets and capsules represent the most advantageous oral dosage unit form, in which case solid pharmaceutical carriers are employed. If desired, tablets may be coated by standard aqueous or nonaqueous techniques.
A second preferred route of administration is topically, for which creams, ointments, shampoos, and the like are well suited.
In addition to the common dosage forms set out above, the compounds of the present invention may also be administered by controlled release means and/or delivery devices and, because of their solubility, may also be employed in parenteral solutions, such as for intravenous administration.
Pharmaceutical compositions of the present invention suitable for oral administration may be presented as discrete units such as capsules, cachets, or tablets, or aerosol sprays, each containing a predetermined amount of the active ingredient, as a powder or granules, or as a solution or a suspension in an aqueous liquid, a non-aqueous liquid, an oil-in-water emulsion, or a water-in-oil liquid emulsion. Such compositions may be prepared by any of the methods of pharmacy, but all methods include the step of bringing into association the active ingredient with the carrier which constitutes one or more necessary ingredients. In general, the compositions are prepared by uniformly and intimately admixing the active ingredient with liquid carriers or finely divided solid carriers or both, and then, if necessary, shaping the product into the desired presentation.
For example, a tablet may be prepared by compression or molding, optionally, with one or more accessory ingredients. Compressed tablets may be prepared by compressing in a suitable machine the active ingredient in a free-flowing form such as powder or granules, optionally mixed with a binder, lubricant, inert diluent, surface active or dispersing agent Molded tablets may be made by molding in a suitable machine, a mixture of the powdered compound moistened with an inert liquid diluent. Desirably, each tablet contains from about 100 mg to about 300 mg of the active ingredient. Most preferably, the tablet, cachet or capsule contains either one of three dosages, about 50 mg, about 100 mg, or about 200 mg of the active ingredient.
For topical application, there are employed as non-sprayable forms, viscous to semi-solid or solid forms comprising a carrier compatible with topical application and having a dynamic viscosity preferably greater than water. Suitable formulations include but are not limited to solutions, suspensions, emulsions, creams, ointments, powders, liniments, salves, aerosols, etc., which are, if desired, sterilized or mixed with auxiliary agents, e.g., preservatives, stabilizers, wetting agents, buffers or salts for influencing osmotic pressure, etc. For topical application, also suitable are sprayable aerosol preparations wherein the active ingredient, preferably in combination with a solid or liquid inert carrier material, is packaged in a squeeze bottle or in admixture with a pressurized volatile, normally gaseous propellant, e.g., a freon.


A process for making pre-cooked pasta from freshly extruded pasta dough and pastas made by the method. The process involves steaming freshly extruded pasta dough, soaking the steamed dough, removing excess moisture from the surface of the pasta dough and toasting. The desired textural attributes can be achieved by manipulating the processing conditions and the moisture content of the pasta dough. The pre-cooked pasta is particularly suited for hot or boiling water pour-over preparation or microwave cooking.

1. Field of the Invention
The present invention concerns processes for making pre-cooked instant pasta and noodles with superior eating quality made from freshly extruded pasta dough and products made by the process. The freshly extruded pasta dough is subjected to a process comprising steaming, soaking in water, removing excess moisture from the surface of the pasta dough, and toasting. The process conditions are dependent upon the shape and size of the pasta or noodle, and the desired texture.
2. Description of Related Art
Presently available instant or quick cooking pasta and noodles are conventionally made by extrusion cooking or cooking subsequent to extrusion by immersion in boiling water and/or steam cooking. Extrusion cooking, however, can result in deterioration of the pasta texture due to the impact of heat and high shear on the protein matrix prior to and during extrusion. When these products are rehydrated, the texture is mushy or soft, not xe2x80x9cal dentexe2x80x9d. The extrusion cooking process is costly, requiring sophisticated equipment and control systems.
U.S. Pat. No. 3,251,694 describes a pre-cooked macaroni wherein the dough is made in a conventional manner and the fresh pasta is said to be completely precooked and dried at 300-700xc2x0 F. for about 3 to 9 minutes. The product, however, is not completely pre-cooked and is expensive because of high processing costs and is limited to pasta shapes that can be extruded with thin walls and still maintain their shape.
A pasta having a helix shape said to be quick cooking is described in U.S. Pat. No. 5,728,418. The pastas are limited to those having a shape of a helix and the reported density of the pasta, between 0.2 g/cm3 and 0.75 g/cm3, is the bulk density, which is a function of the cylindrical space occupied by the pasta, rather than density based on the volume displacement of the pasta or noodle.
U.S. Pat. No. 3,615,677 concerns a pasta said to be rapid cooking made by an extrusion and drying process wherein corn flour is described as a critical binding ingredient which also masks the harsh bitter flavor of soy materials in the formulation. The product of U.S. Pat. No. 3,615,677 has poor structural integrity, a soft mushy structure and the harsh bitter flavor of soy material is not effectively masked.
A process for preparing instant-cooking alimentary pastes using repetitive vaporization treatments is described in U.S. Pat. No. 4,346,119. U.S. Pat. No. 4,359,214 describes a process for making an unexpanded pasta, said to be rapidly rehydratable, involving subjecting the pasta to dry, superheated steam, in the absence of water at between 102xc2x0 C. to 140xc2x0 C. for 7 to 20 minutes such that the pasta comprises an inner core zone in which a substantial amount of the protein remains undenatured and a substantial amount of the starch remains ungelatinized. U.S. Pat. No. 5,256,435 discusses a dried pasta product which is said to be rapidly reconstituted for consumption in which the pasta is pre-cooked with steam while being intermittently sprayed with water at a temperature of 90xc2x0 C. to 98xc2x0 C. and a pH of 5.0 to 5.5. A pasta product that is said to be tolerant to exposure to non-boiling water and capable of microwave preparation is described in U.S. Pat. No. 5,063,072.
U.S. Pat. Nos. 4,044,165, 4,394,397 and 4,540,592 involve pasta products wherein combinations of heat and mechanical stress are used during extrusion processes to fully pre-cook the pasta products. The products of these patents suffer from poor textural qualities and lack of xe2x80x9cal dentexe2x80x9d texture, and are processed using extensive and expensive preparation means.
It was an object of the invention to obtain a process of making a fully pre-cooked pasta product by a method which does not involve extrusion cooking and reduces the time and expense associated with conventional processing methods.
It was a further object of the invention to develop a fully pre-cooked pasta product having faster preparation times and improved textural performance, particularly when prepared by microwave oven cooking or hot or boiling water pour-over.
These objects have been achieved by the process of preparing instant fully precooked pasta which comprises steaming the pasta dough, soaking the steamed pasta dough, removing excess moisture from the surface of the pasta dough and toasting.
All percentages and ratios set forth in this specification are by weight/weight unless designated otherwise.
The pasta or noodle products of the invention have textural properties and density and porosity imparted by the process which enable the pasta to be prepared by simple hot or boiling water pour-over or microwave cooking, as well as conventional means of stove top cooking in boiling water. Reference to xe2x80x9cpastaxe2x80x9d, xe2x80x9cpasta or noodlexe2x80x9d and xe2x80x9cpasta and noodlexe2x80x9d, as used in this Specification, includes reference to both pasta and noodle. The process comprises the steps of steaming freshly extruded pasta dough, soaking the steamed pasta dough, removing excess moisture from the surface of the pasta dough and toasting. The degree of expansion and product density of the pasta product can be manipulated through the control of the moisture content of the extruded dough and toasting conditions. The precise processing conditions will vary depending upon the pasta shape, dimensions and desired texture. Any shape of pasta can be made by the process described herein, and the processing conditions can be manipulated to achieve desired quick cook characteristics.
The process provides a fully pre-cooked product, that is a pasta that has fully gelatinized starch, or nearly fully gelatinized starch, and denatured protein, that reduces the cooking time compared to conventionally processed pasta products and other instant pasta products and allows for more rapid rehydration of the pasta without subjecting the product to cooking in boiling water for long time periods. Thus, the pasta is a quick cooking or convenient pasta that can be prepared by any process capable of hydrating and cooking the pasta, including hot or boiling water pour-over and microwave preparation, as well as traditional stove top cooking. The process results in a pasta with unique textural attributes, porosity and density so that the quick cooking pasta of the invention will have the taste and organoleptic aspects of conventional pasta made in boiling water, when prepared by hot or boiling water pour-over or with microwave cooking.
The pasta products can be made from a wide variety of farinaceous materials which allows use of less expensive materials, and the pasta can be made from a wide variety of flours and starches, including wheat, rice, potato, corn and the like. Also, the process steps are relatively fast compared to processes used to make conventional pasta and other quick cook pastas. The process of the invention eliminates the long drying time, which can be up to 6 to 8 hours, associated with conventional pasta manufacture. Thus, a cost saving can be realized with the process, and pastas made by the process as a result of, among other things, the variety of raw materials that can be used and the time, energy and equipment savings associated with the process.
Additionally, the process can be manipulated to produce a pasta product that has a unique crunchy texture. Accordingly, the pasta can be used as or incorporated into a snack food product. A variety of flavors, herbs, spices or other flavoring ingredients can be blended with the pasta dough prior to processing or coated on the surface of the pasta to make a snack food product.
Pasta dough is made for the process of the invention with water, wheat flour and other ingredients using known extrusion techniques. Accordingly, the ingredients are combined and hydrated with sufficient water to attain the desired consistency and kneaded to make the dough. The dough can be formed into the desired shape by extrusion through a die plate and then cut into pieces of the desired size. In a preferred embodiment of the present invention, freshly extruded pasta dough, cut into shape, is subject to the processing steps described herein. The freshly extruded pasta dough preferably has a moisture content of from about 15% to about 35%, and the textural qualities of the processed pasta products will be, in part, a function of the moisture content of the extruded dough. The pasta dough may be extruded with no vacuum.
The ingredients of the pasta of the invention comprise wheat flour selected from the group consisting of semolina, farina, durum, hard wheat and soft wheat flours and pasta regrind from wheat based pastas and the like. Alternate flours such as those from rice and corn can be employed in amounts from 0% to about 15% and preferably less than about 10%. Starches from sources such as rice, corn, flour, potato and the like also can be employed in amounts from 0% to about 20%, preferably less then about 15%. Protein sources can be optionally added in amounts from about 0.25% to about 10%, and when they are used, they typically are added in amounts of at least about 0.5% to about 5%. Typical protein sources include wheat gluten, milk protein, soy protein and eggs in any form including whole eggs, egg whites, powdered eggs, powdered egg whites and the like. A variety of natural and artificial flavors, herbs, spices, cheeses and the like also can be employed in amounts from 0% to about 20% and when they are employed they typically are added in amounts of at least about 0.1%.
The instant pre-cooked pasta can be made with a processing combination of steaming, soaking, removing excess moisture from the surface of the pasta dough, and toasting. The processing conditions include steaming for about 1 minute to about 10 minutes, soaking in water for up to about 20 minutes, removing excess moisture from the surface of the pasta dough for up to about 10 minutes, and toasting at about 82xc2x0 C. to about 177xc2x0 C. for about 2 to about 30 minutes using a continuous microwave oven and/or forced hot air toaster. These pasta products have improved product texture, porosity, faster preparation times and improved textural tolerance after preparation when prepared by hot or boiling water pour-over or microwave cooking or conventional stove top preparation methods. Processing conditions will vary depending upon pasta shape, dimensions and the desired texture and/or porosity.
Freshly extruded pasta is used for the process, and the freshly extruded pasta product is subjected to the initial steaming step. By xe2x80x9cfreshly extruded pastaxe2x80x9d, it is meant pasta dough that has not been subject to physical or chemical process or non-natural drying prior to initiation of the steaming step, and that the pasta undergoes no or minimal starch gelatinization or protein denaturation during the extrusion. The moisture content of freshly extruded pasta products are from about 15% (semi-moist) to about 35% (wet/moist), preferably from about 26% to about 33% moisture and most preferably from about 28% to about 32% moisture. Complete starch gelatinization (reducing starch cook requirements) and changes in the protein matrix, resulting in the development of a less dense, porous internal structure improves hydration rate and shortens cook time which is particularly suited for hot or boiling water pour-over or microwave preparation. Control of density and texture is also linked to the control of the extruded dough moisture level and toasting conditions.
The degree of expansion and resulting pasta product density can be manipulated during the process steps described herein to deliver the desired texture and hydration rate needed for shorter preparation time. Product density can be controlled from about 0.700 g/cc to 1.100 g/cc. The preferred range of density is generally from about 0.800 g/cc to about 1.000 g/cc. In practice, the preferred range of density is dependent on specific application for which the pasta will be used. Other pre-cooked pasta products and conventionally produced pasta have densities above 1.100 g/cc.
The degree of expansion and density also affects the porosity of pasta product. The internal structure of the pasta having a density of about 0.700 g/cc to 1.100 g/cc is porous having channels or inlets for water to seep into during preparation which is associated with the quick cook times of the pasta for hot or boiling water pour-over and microwave preparation methods. For example, the fully pre-cooked pasta made by the process described herein can be prepared in about 4 minutes whereas other instant pre-cooked pastas require about 5 minutes microwave preparation time.
The first step of the process is the steaming of the freshly extruded pasta dough, which may optionally have been cut into desired shapes prior to the steaming step. The pasta dough is steamed for a period of about 1 minute to about 10 minutes, preferably about 3 minutes to about 5 minutes at a temperature of from about 88xc2x0 C. to about 104xc2x0 C., preferably from about 93xc2x0 C. to about 100xc2x0 C.
The steaming process serves two functions. First, the steam precooks the starch (that is partially gelatinizes the starch), and denatures the protein on the surface of the extruded pasta dough. This significantly strengthens the protein-starch matrix, allowing the pasta dough to withstand the abusive processing conditions during the subsequent soaking, removal of excess moisture from the surface of the pasta dough and toasting steps. Second, the steaming process modifies attributes of the pasta dough which evolve into attributes of the final pasta product after all of the steps, and allows us to design pastas having specific product attributes. These attributes include increased product integrity, increased resistance to xe2x80x9cchecking or crackingxe2x80x9d, reduced starch loss, increased pasta firmness and increased tolerance to over cooking. These attributes are important to the final pasta product as they improve product performance in convenience oriented preparation methods, particularly hot or boiling water pour-over preparation methods, as well as microwave cooking and quick cook stove top preparation.
Steaming can be achieved by injecting food grade steam into a steamer or into the same apparatus that otherwise would be used for toasting. Suitable industrial steamers for continuous processing are generally commercially available such as those from Bxc3xchler, Wenger or Pavan.
After steaming, the pasta is soaked in water for a period of up to about 20 minutes for ambient temperature water, it being understood that soaking time is a function of water temperature. The preferred soaking time is for about 1 minute to about 10 minutes. The soaking step allows water to be absorbed into the steamed pasta dough, and thereby increase the moisture content. Soaking the steamed pasta dough in water at a temperature of about 15xc2x0 C. to about 33xc2x0 C. is most preferred for water absorption. The moisture content of the pasta dough after soaking should be between about 35% and about 55%.
The toasting step achieves nearly full cook (full gelatinization) of the pasta dough, that is up to 100%, preferably from about 95% to 100%, of the starch is gelatinized after the toasting step. The moisture content absorbed into the dough during the soaking process enhances the nearly complete or complete gelatinization of the starch. In order to achieve the desired properties of the pasta product, however, excess moisture must be removed from the surface of the pasta dough after soaking. This can be achieved by any means capable for removing excess moisture, including allowing the pasta to stand at ambient conditions and/or use of forced air and the time required for this step will be dependent upon the amount of excess moisture, shape of the pasta, drying conditions and equipment. Generally, we have found that, at ambient conditions, it will take up to about 10 minutes, preferably from about 1 minute to about 10 minutes, to remove sufficient excess surface moisture, and use of forced air affects the actual time requirements.
The pasta dough is then toasted in a continuous microwave oven and/or hot air toaster at a temperature of about 82xc2x0 C. to about 177xc2x0 C. for about 2 minutes to about 30 minutes, preferably about 93xc2x0 C. to about 149xc2x0 C. for about 3 minutes to about 20 minutes. The water added to the internal structure of the pasta dough through the soaking step helps to achieve complete cook of the product during the toasting process, which provides for up to 100% starch gelatinization, preferably about 95% to 100%, and nearly complete protein denaturation. Complete pre-cooking of the product during the toasting process is important to the product, particularly when prepared by the hot or boiling water pour-over method to obtain a product with fully cooked texture, e.g the texture associated with conventional pastas cooked by traditional means in boiling water, without any uncooked starchy taste.
Control of density, porosity and texture is directly linked to the control of the toasting conditions employed and the moisture content of the soaked pasta dough. Toasting can be performed in single or multiple zones. Higher toasting temperature in first and subsequent toasting zones increases pasta porosity and decreases pasta density.
The preferred processing temperature range for toasting is from about 93xc2x0 C. to about 149xc2x0 C. for from about 3 to about 20 minutes to attain a moisture content of less than about 13%, i.e., from about 2% to about 13%, preferably from about 5% to about 6%. In embodiments where multiple toasting zones are employed, the product leaving the last toasting zone will have a moisture content less than about 13%, preferably less then about 10%, but it is understood that the product may pick up moisture during storage to a maximum of about 13%.
In a preferred embodiment of the invention, toasting is conducted in two, three or more toasting zones as mentioned above. The preferred toasting time and temperature is varied depending upon pasta shape, thickness, porosity and the texture desired. Thicker moist pasta will require longer toasting times and/or higher temperatures.
A multi-zone microwave oven, having from 3 to 5 toasting zones, may be employed in the toasting step. Each separate toasting zone may be used for power levels up to 6 kW of power. The power requirements and number of zones where toasting occurs will depend on the size and configuration of the pasta product. Multi-zone microwave ovens are available from Cober Electronics, Inc., South Norwalk, Conn., USA. Hot air toasters, such as those available from Wolverine Proctor and Schwartz, Horsham, Pa., USA may also be used for the toasting step.
The degree of expansion and resulting pasta product density can be manipulated to deliver the desired texture and hydration rate needed for shorter preparation time. A significant advantage of this invention is in the ability to control the pasta thickness and the degree of porosity and/or density needed to obtain the desired preparation time and texture. Product density is controlled so that the product will have a density from about 0.700 g/cc to 1.100 g/cc. The preferred range of density is generally from about 0.800 g/cc to about 1.000 g/cc. In practice, the preferred range of density is dependent on the specific application for which the pasta will be used. Control of product density is one of the distinguishing characteristics of this invention. Furthermore, the density of the pasta produced by this invention sets it apart from the higher density, more than 1.100 g/cc, of commercially available pre-cooked pasta and conventionally produced pasta. The degree of expansion and product density effects the porosity which provides inlets or channels for water penetration which is pertinent to the quick cook characteristics of the pasta, such as for the pour-over and microwave preparation methods.
Density determinations were made according to the invention using silicone oil according to the following procedure. An 8 ounce jar was preweighed on a top loading balance sensitive to 0.01 grams and precalibrated for volume using Silicone Oil (Fisher Scientific Cat. No. S159-500). 25.0+/xe2x88x920.5 grams of pasta was accurately weighed into the jar and enough silicone oil at 23xc2x0 C. temperature was added to just cover the pasta. A thin metal spatula was used to stir the mass to release any trapped air. Addition of silicone oil was resumed until the oil was almost to the rim of the jar. A preweighed flat 4 and xc2xd inch square, xe2x85x9 inch thick plastic plate containing 24, {fraction (1/16)} inch holes and one center xc2xc inch hole within the area of the top of the jar was placed on top of the jar. It was positioned so that the large hole in the center was close to the center of the jar opening. Silicone oil was again added with a pipette into the center hole until all air was excluded from beneath the plate.
The density of the silicone oil at 23xc2x0 C. of 0.961 g/cc was divided into the weight required to fill the empty jar to establish the jar volume and separately into the weight of the oil added to fill the jar when it contained the pasta, to establish the volume of the pasta by difference. After the pasta weight was adjusted for its moisture content to obtain the weight on a dry basis, the pasta weight was divided by the determined pasta volume to obtain the pasta density.
Density control according to the invention is achieved by the controlling the toasting time and temperature in the toasting zone, and preferably in two or more separate toasting zones. The pasta is conveyed in a bed through the toaster and the thickness of the bed of pasta can be varied depending upon the toasting conditions as would be apparent to one skilled in the art based on the disclosures herein. The thickness of the bed is generally from about 0.5 centimeters to about 5 centimeters. Toasting temperatures in the toasting zones are kept in a range from about 82xc2x0 C. to about 177xc2x0 C., with the preferred range being from about 93xc2x0 C. to about 149xc2x0 C.
Air velocity during toasting has been found to be important to drying uniformity and product uniformity. Effective air velocities employed are from about 15 meters per minute to about 243 meters per minute with the preferred range being from about 15 meters per minute to about 152 meters per minute. Airflow velocities are varied depending on the product shape, thickness and the desired final moisture content of the pasta to attain desired product uniformity and rate of moisture loss.
Following toasting, the toasted pasta is removed from the toaster and cooled to ambient temperature by conventional means such as by using a forced air cooler. The extruded dough may be cut into desired shapes either prior to the toasting process or after the toasted pasta has cooled.
The products of the invention are preferably fully pre-cooked, in that there is up to 100% starch gelatinization. Preferably, the products have from about 95% to 100% starch gelatinization. In order to determine the degree of gelatinization of a pasta product, the total heat absorbed during the gelatinization of a weighed portion of pasta in sufficient water is measured by a differential scanning calorimeter (DSC).
To accomplish this, at least 10 grams of the product is finely ground and 10 milligrams of this is weighed into the bottom portion of a special stainless steel capsule which fits in the instrument. The weighing is done on a microbalance accurate to at least 0.01 milligrams. Twenty milligrams of water is then injected into the capsule bottom on top of the pasta and the total weight of the capsule contents is obtained. The lid of the capsule, which is fitted with a neoprene xe2x80x9cOxe2x80x9d ring, is placed on the capsule bottom as a cover. Pressure is applied to form a hermetic seal which will prevent the loss of moisture during heating. The capsule is placed in the sample well of the DSC instrument chamber and a sealed empty capsule is placed in the reference well. The chamber is uniformly heated at a constant rate and the difference in the heat absorbed by the sample over the blank is determined in joules/gram for a peak in a region of the resulting thermogram near 70xc2x0 C. This result is subtracted from the value similarly determined for a sample of the raw wheat component (such as semolina or durum wheat) utilized in making the product. Since the two values represent how much heat was required to gelatinize the remaining ungelatinized starch present in the individual samples, the difference expressed as a percent (%) is the level to which the product has already been gelatinized.
Additional ingredients, such as salt, gluten, egg white and gums can be used to further modify texture. These ingredients may be added to the pasta dough at any time during the dough making process.
The addition of up to about 3% salt based on the weight of the farinaceous material (such as wheat, corn, soy flours, semolina, farina and the like) also improves hydration by creating voids within the structure of the pasta and noodles after the salt dissolves during cooking. Highly soluble salts dissolve leaving fine trails or voids in the pasta structure that facilitates water penetration during cooking. For example, a 2% salt level improved preparation time when compared to microwave preparation time without salt.
Manipulating the type, quality and quantity of protein in the extruded dough modifies pasta product performance. The addition of protein sources, such as vital wheat gluten, egg proteins, soy and the like in amounts from about 0.25% to about 10% can be used to modify the pasta product attributes, with the typical range being from about 0.5% to about 5.0%. Protein sources are especially useful when farinaceous materials are utilized that are low in protein content or in instances where the native protein functionality is lacking. Added proteins can be used to modify texture, increase firmness, reduce starch loss, improve tolerance to overcooking and maintain product integrity during rigorous preparation procedures that require frequent stirring.
The method of the invention can be applied to any shape of pasta. Pasta can be made in any short and long shape and may be of conventional or thin wall thickness. Wall thicknesses are chosen as a function of the type of preparation method and preparation time requirements needed.
The pasta products also can be made into a snack food or flavored by incorporating a variety of flavoring agents, selected from the group of natural and artificial flavors, herbs, spices, cheeses and/or other ingredients, which may be added at from about 0.1% to about 20% to impart the desired flavor and appearance. Flavors can be blended with the farinaceous materials prior to extrusion and/or can be coated on the surface. Protein sources are typically used from about 0.5% to about 10.0% with a variety of flavors and/or other ingredients, such as those listed above, (i.e. eggs, cheeses) that may be necessary to achieve desired flavor.
The fully pre-cooked pastas of the invention are particularly useful for convenient type foods, e.g. pastas prepared by hot or boiling water pour-over where the pasta is, in essence, merely rehydrated, and pastas prepared in a microwave. The process parameters can be manipulated so that the pasta will have the textural characteristics of conventionally prepared pasta with faster rehydration, short preparation time, improved cook and textural tolerance. The product texture can be manipulated to result in a wide range of textures from soft to firm.
Processing time for the method described herein is significantly shorter than conventional processes and other processes for making quick cook pastas. For example, in a preferred embodiment, the pasta dough is processed in a cold single screw extruder. The processing steps in the method may take about 7 minutes to about 45 minutes compared to hours for other processes and conventional methods. This is, in part, because the pasta dough in the invention is not, as in conventional methods, cooked in the extruder by elevated temperatures and/or pressures which require time and energy expenditures. Also, conventional processes usually employ twin screw extruders which are more costly then single screw extruders.

Process of making instant pasta with improved cooking quality


In one embodiment, a meta-module having circuitry for two or more modules is formed on a substrate, which is preferably a laminated substrate. The circuitry for the different modules is initially formed on the single meta-module. Each module will have one or more component areas in which the circuitry is formed. A metallic structure is formed on or in the substrate for each component area to be shielded. A single body, such as an overmold body, is then formed over all of the modules on the meta-module. At least a portion of the metallic structure for each component area to be shielded is then exposed through the body by a cutting, drilling, or like operation. Next, an electromagnetic shield material is applied to the exterior surface of the body of each of the component areas to be shielded and in contact with the exposed portion of the metallic structures.

Electronic components have become ubiquitous in modern society. The electronics industry routinely announces accelerated clocking speeds, higher transmission frequencies, and smaller integrated circuit modules. While the benefits of these devices are myriad, smaller electronic components that operate at higher frequencies also create problems. Higher operating frequencies mean shorter wavelengths, where shorter conductive elements within electronic circuitry may act as antennas to unintentionally broadcast electromagnetic emissions throughout the electromagnetic spectrum. If the signal strengths of the emissions are high enough, the emissions may interfere with the operation of an electronic component subjected to the emissions. Further, the Federal Communications Commission (FCC) and other regulatory agencies regulate these emissions, and as such, these emissions must be kept within regulatory requirements.
One way to reduce emissions is to form a shield about the modules that either cause emissions or are sensitive to emissions. Typically, a shield is formed from a grounded conductive structure that covers a module or a portion thereof. When emissions from electronic components within the shield strike the interior surface of the shield, the electromagnetic emissions are electrically shorted through the grounded conductive material that forms the shield, thereby reducing emissions. Likewise, when external emissions from outside the shield strike the exterior surface of the shield, a similar electrical short occurs, and the electronic components on the module do not experience the emissions.
However, as modules continue to become smaller from miniaturization, creating effective shields that do not materially add to the size of the module becomes more difficult. Thus, there is a need for a shield that is inexpensive to manufacture on a large scale, does not substantially change the size of the module, and effectively deals with interference caused by unwanted electromagnetic emissions.