The invention discloses a composition comprising a sulfur-containing glycine residue combined with urea to increase the permeation of an active agent or drug through human nail tissue. The invention further provides methods of applying the composition to a nail surface.

Onychomycosis is a fungal disease of the human nail. The symptoms of this disease are split, thickened, hardened, and rough nail plates. This is caused by any of a number of organisms and is particularly prevalent in the elderly. Typically, fungal infections are treated by topical application of antifungal agents and/or oral administration of antifungal agents. The main challenge associated with developing topical treatments for nail disorders is to deliver the active compounds in therapeutically effective concentrations to the site of infection, which is often under the nail. If the nail barrier is modified, reduced, or eliminated, topical antifungal drug treatment is effective for onychomycosis. For example, both miconazole and ketoconazole have been demonstrated to be effective in topically treating onychomycosis after nail removal. However, most consumers would certainly prefer a less dramatic treatment of nail fungal infection than removal of the nail.
Nail psoriasis is another common nail disorder affecting up to 50% of patients with psoriasis. Characteristic nail psoriasis symptoms include pitting, which appears as punctuated or irregularly shaped depressions arranged on the surface of the body of the nail; discoloration of the nail bed; onycholysis or detachment of the body of the nail from the nail bed; subungual keratosis; or anomalies of the body of the nail. As with nail fungal infections, current methods of treatment are not satisfactory. One treatment method, the systemic method, consists of long-term administration of methotrexate, retinoids or cyclosporin A orally which can lead to intoxication. Another method consists of injecting intralesional corticosteroids. This method is naturally very painful and patients often refuse treatment. A further method consists of surgically removing the affected nails, but intervention is only temporary because within one week after regeneration of the body of the nail psoriasis may return. A fourth, gentler, method consists of treating the nails locally with specific, antipsoriatic substances such as dithranol, vitamin D analogs, or corticosteroids, however, as with nail infections, effective delivery of the active compounds is a problem.
The nail plate is thick, hard, dense, and represents a formidable barrier for drug penetration. Although nail material is similar to the stratum corneum of the skin, being derived from epidermis, it is composed primarily of hard keratin, which is highly disulfide-linked, and is approximately 100-fold thicker than stratum corneum. In order to deliver a sufficient amount of drug into the nail plate, the permeability of the nail plate to the drug must be enhanced. This is particularly true in fungal diseases where a common symptom of the disease is thickened nail plate.
Recent research efforts have focused on improving penetration by chemically modifying the nail keratin matrix (Kobayashi, et al. (1998) Chem Pharm Bull 46(11):1797-1802). Examples of compounds which interact with keratin include mercaptan compounds, sulfites and bisulfites, keratolytic agents, and surfactants.
Mercaptan Compounds. The utility of compounds possessing sulfhydryl (SH) groups, i.e., mercaptan compounds, to enhance nail penetration has been reported (Soong (1991) Transport properties of drugs and model compounds across the human nail. Ph.D. Dissertation. University of Minnesota; U.S. Pat. No. 5,696,164). EP0440298 A1 discloses the use of sulfur-containing cysteine derivatives in topical preparations for treatment of nail diseases such as onychomycosis. Furthermore, U.S. Pat. No. 5,696,164 to Sun et al. discloses the use of sulfhydryl-containing cysteine and N-acetyl cysteine in combination with urea to increase drug permeability in a nail plate. Moreover, U.S. Pat. No. 6,123,930 provides a composition of sulphur-bearing amino acid together with sodium tetraborate for the treatment of nails. Mercaptan compounds reduce keratin in human hair via a sequence of two reversible, nucleophilic displacements (Robbins (1997) Chemical and physical behavior of human hair, 3rd ed. New York: Springer-Verlag. pp. 93-130; Wolfram (1981) In: Orfanos, et al, eds. Hair research: Status and future aspects. New York: Springer-Verlag. pp. 479-500). High concentrations of the mercaptan and alkaline pH favor the forward reaction due to the increased formation of the mercaptide anion required for reduction (Herrmann (1963) Trans Farady Soc 59:1663-1671; Wickett (1983) J Soc Cosmet Chem 34:301-316).
Pyrithione (2-mercaptopyridine-1-oxide, PTO) is a fungicidal and bactericidal agent. The zinc (ZnPTO) and sodium (NaPTO) derivatives of pyrithione possess fungicidal activity and ZnPTO is commonly used in antidandruff preparations. Compounds containing a SH group are themselves oxidized while reducing disulfide linkages in nail keratin (Robbins (1997) Chemical and physical behavior of human hair, 3rd ed. New York: Springer-Verlag. pp. 93-130; Wolfram (1981) In: Orfanos, et al, eds. Hair research: Status and future aspects. New York: Springer-Verlag. pp. 479-500). For PTO, such self-oxidation would result in the formation of the dipyrithione dimer which possesses antifungal activity.
Terpenes are also known to be effective skin penetration enhancers. Menthone, in particular, has been found to enhance penetration of several different drugs across skin (Kragh, et al. (1993) STP Pharma Sci 3:499-506; Yamane, et al. (1995) Int J Pharm 116:237-251). 1,4-Dithiothreitol, which contains two SH groups, has been shown to be a particularly effective reducing agent, because this molecule can undergo rapid autocleavage during the reduction process to form a sterically favored cyclic disulfide as the end product (Wolfram (1981) In: Orfanos, et al, eds. Hair research: Status and future aspects. New York: Springer-Verlag. pp. 479-500).
Sulfites and Bisulfites. Sulfites and bisulfites are known to be reducers of disulfide linkages in keratin, and thus are popularly used for permanent waving of hair (Robbins (1997) Chemical and physical behavior of human hair, 3rd ed. New York: Springer-Verlag. pp. 93-130).
Keratolytic Agents. Salicylic acid (SA), urea (U), and guanidine hydrochloride (GnHCl) are substances which may disrupt the tertiary structure, and possibly secondary linkages (such as hydrogen bonds) in keratin, thus promoting penetration through the nail. Compounds such as urea and guanidine hydrochloride are known to be denaturing agents, resulting in disruption of the water structure around proteins, decreasing the hydrophobic effect, and thereby promoting unfolding and dissociation of the protein molecules (Alber (1989) In: Fasman G D, ed. Prediction of protein structure and the principles of protein conformation. New York: Plenum Press. pp. 161-192; Manning, et al. (1989) Pharm Res 6(11):903-918; Mathews and van Holde (1990) Biochemistry. Redwood City: The Benjamin/Cummings Publishing Co, pp. 213-215).
Surfactants. Surfactants, primarily of the anionic type, are known to be able to interact with keratin. Concentrated solutions of sodium lauryl sulfate are commonly used to solubilize proteins. These detergents are thought to form micelles around individual polypeptide chains and thus promote dissociation of protein molecules (Mathews and van Holde (1990) Biochemistry. Redwood City: The Benjamin/Cummings Publishing Co, pp. 213-215).
European Patent Application EP 503988 discloses other nail penetration agents including glycols, glycol ethers, dimethyl sulfoxide, caprolactam, and other hydrophilic compounds to facilitate the penetration of allylamine fungicides into the nail.
The present invention provides a composition which comprises sulfur-containing glycine residues and urea to increase the permeation of an active agent through nail tissue.
The invention further provides methods of applying the composition of the invention to a nail prior to, or in conjunction with, an active agent to increase the permeation of said active agent through the nail tissue.
The present invention relates to methods and a composition of N-(2-mercaptopropionyl) glycine (MPG) and urea for treating fingernails and toenails. Of many combinations of potential penetration enhancers, the composition of the present invention was the most effective. Results of a screen monitoring tritiated water permeation of gels containing keratolytic agents either alone or in combination with a mercaptan derivative of an amino acid (MPG) are shown in Table 1.
All enhancers were screened with three replicates; however, in some cases one of the nails split due to weakening of the nail as a result of effective enhancer treatments. Hence, in these cases, n=2. Permeation profiles for gels containing urea alone (IV), MPG alone (V), 10% MPG and 20% urea (VII), and their control (I) are typical for cumulative permeation data and show that steady state is achieved after an initial lag time.
Gel II (positive control) gave the greatest increase in normalized water flux compared with the control (Gel I), resulting in an enhancement factor, EFwater, of 7.99, confirming that the technique was suitable for screening potential enhancers. The high EFwater value is attributed to the fact that the positive control contained a higher amount of water relative to the other gels, and hence, an increased water flux was observed.
Gels containing the keratolytic agents alone, 20% SA (Gel III) or 20% U (Gel IV), were ineffective in enhancing the permeation of water through nails relative to the control (Gel I). Gel V, containing 10% MPG, apparent pH=9.0, resulted in an approximately 2.5-fold increase in normalized water flux that was found to be statistically significant when contrasted with that of the control (t-test, xcex1=0.05). When 10% MPG was combined with 20% SA (Gel VI, apparent pH=4.3), an EFwater value of 2.27, similar to that seen with Gel V, containing 10% MPG (EFwater=2.49), was observed. These results indicate that SA was ineffective in permeation enhancement. Moreover, because the gels containing 10% MPG alone or in combination with SA resulted in similar flux enhancement values, alkaline pH did not appear to favor permeation as compared with acidic conditions. Thus, although a pH of 8-9 has been reported to be optimal for reduction of disulfide linkages (Robbins C R. 1997. Chemical and physical behavior of human hair, 3rd ed. New York: Springer-Verlag. pp. 93-130), pH did not seem to be a major controlling factor for nail penetration enhancement with MPG.
When 20% U was present along with 10% MPG (Gel VII), an approximately four-fold increase in normalized water flux was seen when compared with the control. The enhancement effect of MPG may result from its ability to reduce the disulfide linkages in the nail keratin matrix. Further, its small size and the fact that it is an amino acid may allow incorporation in the nail keratin matrix and exert its effect. Urea acted synergistically with the sulfhydryl-containing reducing agent, MPG, and resulted in an improvement in the EFwater value from 2.49 for MPG alone to 3.54 for 10% MPG and 20% U.
The effect of 31.81% GnHCl, equivalent to 20% U on a molar basis, in conjunction with 10% MPG (Gel VIII) was investigated. Urea and GnHCl are structurally similar, however, the slight increase in J* for water observed with Gel VIII was not statistically significant when compared with the control (Gel I) using a t-test at the 0.05 level of significance. Hence, although GnHCl and urea have been reported to have similar denaturing properties (Mathews and van Holde (1990) Biochemistry. Redwood City: The Benjamin/Cummings Publishing Co, pp. 213-215), the results herein indicate that GnHCl is ineffective as a nail penetration enhancer when combined with MPG. It is possible that much higher concentrations of GnHCl may result in improved nail penetration; however, increasing the level of GnHCl above 32% may not be feasible because of solubility limitations.
Having established that the combination of MPG and urea was effective in nail penetration enhancement of water, the effect of concentration of these enhancers was investigated. To study the effect of concentration of MPG, gels were prepared containing 20% U and MPG at three different levels, 0, 3.33, and 10% (Gels IV, IX, and VII, respectively). To study the effect of concentration of U, the gels contained 10% MPG and three different levels of U, 0, 6.67, and 20% (Gels V, X, and VII, respectively). Varying levels of MPG with 20% U indicated that the concentration of mercaptan (MPG) is more important than the urea concentration in penetration enhancement of water. Thus, the profile relating J* of water with the concentration of MPG has a steeper slope compared to that observed with concentration of urea. The importance of MPG concentration is also seen in Table 1, which shows that the EFwater value for Gel IX containing 3.33% MPG and 20% U is only 1.70, compared to the EFwater value of 3.54 for the gel containing 10% MPG and 20% U (Gel VII). However, in the presence of 10% MPG and 6.67% U (Gel X), the EFwater value is 2.94, which is comparable to that seen with 10% MPG and 20% U (Gel VII, EFwater=3.54). These results indicate that reduction in the mercaptan levels can lower the enhancement effect considerably; however, urea concentration may be decreased without compromising penetration enhancement.
To investigate whether incorporation of a surfactant, SLS, into a gel containing the effective enhancer combination of MPG and urea further improved nail penetration, Gel XI was screened. Thumbnails were used in these studies to compare Gel XI and its control. As seen in Table 1, the control for Gel (XI), run on thumbnails, gave a J* value of 9.6xc3x9710xe2x88x922 mg cmxe2x88x921hxe2x88x921, which is considerably lower than the J* value of 15.7xc3x9710xe2x88x922 mg cmxe2x88x921hxe2x88x921 for Control (I), run on toenails. This result can be attributed to differences in nail thickness and keratin structure of thumbnails and toenails. Thumbnails were effective barriers to permeation despite their reduced thickness, hence resulting in lower J* values compared to toenails (Malhotra and Zatz (2000) J Cosmet Sci 51:367-377).
Gel XI, when compared with its control, resulted in an enhancement factor of 0.89 (Table 1), indicating that the permeation of water was not significantly enhanced when compared with its control (t-test, xcex1=0.05). Thus, although SLS has denaturing properties the concentration of 10% used in Gel XI may be insufficient to cause penetration enhancement through nails. The increase in J* values, relative to control formulations observed with gels containing MPG alone or in combination with keratolytic agents, are consistent with other reports in the literature wherein agents such as N-acetyl cysteine and dithiothreitol were shown to increase permeation of model compounds (Kobayashi, et al. (1998) Chem. Pharm. Bull. 46(11):1797-1802; U.S. Pat. No. 5,696,164; Soong (1991) Transport properties of drugs and model compounds across the human nail. Ph.D. Dissertation. University of Minnesota).
Pyrithione and its Derivatives. The screening results for gels containing another mercaptan, PTO, and its derivatives are shown in Table 2.
NaPTO was ineffective at the 4 and 10% level in enhancing permeation of water through nails, relative to the control, thus resulting in EFwater values close to 1. ZnPTO and PTO were screened using gels predominantly composed of DMSO. The J* value of 0.75xc3x9710xe2x88x922 mg cmxe2x88x921hxe2x88x921 for the control for Gels XIV-XVII was much lower than the J* value of 15.7xc3x9710xe2x88x922 mg cm-1h-1 for control (I). This is primarily because the former gel contained less than 2% water, due to the limited water solubility of ZnPTO and PTO, compared to Gel I, which contained 17% water. Intrinsic differences in nail structure could also contribute to the variability in J* values above. ZnPTO did not enhance water permeation relative to its control (EFwater=1.13). PTO alone at a concentration of 10% resulted in a 2.6-fold increase in J* for water relative to its control. Thus, 10% PTO may be an effective enhancer of nail permeation. However, the drawback of this compound is its extremely poor solubility in almost all solvents, leading to practical formulation difficulties.
PTO was further investigated in conjunction with urea as a potential penetration enhancer (Gels XVI and XVII). However, when urea was dosed either alternately or concurrently with PTO, the J* values for water did not increase (EFwater=1.09 and 1.07, respectively, for Gels XVI and XVII). Thus, it was concluded that urea does not improve nail penetration in combination with PTO. A possible explanation for this could be that urea is unable to exert its keratolytic action in a very hydrophobic environment. For Gels XVI and XVII, urea was present in a vehicle containing mostly DMSO and  less than 2% water, which may not be conducive to swelling and hydration of the nail.
Other Mercaptan Compounds. 8-mercaptomenthone and meso-2,3-dimercapto succinic acid, had results similar to that of PTO (Table 3).
10% 8-mercaptomenthone did not enhance penetration of water relative to the control (EFwater=1.05). The ineffectiveness of 8-mercaptomenthone as a nail penetration enhancer may be due to the nature of the parent molecule. 8-Mercaptomenthone is a terpene derivative. Terpene derivatives are effective skin penetration enhancers and may act by inserting themselves in the lipid bilayers of the skin thereby disturbing their ordered structure (Clarys, et al. (1998) Eur J Pharm Biopharm 46:279-283; Gay, et al. (1994) J Invest Dermatol 103:233-239). However, the lipid content of the nail plate is very low (Runne and Orfanos (1981) Curr Probl Derm 9:102-149). Thus, even if the terpene molecules do result in lipid transitions in the nail, this action may be insignificant to cause major changes in the nail barrier properties.
Gels containing meso-2,3-dimercapto succinic acid either alone or in combination with urea had a high water content of 70-85% due to the good water solubility of these molecules. Hence, the control gel for these enhancers also had a high water content, resulting in large J* values of 123xc3x9710xe2x88x922 mg cmxe2x88x921hxe2x88x921, compared to 15.7xc3x9710xe2x88x922 mg cmxe2x88x921hxe2x88x921 for control Gel I. Meso-2,3-dimercapto succinic acid was ineffective in increasing nail permeation of water either when used alone or in combination with urea, thus resulting in EFwater values close to 1. In the case of meso-2,3-dimercapto succinic acid, the SH groups are present on adjacent carbon atoms (second and third) and the reduction of disulfide bonds may lead to the formation of a sterically unfavorable product. Moreover, gels containing meso-2,3-dimercapto succinic acid were prepared by adjusting the pH to approximately 9.0. At this pH, the two carboxylic acid groups and the two sulfhydryl groups in the molecule would be ionized. Reports in the literature suggest that compounds such as benzoic acid and pyridine preferentially permeate the nail in the undissociated state (Soong (1991) Transport properties of drugs and model compounds across the human nail. Ph.D. Dissertation. University of Minnesota; Mertin and Lippold (1997) J Pharm Pharmacol 49:30-34). Also, because both sulfhydryl groups on adjacent carbon atoms in meso-2,3-dimercapto succinic acid were ionized at pH 9, intramolecular disulfide bond formation could have occurred, thus rendering the molecule ineffective for reduction of disulfide linkages in the nail keratin matrix.
Sulfites and Keratolytic Agents. The screening results for the gels containing 10% sodium metabisulfite (Na2S2O5), either alone or in combination with 20% U, are shown in Table 4.
The control formulations exhibited high J* values because these gels were aqueous in order to dissolve Na2S2O5 and urea. It was found that Na2S2O5 did not enhance the penetration of water, when used alone or in conjunction with urea (EFwater values close to 1). Bisulfites are known to be weaker reducing agents than mercaptans for the disulfide bonds in hair keratin, particularly at room temperature, where extremely long time periods are required to break enough cystine linkages for hair waving (Edman and Klemm (1979) C and T Magazine 94:35-38). Thus, reduction by Na2S2O5 may have been insignificant to elicit nail penetration enhancement.
The results from the studies described above indicate that the chemical structure of the enhancer is the most important factor determining its ability to enhance nail permeation. Effective penetration enhancement was obtained from a mercaptan derivative of an amino acid, MPG. However, the presence of a SH group was not sufficient to elicit penetration enhancement in all cases. Urea in conjunction with MPG, acted synergistically to increase nail permeation to the greatest extent. Moreover, the effective enhancers resulted in softening of the nail, thus confirming structural changes in the nail plate.
Barrier integrity of nails after enhancer screening studies was evaluated. The normalized water flux values before and after treatment with various chemical modifiers (MPG and keratolytic agents) are shown in Table 5.
Treatment with the positive control (Gel II), 10% MPG (Gel V), and 10% MPG+20% Urea (Gel VII) all resulted in a threefold or greater increase in J* for water posttreatment and washout. Because these treatments were effective in nail penetration enhancement, it was concluded that these enhancers had irreversibly altered the structure of the keratin matrix. Thus, J* values remained consistently higher than baseline levels even after washout. Treatment with keratolytic agents alone (salicylic acid, Gel III and urea, Gel IV) did not appear to result in structural changes in the nail keratin as J* values for water returned to their original levels. Because the other enhancers screened, pyrithione and its derivatives, 8-mercaptomenthone, meso-2,3-dimercapto succinic acid, sodium lauryl sulfate, and sodium metabisulfite, were all ineffective in nail penetration enhancement, their J* values posttreatment and washout returned to original levels.
Clotrimazole Studies. Clotrimazole, a broad-spectrum antifungal agent, was tested in combination with the composition of the invention. Antifungal permeation was significantly enhanced by a sulfhydryl containing reducing agent (MPG), but not by keratolytic agents alone. The normalized clotrimazole flux (J*), relative flux enhancement (EFclotrimazole), and drug uptake by nails after treatment with gels containing 5% clotrimazole, and keratolytic agents either alone or in combination with a mercaptan derivative of an amino acid (MPG), are shown in Table 6.
The J* values for clotrimazole from gels containing the keratolytic agents alone [20% SA (B) or 10% U (C)] were not statistically significant when compared with the control (A) (t-test, xcex1=0.05). For the gel containing 10% MPG alone (D), a 5-fold increase in normalized clotrimazole flux, relative to control, was observed. These results indicate that the mercaptan compound itself was effective in enhancing permeation of clotrimazole through nails, whereas the keratolytic agents were ineffective when used alone.
When 10% MPG was combined with 20% SA (Gel E), an EFclotrimazole value of 2.72 was observed, which was lower than that seen with the gel containing 10% MPG alone (D). Thus, salicylic acid did not improve permeation enhance of clotrimazole, when present along with the mercaptan compound. However, when 20% urea was used in place of salicylic acid along with 10% MPG (Gel F), a 9-fold increase in normalized clotrimazole flux was seen when compared with the control. Hence, 10% MPG and 20% urea was the most effective enhancer combination for clotrimazole permeation, as was seen in the screening studies with water.
Clotrimazole uptake by nails, calculated from the sum of extractions, indicated that salicylic acid alone (Gel B) was ineffective in promoting penetration of the lipophilic maker, clotrimazole, into nails. Treatment of nails with the gel containing urea alone (C) resulted in an increase relative clotrimazole uptake when compared with the control; however, this increase was not statistically significant (t-test, xcex1=0.05).
Trends for relative clotrimazole uptake for the remaining gels (D-F) were similar to the corresponding effects for flux enhancement. Once again, the highest increase in clotrimazole uptake, 5-fold relative to the control, was observed for the enhancer combination of 10% MPG and 20% U, and this increase was statistically significant (t-test, xcex1=0.05). Thus, as seen in the screening studies with water, the best formulation for enhancement of clotrimazole penetration through nails contained 10% MPG and 20% urea, under infinite dose conditions.
Additional permeation parameters, including EFclotrimazole values, for gels containing the keratolytic agents alone or in combination with the effective enhancer, MPG (Gels A-F) are shown in Table 7.
Similar trends to these seen in screening studies with water were observed with clotrimazole. A statistically significant increase in P* values, relative to the control (t-test, xcex1=0.05), was observed for the effective gels containing 10% MPG alone (D), 10% MPG+20% SA (E), and 10% MPG+20% U (F). Lag times were increased and diffusion coefficients were decreased in comparison to the control, for effective gels; however, these differences were not statistically significant at the 0.05 level.
To study the effect of concentration of MPG on clotrimazole permeation, gels were prepared containing 10% urea and MPG at three different levels, 0, 3.33, and 10% (Gels C, G, and H, respectively). For effect of concentration of urea on clotrimazole permeation, the gels contained 10% MPG and three different levels of urea, 0, 10, and 20% (Gels D, H, and F, respectively). The normalized fluxes for clotrimazole were linearly dependent on enhancer concentration. In screening studies with water, the concentration of mercaptan (MPG) was more important than the urea concentration in penetration enhancement of clotrimazole. Thus, the slope of the trend line for the effect of varying mercaptan concentration was steeper than the corresponding slope for varying urea levels. As with water, reduction in the mercaptan levels could significantly lower the enhancement effect, however, urea concentration could be decreased without compromising clotrimazole penetration enhancement significantly. Thus, for the gel containing reduced MPG levels (3.33%, Gel G), the EFclotrimazole value was only 1.76; however for reduced urea levels (10%, Gel H), the EFclotrimazole value was 7.63, which is comparable to Gel F containing 20% urea.
The effect of varying levels of clotrimazole on normalized flux (J*) and drug uptake by nails in the presence of the effective enhancers (10% MPG and 20% U) showed a non-linear relationship existed between J* and clotrimazole concentration. The empirical regression equation relating J* and clotrimazole concentration was y=49.30 log(x)+23.67, R2=0.9962. This result differed from that seen for the effect of enhancer concentration on J* of clotrimazole, where a direct linear relationship between these two variable was observed.
Drug uptake by nails, calculated from the sum of the extractions, was directly linearly related to clotrimazole concentration, in the presence of 10% MPG and 20% urea. The regression equation in this case was y=954.45(x), R2=0.9737. The differing relationships between J* on drug uptake and clotrimazole concentration may arise due to the highly complex nature of the keratin matrix. Moreover, these studies were done in the presence of the effective enhancers, MPG and urea, which may have caused varying degrees of change in the keratin structure for different formulations. These results indicate that the enhanced permeation of clotrimazole may not depend linearly on the clotrimazole concentration.
The optimal formulation (10% MPG and 20% urea, Gel F) and the control gel (Gel A), both containing clotrimazole, were studied under conditions of finite dosing, wherein a small volume of 5 xcexcL of the donor gel was applied. The gels were spread in a thin film over the nails and the diffusion cells were not covered during the experiment to allow for a supersaturated layer of gel on the nail surface. Finite dose experiments were carried out to mimic in vivo conditions of use.
Table 8 shows a statistically significant increase (t-test, xcex1=0.05) in normalized clotrimazole flux (J*) for the test relative to the control for infinite and finite dosing.
The absolute values for J* were much higher in infinite dose studies than those seen with finite dosing, due to the much smaller volume of application and thus decreased amounts of drug penetration under finite dose conditions. However, the relative flux enhancement under finite dose conditions (EFclotrimazole=13.40) was comparable to that seen under infinite dose conditions (EFclotrimazole=9.02). Also, the test gel resulted in a 5-fold greater drug uptake by nails as compared with the control under finite dose conditions, which was similar to the relative nail uptake with infinite dosing.
The normalized water flux values before and after treatment with various antifungal gels containing chemical modifiers (MPG and keratolytic agents) are shown in Table 9.
Under infinite dose conditions, treatment with all antifungal gels, except the control, resulted in a statistically significant increase in J* for water post treatment and washout relative to baseline J* values (t-test, xcex1-0.05). These results suggest that clotrimazole itself may have affected the nail structure, since ineffective gels, containing salicylic acid (B) and urea (C), also resulted in a compromised barrier. Moreover, all antifungal studies were done on fingernails, as opposed to toenails used for screening studies with water. Since fingernails are thinner than toenails, clotrimazole treatment itself may have resulted in some structural changes in the keratin matrix. The ratio of J* for treated nail to J* for untreated nail for the most effective gel containing 10% MPG+20% U (F) was statistically significantly higher than this ratio for the control formulation (t-test, xcex1-0.1). These results indicated that this effective enhancer gel resulted in irreversible changes in the keratin matrix of nails.
For finite dose treatment, the control and test gel both resulted in a statistically significant increase in J* for water post treatment relative to baseline J* values (t-test, xcex1-0.05). These results, again, indicated that clotrimazole itself may effect nail structure. However, the J* ratio for treated to untreated nail for the test gel was not significantly different from the J* ratio for the control gel. Finite dose studies had a small volume of application and therefore, the test gel may not have affected nail structure more than the control gel.
Water and Clotrimazole Comparisons. Penetration enhancement by the mercaptan compound, MPG, and the keratolytic agents, salicylic acid and urea, for the two marker molecules, water and clotrimazole, is summarized in Table 10.
The individual fluxes and relative flux enhancement values (EFwater and EFclotrimazole) are shown. The absolute J* values for water were much higher than for clotrimazole because water is a much smaller, hydrophilic molecule compared to clotrimazole. Various enhancer treatments gave qualitatively similar results for both water and clotrimazole. Thus, with both markers, there was a statistically significant increase in J*, relative to control, observed for gels containing 10% MPG, 10% MPG+20% SA, and 20% MPG+20% U using a t-test at the 0.05 level of significance. Also, the gel with 10% MPG and 20% urea resulted in the greatest increase in permeation for each marker. However, the relative flux enhancements for water and clotrimazole were quantitatively different. Therefore, while treatment with 10% MPG resulting in a 2.5-fold increase in J* for water, a greater than 5-fold increase in J* for clotrimazole was observed. Similarly, a greater degree of enhancement in clotrimazole permeation was observed upon treatment with 10% MPG and 20% urea, as compared to water permeation enhancement (EFwater=3.67 and EFclotrimazole=9.02).
Additional comparative results for water and clotrimazole permeation from the control and optimal formulation, 10% MPG and 20% urea, are shown in Table 11.
The permeation for both markers was performed on fingernails, thumbnails for water permeation and thumbnails and other fingernails for clotrimazole permeation. The normalized water flux was about 4-fold higher than the control from gels containing 10% MPG+20% urea for studies on thumbnails, similar to the 4-fold enhancement observed when toenails were used. Clotrimazole flux enhancement was about 9-fold higher than the control. The absolute values for water uptake were much higher than for clotrimazole uptake. Although the test formulation resulted in an approximately 2-fold increase after uptake by nails, this increase was not statistically significant (t-test, xcex1=0.05). However, as before, the effect of enhancers on clotrimazole uptake was much more pronounced. Thus, an approximately 5-fold increase in clotrimazole uptake was observed, and this increase is statistically significant when compared with the control (t-test, xcex1=0.05). These results suggest that enhancers such as MPG and urea can improve the penetration of larger, lipophilic molecules more dramatically than smaller, hydrophilic compounds, and thus are particularly useful in antifungal formulations for treatment of nail infections and the like.
The composition of the present invention may be used prior to or in conjunction with active agents or drugs for treating diseased nails, nutrients or nail conditioners which may be used to improve damaged nails or maintain healthy nails, and nail growth promoters which may be used on damaged or healthy nails. The active agents include but are not limited to antifungal drugs used to treat onychomycosis, antibiotics (or antiseptics) for bacterial infection of nails, and antipsoriatic drugs for psoriatic nail treatment. Examples of antifungal drugs include but are not limited to miconazole, econazole, ketoconazole, itraconazole, fluconazole, bifoconazole, terconazole, butoconazole, tioconazole, oxiconazole, sulconazole, saperconazole, clotrimazole, undecylenic acid, haloprogin, butenafine, tolnaftate, nystatin, ciclopirox olamine, terbinafine, amorolfine, naftifine, elubiol, griseofulvin, and their pharmaceutically acceptable salts. The preferred antifungal drugs are an azole, an allylamine, or a mixture thereof. Preferred azoles are selected from the group consisting of itraconazole, ketoconazole, miconazole, econazole, fluconazole, voriconazole, clotrimazole, butenafine, undecylenic acid, clioqinol, and their pharmaceutically acceptable salts. Preferred allylamines are selected from the group consisting of terbinafine, naftifine and mixtures thereof.
Examples of antibiotics (or antiseptics) include but are not limited to mupirocin, neomycin sulfate, bacitracin, polymyxin B, 1-ofloxacin, tetracyclines (chlortetracycline hydrochloride, oxytetracycline hydrochloride and tetracycline hydrochloride), clindamycin phosphate, gentamicin sulfate, benzalkonium chloride, benzethonium chloride, hexylresorcinol, methylbenzethonium chloride, phenol, quaternary ammonium compounds, triclocarbon, triclosan, tea tree oil, and their pharmaceutically acceptable salts. Preferred antibiotics and antiseptics include mupirocin, neomycin sulfate, bacitracin, polymyxin B, 1-ofloxacin, tetracyclines, benzalkonium chloride, benzethonium chloride, triclocarbon, and triclosan.
Examples of antipsoriatic drugs include but are not limited to corticosteroids (e.g., betamethasone dipropionate, betamethasone valerate, betamethasone benzoate, clobetasol propionate, diflorasone diacetate, halobetasol propionate, budesonide, chloquinaldol, clioquinol, amcinonide, alclometasone dipropionate, beclomethasone dipropionate, bendacort, clobetasol butyrate, desonide, dexamethasone, dichlorisone, diflorasone diacetate, diflucortolone valerate, difluprednate, fluazacort, fluclorolone, desoximetasone, fluocinonide, fluocinolone acetonide, fludroxycortide, flumethasone pivalate, fluocortolone, fluorometholone, flupamesone, fluprednidene, fluprednidene acetate, halometasone, hydrocortamate, prednicarbate, prednisolone, prednisone, tixocortol, halcinonide, triamcinolone acetate, hydrocortisone, hydrocortisone verlerate, hydrocortisone butyrate, aclometasone dipropionate, flurandrenolide, mometasone furoate, methylprednisolone acetate), calcipotriene and anthraline. Preferred antipsoriatic drugs include betamethasone dipropionate, betamethasone valerate, and clobetasol propionate. The corticosteroids may be present either as free alcohols or in the form of their esters.
When the active agents are nail growth promoters, such agents include but are not limited to minoxidil, minoxidil sulfate, retinoids, cysteine and acetyl cysteine, methionine, glutathione, biotin, finasteride and ethocyn, as well as pharmaceutically acceptable salts of these compounds. Preferred growth promoters include minoxidil, minoxidil sulfate, retinoids, cysteine and acetyl cysteine. Particularly preferred nail growth promoters are 2% minoxidil, 2% minoxidil sulfate, and 0.1% retinol.
When the active agents include nutrients, they include but are not limited to vitamins, amino acids, and their derivatives. Examples of such agents include, but are not limited to, vitamin B complex: thiamine, nicotinic acid, biotin, pantothenic acid, choline riboflavin, vitamin B6, vitamin B12, pyridoxine, inositol, carnitine; ascorbic acid, ascorbyl palmitate, vitamin A, vitamin K, vitamin E, vitamin D, cysteine and N-acetyl cysteine, herbal extracts, and their derivatives.
When the active agents include nail conditioners they include, but are not limited to, mineral-containing compounds, flavonoids and retinoids. These nail conditioners improve general nail conditions, such as strengthening the nails to prevent nail chipping and cracking, and to beautify the nails. Examples of such agents include but are not limited to calcium pantothenate, calcium carbonate, and calcium gluconate. Examples of retinoids include, but are not limited to, retinol (Vitamin A alcohol), retinal (Vitamin A aldehyde), retinyl acetate, retinyl palmitate, retinoic acid, 9-cis-retinoic acid and 13-cis-retinoic acid. When retinoids are the active agents, the concentration of retinoids is from about 0.01% to about 0.5%, preferably, from about 0.05 to about 0.1%. Examples of flavonoids include, but are not limited to, naringenin, quercetin, catechins (e.g., epigallocatechin gallate), theaflavins, robustaflavone, hinokiflavone, amentoflavone, agathisflavone, volkensiflavone, morelloflavone, rhusflavanone, and succedangeaflavanone.
Overall, the preferred active agents are miconazole nitrate, itraconazole, econazole nitrate, ketoconazole, clotrimazole, and terbinafine. The active agent is present in about 0.05% to about 10% w/w, preferably, from about 0.1% to about 5%, more preferably from about 0.5% to about 2%.
Aside from the MPG, urea and the active agent, the compositions of this invention may include other substances, such as preservatives, cosmetic additives, antioxidants, chelating agents, opacifiers, and pigment flakes. Examples of such agents include, but are not limited to, benzoic acid, benzyl alcohol (as preservative), glycerol, propylene glycol as emollient, butylated hydroxy toluene, butylated hydroxyanisole, ascorbic acid, ascorbyl palmitate, N-acetyl cysteine as antioxidant, citric acid, edetic acid and its sodium salts as chelating agent.
An example of a topical formulation comprises 1% clotrimazole as active agent, 10% MPG and 20% urea as nail penetration enhancers, and 0.1% butylated hydroxy toluene as antioxidant.
The invention includes a lacquer composition comprising at least one active agent, at least one penetration enhancer, at least one volatile solvent, and at least one polymeric film former. As defined herein, lacquer refers to a liquid substance which typically dries to form a continuous or a non-continuous film by evaporation of the solvent. A polymeric film former refers to a polymer which may be added to a volatile solvent and other substances to form a polymeric solution which may be applied to form a film. Examples of polymeric film formers include, but are not limited to, acrylic copolymers/acrylic polymers, (such as CARBOSET(trademark) or AVALURE(trademark) polymers, made by B F Goodrich); polymers of methacrylic acid and its esters (such as EUDRAGIT(trademark) polymers: S, L, RS and RL series, made by Rohm Pharma); cellulose polymers, nitrocellulose, methyl cellulose, ethyl cellulose, cellulose acetates (such as cellulose triacetate, cellulose acetate butyrate); nylon, polyvinyl acetate, polyvinyl acetate phthalate, formaldehyde resin, and polymer blends of the aforementioned polymers. Preferred polymeric film formers are selected from the group consisting of acrylic copolymers/acrylic polymers, (such as CARBOSET(trademark) or AVALURE(trademark) polymers, made by B F Goodrich); polymers of methacrylic acid and its esters, (such as EUDRAGIT(trademark) polymers: S, L, RS and RL series, made by Rohm Pharma). An example of a volatile solvent includes, but is not limited to, water.
Lacquers may have different viscosities. The viscosity of the lacquer is related to the thickness of the film that will be left on a surface once the volatile solvent has evaporated. If one desires a thick and viscous lacquer, which will deposit a thick film on a surface, the concentration of the polymeric film former should be about 0.1% to about 30%, preferably from about 0.5% to about 15% of the total composition. If one desires a thin lacquer which will deposit a thin film on a surface, the concentration of the polymeric film former should be about 0.1% to about 15%, preferably about 0.5% to about 5.0% of the total composition.
The lacquers of the invention may have other additives such as plasticizers (to maintain the pliability of the film formers), non-volatile drug solubilizers, cosmetic additives, and pharmaceutical additives.
When plasticizers and non-volatile drug solubilizers are used, examples of these substances include, but are not limited to, phthalate esters (e.g., dibutyl phthalate), citrate esters, triacetin, isopropyl myristate, N-methyl-2-pyrrolidone, fatty acids and fatty acid esters, propylene glycol, butylene glycol, hexylene glycol, propylene carbonate, poly-propylene glycol, methoxypolyethylene glycol, polyethylene glycol, glycerin. When plasticizers are used they are preferably about 0.001 to about 10% by weight of the total composition.
Pharmaceutical additives include but are not limited to antioxidants and chelating agents. Examples of antioxidants include, but are not limited to, butylated hydroxy toluene, butylated hydroxyanisole, ascorbic acid, ascorbyl palmitate, N-acetyl cysteine. Examples of chelating agents include but are not limited to citric acid, edetic acid and its sodium salts. Cosmetic additives include, but are not limited to, coloring agents, fragrance, pigments, as well as powders of silica, zinc oxide, and titanium oxide.
The typical topical formulation containing the lacquer composition comprises 1% clotrimazole as active agent, 10% MPG and 20% urea as nail penetration enhancers, 15% acrylic polymer (CARBOSET(trademark) or AVALURE(trademark) AC 315) as film former, 0.7% isopropyl myristate as non-volatile drug solubilizer, 0.1% butylated hydroxy toluene as antioxidant, 0.1% citric acid, and 43% ethyl alcohol and 40% ethyl acetate as volatile solvents.
The invention includes a method of treating disease infected human nails by topically applying either a composition comprising at least one active agent, MPG, and urea or a lacquer composition comprising at least one active agent, at least one volatile solvent, MPG, urea, and at least one polymeric film former.
Any method of physically transferring the composition of the invention to the nail may be used. Such methods include, but are not limited to, painting the composition or lacquer on the surface of the nail; spraying the composition or lacquer using a spray pump, and combining the composition or lacquer with a propellant so that it is sprayed on the nail as an aerosol.
Typically for the treatment of nail diseases, the composition or lacquer is initially applied for once or twice per day and may be reduced to once or twice a week depending upon the intensity and resilience of the underlying infection.
As used herein, disease refers to fungal diseases, bacterial diseases and psoriasis. Fungal diseases of the human nail that can be treated in accordance with the invention include, but are not limited to, onychomycosis. This disease is typically caused by an infection of Epidermophyton floccosum; several species of Trichophyton, such as T. rubrum, T. megninii, T. schoenleinii, T. tonsurans, T. mentagrophytes; yeast, such as Candida albicans; molds, such as Scopulariopsis cephalosporium and Aspergillus fusarium; or Hendersonula toruloideo.
Fungal infections which may be treated using the compositions and methods of the invention are usually characterized by tarnished white, yellowed, or blackened nails. The nails will usually pull away from the pink nail bed along the sides or out edges, and infections are usually exacerbated by hot, damp conditions inside the shoes or in environments where hands or feet are continually exposed to moisture. The fungal infections are most commonly found in the toenails and may spread from toe to toe, foot to foot, and foot to hand. Diagnosis of the fungal infections may be microscopic identification and/or culture of the infected areas.
Specific infections which may be treated by the compositions and methods of the invention include distal subungual onychomycosis, caused by infection with C. trichophyton, Scopularosis, and Aspergillus); superficial white onychomycosis, caused by T. mentagrophytes; proximal white subungual onychomycosis, caused by Trichophyton species; total secondary dystrophic onychomycosis, caused by yeast and Trichophytons; and total dystrophic primary onychomycosis, caused by Candida species.
The topical treatment of the invention may be employed in combination with systemic treatment. For example, an antifungal drug, such as, itraconazole, terbinafine, griseofulvin or other antifungal drugs, may be given orally over a period of time. This time period may be concurrently during the entire topical treatment regimen, or concurrently during a portion (usually the latter phase) of the topical treatment regimen, or following the topical treatment.
The invention is described in greater detail by the following non-limiting example.

Composition and method for topical nail treatment


A negative resist composition, comprising:

The present invention relates to high-performance radiation sensitive resist compositions and their use in lithography processes to fabricate semiconductor devices. Specifically, the present invention is concerned with negative-tone silicon-containing resist compositions based on an acid catalyzed crosslinking of certain silicon-containing polymers. The resist composition of the present invention can be used to fabricate semiconductor devices using various irradiation sources, such as mid-ultraviolet (UV), deep-UV (for example 248 nm, 193 nm and 157 nm), extreme UV, X-ray, electron-beam and ion-beam irradiation. The resist compositions of the present invention exhibit enhanced sensitivity to e-beam and i-line irradiation along with resistance to high etch resistance to reactive ion etching in the presence of oxygen and chlorine. Compositions of the present invention are developable in aqueous base compositions.
In the manufacture of patterned devices such as semiconductor chips and chip carriers the steps of etching different layers, which constitute the finished product are among the most critical and crucial steps involved.
In semiconductor manufacturing, optical lithography has been the main stream approach to pattern semiconductor devices. In typical prior art lithography processes, UV light is projected onto a silicon wafer coated with a layer of photosensitive resist through a mask that defines a particular circuitry pattern. Exposure to UV light, followed by subsequent baking, induces a photochemical reaction, which changes the solubility of the exposed regions of the photosensitive resist. Thereafter, an appropriate developer, typically an aqueous base solution, is used to selectively remove the resist either in the exposed regions (positive-tone resists) or, in the unexposed region (negative-tone resists). The pattern thus defined is then imprinted on the silicon wafer by etching away the regions that are not protected by the resist with a dry or wet etch process.
The current state-of-the-art optical lithography uses DUV irradiation at a wavelength of 248 nm to print features as small as 250 nm in volume semiconductor manufacturing. The continued drive for the miniaturization of semiconductor devices places increasingly stringent requirements for resist materials, including high resolution, wide process latitude, good profile control and excellent plasma etch resistance for image transfer to substrate. Several techniques for enhancing the resolution, such as reduced irradiation wavelength (from 248 nm to 193 nm), higher numerical aperture (NA) of the exposure systems, use of alternate masks or illumination conditions, and reduced resist film thickness are currently being pursued. However, each of these approaches to enhance resolution suffers from various tradeoffs in process latitude, subsequent substrate etching and cost. For example, increasing NA of the exposure tools also leads to a dramatic reduction in the depth of focus. The reduction in the resist film thickness results in the concomitant detrimental effect of decreased etch resistance of the resist film for substrate etching. This detrimental effect is exasperated by the phenomenon of etch induced micro-channel formation during substrate etch, effectively rendering the top 0.2-0.3 um resist film useless as an etch mask for substrate etching.
Achieving further miniaturization would be facilitated by providing resists that exhibit enhanced sensitivity to e-beam and e-beam irradiation. However, obtaining resists that are sensitive to e-beam and i-line as well as being highly resistant to plasma and reactive ion etching is not an easy task. This is further complicated if a water developable system instead of an organic solvent developable system is desired.
Most lithographic processes (excluding so-called direct-write techniques) typically employ some type of patterned mask through which the imaging radiation is projected onto the resist material to be patterned on the substrate of interest. Typically, the mask itself is formed by a lithographic technique such as direct-write electron beam lithography or in some instances by projection UV lithography (especially i-line or deep UV) using an appropriate resist material. Typically, the mask comprises a patterned metal layer(s) (e.g., chromium) on a quartz plate (or other transparent plate).
A resist composition must possess desirable radiation response characteristics to enable image resolution upon exposure to a desired radiation development. Thus, a patternwise exposed positive resist must be capable of appropriate response (i.e. selective dissolution of exposed areas) to a developer to yield the desired resist structure. Given the extensive experience in the lithographic arts with the use of aqueous alkaline developers, it is important to achieve appropriate dissolution behavior in such commonly used developer solutions.
The resist composition must also possess suitable chemical and mechanical properties to enable transfer to the image from the patterned resist to an underlying substrate layer(s). Typically, pattern transfer is performed by some form of wet chemical etching or ion etching. The ability of the patterned resist layer to withstand the pattern transfer etch process (i.e., the etch resistance of the resist layer) is an important characteristic of the resist composition. In the case of typical mask making processes, a chlorine-containing etchant such as combination of Cl2 and O2 is generally a preferred etchant. Halogen-based etchants other than fluorine (i.e., Cl, Br, or I) are also preferred etchants for patterning metals and semiconductor (e.g., polycrystalline silicon) materials.
With demands for finer detailed masks and patterned metals/semiconductor materials, the performance of higher atomic weight halogen-based (i.e., Cl, Br, or I) etching processes has been increasingly problematic due to excessive erosion of the resist during the etching step needed for pattern transfer. Additionally, the desire to use lower energy e-beam imaging tools (e.g., 10 KeV tools) generally means that the resist layer must be thinner to be imaged by the lower energy beam. Thus, there is a need for improved processes for making patterned metal and/or semiconductor features and especially for making lithographic masks containing patterned metal layers.
It would therefore be desirable to provide a resist composition that has all of the above-mentioned attributes.
Accordingly, to the present invention a highly sensitive, high resolution negative-tone resist compositions is provided.
In addition, resist compositions of the present invention exhibit high resistance to reactive ion etching in employing oxygen and/or chlorine. Furthermore, resist compositions of the present invention can be developed in aqueous base compositions.
More particularly, the negative-tone resist compositions of the present invention comprise:
(a) a silicon-containing polymer with pendant fused moieties selected from the group consisting of fused aliphatic moieties, homocyclic fused aromatic moieties, and heterocyclic fused aromatic moieties and sites for reaction with a crosslinking agent,
(b) an acid-sensitive crosslinking agent, and
(c) a radiation-sensitive acid generator.
Another aspect of the present invention relates to a method of forming a patterned material layer on a substrate. The method comprises:
(a) providing a substrate having a material layer on a surface,
(b) providing a layer of resist over the material layer, the resist comprising:
(i) a silicon-containing polymer with pendant fused moieties selected from the group consisting of fused aliphatic moieties, homocyclic fused aromatic moieties, and heterocyclic fused aromatic moieties and sites for reaction with a crosslinking agent,
(ii) an acid-sensitive crosslinking agent, and
(iii) a radiation-sensitive acid generator;
(c) patternwise exposing the resist layer to imaging radiation,
(d) removing portions of the resist layer not exposed in step (c) to create spaces in the resist layer corresponding to the pattern, and
(e) removing portions of the material layer at the spaces.
Still other objects and advantages of the present invention will become readily apparent by those skilled in the art from the following detailed description, wherein it is shown and described only the preferred embodiments of the invention, simply by way of illustration of the best mode contemplated of carrying out the invention. As will be realized, the invention is capable of other and different embodiments, and its several details are capable of modifications in various obvious respects, without departing from the invention. Accordingly, the description is to be regarded as illustrative in nature and not as restrictive.
The present invention relates to a high sensitivity, high resolution, aqueous base developable silicon-containing negative-tone resist composition. The resist compositions of the present invention comprise (a) silicon-containing polymer with pendant fused moieties selected from the group consisting of fused aliphatic moieties, homocyclic fused aromatic moieties, and heterocyclic fused aromatic moieties, (b) acid-sensitive crosslinking and (c) radiation-sensitive acid generator.
The silicon-containing polymer may be a polymer containing SiO moieties in the polymer backbone and/or in pendant groups. Preferably, the polymer contains SiO moieties in its backbone. The polymer is preferably an organosiloxane, more preferably organosilsesquioxane. The polymer should have solution and film-forming characteristics conducive to forming a layer by conventional spin-coating. In addition, the SiO-containing polymer can contain a plurality of reactive sites distributed along the polymer for reaction with the crosslinking component.
Examples of suitable polymers include polymers having the silsesquioxane (ladder or network) structure. Such polymers preferably contain monomers having structures (I) and (II) below:
where R1 comprises a chromophore and R2 comprises a reactive site for reaction with the crosslinking component.
Alternatively, general linear organosiloxane polymers containing monomers (III) and (IV) can be used:
where R1 and R2 are as described above. In some cases, the polymer contain various combinations of monomers (I)-(IV) such that the average structure of R1-containing monomers may be represented as structure (V) below and the average structure for R2-containing monomers may be represented by structure (VI) below:
where x is from about 1 to about 1.5. In theory, x may be greater than 1.5, however, such composition generally do not possess characteristics suitable for spin-coating processes (e.g., they form undesirable gel or precipitate phases).
Generally, silsesquioxane polymers are preferred on the basis of superior etch resistance. If the ordinary organosiloxane polymers are used (e.g., monomers of structures (III) and (IV)), then preferably, the degree of crosslinking is increased by compared to formulations based on silsesquioxanes.
Preferably, the SiO-containing polymer (before grafting of the fused aromatic moieties) is poly(4-hydroxybenzylsilsesquioxane). Examples of other silsesquioxane polymers of the invention include:
poly(p-hydroxyphenylethylsilsesquioxane),
poly(p-hydroxyphenylethylsilsesquioxane-co-p-hydroxy-xcex1-methylbenzylsilsesquioxane),
poly(p-hydroxyphenylethylsilsesquioxane-co-methoxybenzylsilsesquioxane),
poly(p-hydroxyphenylethylsilsesquioxane-co-t-butylsilsesquioxane),
poly(p-hydroxyphenylethylsilsesquioxane-co-cyclohexylsilsesquioxane),
poly(p-hydroxyphenylethylsilsesquioxane-co-phenylsilsesquioxane),
poly(p-hydroxyphenylethylsilsesquioxane-co-bicycloheptylsilsesquioxane),
poly(p-hydroxy-xcex1-methyl benzylsilsesquioxane),
poly(p-hydroxy-xcex1-methylbenzylsilsesquioxane-co-p-hydroxybenzylsilsesquioxane),
poly(p-hydroxy-xcex1-methylbenzylsilsesquioxane-co-methoxybenzylsilsesquioxane),
poly(p-hydroxy-xcex1-methylbenzylsilsesquioxane-co-t-butylsilsesquioxane),
poly(p-hydroxy-xcex1-methylbenzylsilsesquioxane-co-cyclohexylsilsesquioxane),
poly(p-hydroxy-xcex1-methylbenzylsilsesquioxane-co-phenylsilsesquioxane),
poly(p-hydroxy-xcex1-methylbenzylsilsesquioxane-co-bicycloheptylsilsesquioxane), and
poly(p-hydroxybenzylsilsesquioxane-co-p-hydroxyphenylethylsilsesquioxane).
The SiO-containing polymers typically have a weight average molecular weight, before reaction with the crosslinking component, of at least about 1000, more typically a weight average molecular weight of about 1000-10000.
Examples of suitable aromatic fused-ring moieties include anthracyl and phenathracyl.
The compounds containing the aromatic fused-rings also include a reactive group for grafting onto the silicon polymer such as reactive hydroxyl groups.
The aromatic fused-ring moieties may be chemically attached to the SiO containing polymer by acid-catalyzed O-alkylation or C-alkylation such as by Friedel-Crafts alkylation. Alternatively, the aromatic fused-ring moiety may be attached by an esterification mechanism. A preferred acid for Friedel-Crafts catalysis is HCl. The site for attachment of the aromatic fused-ring is preferably an aromatic group such as a hydroxybenzyl or hydroxymethlbenzyl group. Alternatively, the aromatic fused-ring may be attached by reaction with other moieties such as cyclohexanol or other alcohols. The reaction to attach the aromatic fused-ring is preferably an esterification of the alcoholic OH group.
Alternatively, the pendant fused moiety may be a heterocyclic aromatic moiety (e.g. containing S,N or O in a ring position) or a fused ring aliphatic moiety. Fused-ring aromatic moieties (homocyclic or heterocyclic) are preferred for ease of synthesis as indicated below. The aliphatic moiety may require more elaborate synthesis techniques (e.g., use of gringard reagents and/or hydrogenation).
The amount of the compound containing the fused moiety is preferably employed in amounts of about 5 to about 35 mole % and more preferably about of 5 to about 20 mole % based on the monomer units contained in the polymer.
The crosslinking component is preferably a crosslinker that can be reacted with the SiO containing polymer in a manner which is catalyzed by generating acid and/or by heating. Generally, the crosslinking component used in the compositions of the invention may be any suitable crosslinking agent known in the negative photoresist art which is otherwise compatible with the other selected components of the composition. The crosslinking agents preferably act to crosslink the polymer component in the presence of a generated acid. Preferred crosslinking agents- are glycoluril compounds such as tetramethoxymethyl glycoluril, methylpropyltetramethoxymethyl glycoluril, and methylphenyltetramethoxymethyl glycoluril, available under the POWDERLINK trademark from American Cyanamid Company. Other possible crosslinking agents include: 2,6-bis(hydroxymethyl)-p-cresol, compounds having the following structures:
including their analogs and derivatives, such as those found in Japanese Laid-Open Patent Application (Kokai) No. 1-293339, as well as etherified amino resins, for example methylated or butylated melamine resins (N-methoxymethyl- or N-butoxymethyl-melamine respectively) or methylated/butylated glycolurils, for example as can be found in Canadian Patent No. 1,204,547. Other crosslinking agents such as bis-epoxies or bis-phenols (e.g., bisphenol-A) may also be used. Combinations of crosslinking agents may be used.
The photo acid generator used in the resist formulation of the present invention are compounds which generate an acid upon exposure to energy. They are commonly employed herein as well as in the prior art to generate stable carbocations of the crosslinking agents for the crosslinking of the silicon-containing polymer resins. Illustrative classes of such acid generators that can be employed in the present invention include, but are not limited to: nitrobenzyl compounds, onium salts, sulfonates, carboxylates and the like. To minimize acid diffusion for high resolution capability, the acid generators should be such that they generate bulky acids upon exposure to energy. These bulky acids contain at least 4 carbon atoms. A preferred acid generator employed in the present invention is an onium salt such as an iodonium salt or a sulfonium salt. Examples of photoacid generators are discussed in great length in disclosure of which is incorporated herein by reference. More preferred acid generators are di(t-butylphenyl) iodonium perfluorobutane sulfonate, di(t-butylphenyl) iodonium perfluorohexane sulfonate, di(t-butylphenyl) iodonium perfluoroethylcyclohexane sulfonate, and di(t-butylphenyl) iodonium camphoresulfonate.
The specific photoacid generator selected will depend on the irradiation being used for patterning the resist. Photoacid generators are currently available for a variety of different wavelengths of light from the visible range to the X-ray range; thus, imaging of the resist can be performed using deep-UV, extreme-UV, e-beam, laser or any other irradiation source deemed useful.
The compositions of the invention typically contain (on a solids basis) (i) about 50-98 wt. % of the SiO-containing polymer, more typically about 70-80 wt. %, (ii) about 1-50 wt. % of crosslinking component, more typically about 3-25%, most preferably about 5-25 wt. %, and (iii) about 0.1-20 wt. % acid generator, more typically about 0.5-15 wt. %.
Solvents that can be employed in the resist formulation of the present invention are solvents well known to those skilled in the art. They are used to dissolve the silicon-containing polymer, the crosslinking agent, the photoacid generator and other components. Illustrative examples of such solvents include, but are not limited to: ethers, glycol ethers, aromatic hydrocarbons, ketones, esters and the like.
Suitable glycol ethers that can be employed in the present invention include: 2-methoxyethyl ether (diglyme), ethylene glycol monomethyl ether, propylene glycol monomethyl ether, propylene glycol monoether acetate (PGMEA) and the like. Examples of aromatic hydrocarbons that may be employed in the present invention include toluene, xylene and benzene; examples of ketones include methylisobutylketone, 2-heptanone, cycloheptanone, and cyclohexanone; an example of an ether is tetrahydrofuran; whereas ethyl lactate and ethoxy ethyl propionate are examples of esters that can be employed in the present invention. Of the solvents mentioned hereinabove it is preferred that a glycol ether or ester be employed, with PGMEA being the most preferred glycol ether and ethyl lactate is the most preferred ester.
The compositions can also include optional components such as basic materials and surfactants.
The bases that can be employed in the present invention, include, but are not limited to: Coumarins, berberine, cetyltrimethylammonium hydroxide, 1,8-bis(dimethylamino)naphthalene, tetrabutyl ammonium hydroxide (TBAH), amines, polymeric amines and the like.
The surfactants that can be employed in the present invention as those that are capable of improving the coating homogeneity of the chemically amplified negative-tone resist compositions of the present invention. Illustrative examples of such surfactants include: fluorine-containing surfactants such as 3M""s FC-430 and siloxane-containing surfactants such as Union Carbide""s SILWET series and the like.
When the compositions contain a solvent such is typically present in amounts of about 40 to about 99.5 wt. % of the composition.
If a photosensitizer is present, it is preferably present in an amount of from about 0.001 to about 8 wt. %. When a base and/or surfactant are used, they are preferably present in an amount of from about 0.001 to about 16 wt. % of the base and from about 100 to about 1000 PPM wt. % of the surfactant. More typically, the negative-tone resist composition of the present invention comprises from about 0.5 to about 30 wt. % of the silicon resin component; from about 0.05 to about 20 wt. % of the crosslinking component; from about 0.005 to about 10 wt. % the acid generators from about 80 to about 98 wt. % of the solvent; and, if present, from about 50 to about 800 PPM wt % of a base, and from about 250 to about 1000 PPM wt. % of a surfactant.
In accordance with the present invention, the silicon-containing resist compositions can be used as an imaging layer in the manufacturing of semiconductor devices.
The silicon-containing imaging layer is applied usually by spin coating on the substrate, and baked to give a layer thickness typically about 50 to 400 nm, more typically about 100 to 300 nm. If desired it can be exposed to elevated temperatures of about 80xc2x0 to about 140xc2x0 C. to drive off the solvent. The imaging layer is exposed to an appropriate irradiation source. This is followed by post-exposure baking and development in an aqueous base developer, such as aqueous tetramethyl ammonium hydroxide (TMAH) solution.
The pattern from the resist structure may then be transferred to the material (e.g., ceramic, metal or semiconductor) of the underlying substrate. Typically, the transfer is achieved by reactive ion etching or some other etching technique. The most preferred application for the resist materials of the invention is in the patterning of metal layers, especially chromium-containing metal compositions as are commonly used for mask-making. In such applications, a halogen compound-containing pattern transfer etchant where the halogen is Cl, Br or I is typically used (e.g., Cl2, Br2, I2, and BCl3). The halogen compound-containing etchant may contain a combination of halogen compounds and/or may contain additional compounds such as a strong oxidant (e.g., O2). A combination of Cl2 and O2 is a generally preferred etchant. The etching process described in U.S. Pat. No. 5,948,570 may be used except that no post-development oxidation step is required using the resist of the present invention. The disclosure of U.S. Pat. No. 5,948,570 is incorporated herein by reference. Other suitable etching techniques also may be used.
The compositions of the invention and resulting resist structures can be used to create other patterned material layer structures such as metal wiring lines, holes for contacts or vias, insulation sections (e.g., damascene trenches or shallow trench isolation), trenches for capacitor structures, etc. as might be used in the design of integrated circuit devices.
The processes for making these (ceramic, metal or semiconductor) features generally involve providing a material layer or section of the substrate to be patterned, applying a layer of resist over the material layer or section, patternwise exposing the resist to radiation, developing the pattern by contacting the exposed resist with a solvent, etching the layer(s) underlying the resist layer at spaces in the pattern whereby a patterned material layer or substrate section is formed, and removing any remaining resist from the substrate. In some instances, a hard mask may be used below the resist layer to facilitate transfer of the pattern to a further underlying material layer or section. Examples of such processes are disclosed in U.S. Pat. Nos. 4,855,017; 5,362,663; 5,429,710; 5,562,801; 5,618,751; 5,744,376; 5,801,094; 5,821,469, and 5,948,570, the disclosures of which patents are incorporated herein by reference. Other examples of pattern transfer processes are described in Chapters 12 and 13 of xe2x80x9cSemiconductor Lithography, Principles, Practices, and Materialsxe2x80x9d by Wayne Moreau, Plenum Press, (1988), the disclosure of which is incorporated herein by reference. It should be understood that the invention is not limited to any specific lithography technique or device structure.
The following non-limiting examples are given to further illustrate the present invention. Because these examples are given for illustrative purposes only, the invention embodied therein should not be limited thereto.

Radiation sensitive silicon-containing negative resists and use thereof

Abstract: (a) silicon-containing polymer with pendant fused moieties selected from the group consisting of fused aliphatic moieties, homocyclic fused aromatic moieties, and heterocyclic fused aromatic and sites for reaction with a crosslinking agent,

Abstract: (c) a radiation-sensitive acid generator is provided. The resist composition is used to form a patterned material layer in a substrate.

International Business Machines Corporation


Provided with a tooth paste composition which contains an abrasive cleaning agent, a humectant, a binder or thickener and a flavouring agent, the tooth paste, and includes a rose-seed oil, wherein the rose-seed oil is contained in an amount of 1-6% by weight based on the total weight of the tooth paste composition.

1. Field of the Invention
The present invention relates to a tooth paste composition efficacious for a preventive and remedy against a paradental disease and a preventive against caries and, more particularly, to a composition for dental hygiene in which use is made of a rose-seed oil to prevent and treat a paradental disease or prevent caries.
2. Description of the Related Art
Brushing the teeth with a toothbrush and a tooth paste is the most general measure to maintain dental hygiene. The reason why the tooth paste is used lies in that the tooth paste contains an abrasive and a cleaner which help mechanical removal of plaque, smooth the surface of teeth, rinse the mouth with a refreshed feeling, making it pleasant to clean the mouth. However, this simple method for removing the plaque is not so effective to maintain dental hygiene and prevent paradental diseases, as a result of which more people suffer from paradental diseases with an increase of their age.
It is well known that sodium chloride, anti-plasmin agent, allantoin derivatives, vitamins and amino acids are widely used in a composition for dental hygiene in a sole form or in combination thereof for the purpose of a preventive and cure against paradental diseases and a preventive against a caries. However, these substances are not effective and there is a demand for a new tooth paste composition that takes an effect against the paradental diseases in three ways: eliminating causal bacteria, reducing inflammation of the teethridge, etc., and restoring a tissue such as teethridge.
Accordingly, an object of the present invention is to provide a tooth paste composition efficacious against paradentitis, gingivitis, caries, stomatitis, etc.
That is, the object of the present invention is to provide a tooth paste composition containing a rose-seed oil efficacious against paradental diseases, in which the rose-seed oil which has been reported to be effective in regeneration of skin, reduction and restoration of wound and treatment of inflammation is added to a tooth paste base.
To achieve the object of the present invention, there is provided a tooth paste composition which contains an abrasive cleaning agent, a humectant, a binder and a flavouring agent; the tooth paste comprises a rose-seed oil. More preferably, the rose-seed oil is contained in an amount of 1-6% by weight based on the total weight of the tooth paste composition.
The toothpaste composition is most preferably to be stored in a light-impeding container. The toothpaste composition therapeutic potency at room temperature in a light impeding or other type of container.
Now, the present invention will be described in detail.
It is reported that a rose-seed oil is effective for nourishment and regeneration of the skin (See. British Journal of Dermatology, April 1997), reduction and treatment of the wound and treatment of the burned skin (See. Cancer Chemotherapy and Pharmacology, March 1979), inflammation of the skin (See. American Journal of Obstetrics and Gynecology) and pimple (See. Journal of American Academy of Dermatology).
According to a toxicological experiment in which the rose-seed oil is administered to a rat, it is demonstrated that the rose-seed oil has no harm to the human body with LD 50, that is, 5 g/kg (weight). The rose-seed oil is also turned out to be nonpoisonous to the skin, in another experiment.
The rose-seed oil used herein is derived from a rose whose botanical name is Rosa aff. Rubignosa L that is grown naturally or artificially in a wet climate. The rose has thorny stem and branches and the flowers are white and pink, or in some times, yellow. The flower is 3-6 cm in size and has 5 flower cups per 7-15 buds. The floral stalk is 2 mts long and about 3 mts in radius, and the leaves are oval and green-colored. The rose has about 15-20 fruits containing an ordinary oil. The fruits are reddish and egg-shaped with a diameter of 1.5-2.5 mm. The outer skin of the fruit is 1-3 mm thick and contains a large content of ascorbic acid and pectin and a small content of sugar. The seeds consist of unsaturated fatty acid, tretinoin, gums, margarine, cartenoides, cetonic, etc. Gums, margarine and cartenoides are removed in the course of extraction of the oil.
The extraction of the rose-seed oil includes the two steps of dissolving the rose seeds in a solvent, and distilling the oil-containing extracted solvent i.e., micella to recover the solvent and then separating the oil. The solvent used herein is petroleum benzene, benzol, hexane, or the like. To extract the rose-seed oil, the rose seeds carefully selected are pressed into flakes in order for the solvent to be penetrated into the seeds. The flakes are strengthened under conditions of 3-11% water content and a temperature of 50-60 degrees. These flakes are then added to an extractor to extract the solvent. The solvent is separated from the micella obtained through the extraction in two steps of volatilization and stripping. The micella generated from the extractor contains a 25-30% oil content. The oil content is increased to 90-95% by volatilizing the solvent. The concentrated micella is transferred to an apparatus called a stripper in which the micella is brought in direct contact with water vapors in a vacuum of about 50-200 mmHg to perfectly remove the residual solvent and obtain the rose-seed oil.
It is preferable that the present tooth paste composition contains 1-6% by weight of the rose-seed oil based on the total weight of the composition. The other components may be a mixture of the gradients of an ordinary tooth paste composition.
For example, a humectant used herein is at least one or two substances selected from the group consisting of glycerine, sorbitol solution and amorphous sorbitol solution. An abrasive cleaning agent used herein is calcium hydrogen phosphate, calcium carbonate, aluminum oxide, etc. Additives used in a small content are ordinary components used in the tooth paste and include sweetening agents, pH controlling agents, antiseptic substances, coloring agents and binders.
The sweetening agents are sodium saccharide, aspartame, etc., the pH controlling agents are sodium phosphate, disodium phosphate, citric acid, etc., and the antiseptic substances are paraoxy benzoin methyl, sodium benzoin, etc.
The binders or thickeners are sodium carboxymethyl cellulose, carrageenan, xantan gum, etc. A foaming agent used herein may be anionic and non-ionic surfactants of sodium lauryl sulfate, saccharose carboxylic ester and sorbitan carboxylic ester in a sole form or in a combination of at least two thereof.
An flavouring agent used herein is a mixture of peppermint oil, spearmint oil, menthol, etc., and other additives are enzymes such as dextranase, etc.
The preparation of the tooth paste composition in the present invention comprises: dispersing a small powder content of sodium carboxymethyl cellulose, saccharine and the like in a humectant e.g., amorphous sorbitol solution, diluting the solution with a purified water, first mixing the solution and the purified water in a mixer, adding an abrasive cleaning agent such as calcium hydrogen phosphate, etc. and then 1-6% by weight of a rose-seed oil, and adding a foaming agent, a stabilizer, an flavouring agent, etc.
Reference will be made to embodiments and comparative examples for the detail description of the present invention.

Tooth paste composition containing rose-seed oil