阅读说明：本技术 生物活性硼酸盐玻璃及其方法 (Bioactive borate glass and method ) 是由 邓华云 付强 魏莹 于 2018-11-27 设计创作，主要内容包括：生物活性硼酸盐玻璃组合物,其包含例如：30至60％B<Sub>2</Sub>O<Sub>3</Sub>,0.5至20％ZrO<Sub>2</Sub>,3至30％Na<Sub>2</Sub>O,0.1至15％K<Sub>2</Sub>O,0.1至15％MgO,5至30％CaO,和1至5％P<Sub>2</Sub>O<Sub>5</Sub>,以摩尔％计,以总组成为100摩尔％计。还公开了组合物以及生物活性硼酸盐玻璃牙本质治疗制剂的制造方法和使用方法。(A bioactive borate glass composition comprising, for example: 30 to 60% B 2 O 3 0.5 to 20% ZrO 2 3 to 30% Na 2 O, 0.1 to 15% K 2 O, 0.1 to 15% MgO, 5 to 30% CaO, and 1 to 5% P 2 O 5 In mole%, based on 100 mole% of the total composition. Also disclosed are compositions and methods of making and using the bioactive borate glass dentinal therapeutic formulations.)

1. A bioactive borate glass composition comprising:

30 to 60% B₂O₃；

0.5 to 20% ZrO₂；

3 to 30% Na₂O；

0.1 to 15% K₂O；

0.1 to 15% MgO;

5 to 30% CaO; and

1 to 5% P₂O₅In mole%, based on 100 mole% of the total composition.

2. The bioactive borate glass composition of claim 1 which isIn the composition, Al is not contained₂O₃、SiO₂Or mixtures thereof.

3. The bioactive borate glass composition of claim 1 or 2, further comprising a material selected from NaF, SnF₂、CaF₂Or mixtures thereof in an amount of 1 to 25 mole percent based on the super addition of the composition.

4. A bioactive borate glass composition comprising:

30 to 60% B₂O₃；

0.5 to 20% ZrO₂；

3 to 30% Na₂O；

0.1 to 15% K₂O；

5 to 30% CaO; and

1 to 5% P₂O₅In mole%, based on 100 mole% of the total composition.

5. The bioactive borate glass composition of claim 4, wherein the composition is free of Al₂O₃Is free of SiO₂MgO or a mixture thereof.

6. The bioactive borate glass composition of claim 4 or 5, further comprising a material selected from NaF, SnF₂、CaF₂Or mixtures thereof in an amount of 1 to 25 mole percent based on the super addition of the composition.

7. A method of treating dentinal hypersensitivity comprising:

contacting at least one surface of a tooth sample having at least one phenomenon of dentinal hypersensitivity with a formulation comprising the composition of any of claims 1-3.

8. The method of claim 7, wherein contacting is done at a time zero of at least 1 day.

9. The method of claim 7 or 8, wherein contacting is accomplished by: 1 to 10 times daily for a period of 1 to 12 weeks.

10. A method of treating dentinal hypersensitivity comprising:

contacting at least one surface of a tooth sample having at least one phenomenon of dentinal hypersensitivity with a formulation comprising the composition of any of claims 4-6.

11. The method of claim 10, wherein contacting is done at a time zero of at least 1 day.

12. The method of claim 10 or 11, wherein contacting is accomplished by: 1 to 10 times daily for a period of 1 to 12 weeks.

Background

The present disclosure relates to glass compositions, bioactive glass compositions, and methods of making and using the compositions.

Disclosure of Invention

In an embodiment, the present disclosure provides a bioactive borate glass composition comprising, for example: 30 to 60% B₂O₃0.5 to 20% ZrO₂3 to 30% Na₂O, 0.1 to 15% K₂O, 0.1 to 15% MgO, 5 to 30% CaO, and 1 to 5% P₂O₅Expressed in mole percentages, based on 100 mole% of the total composition, it is for example: does not contain Al₂O₃SiO-free₂Or mixtures thereof may be absent.

In an embodiment, the present disclosure provides a bioactive borate glass composition comprising, for example: 30 to 60% B₂O₃0.5 to 20% ZrO₂3 to 30% Na₂O, 0.1 to 15% K₂O, 5 to 30% CaO, and 1 to 5% P₂O₅It is, for example, in mole percent, based on 100 mole% of the total composition: does not contain Al₂O₃、SiO₂MgO, or mixtures thereof.

In embodiments, the disclosed bioactive borate glass compositions exhibit excellent biocompatibility.

In embodiments, the present disclosure provides bioactive borate glass compositions and formulations that plug at a rate twice as fast as, for example, bioactive 45S 5-containing glass formulations in dentinal therapy experiments.

In embodiments, the present disclosure provides formulations and methods for treating dentinal hypersensitivity.

Drawings

In an embodiment of the present disclosure:

fig. 1A to 1F show optical images of cell morphology from live/dead cell assays over a seven day (7 day) cycle.

FIG. 2 shows an ATP assay of example composition 1.

Fig. 3A to 3D show SEM micrographs of test dentin disks with different treatments.

Detailed Description

Various embodiments of the present disclosure are described in detail below with reference to the figures (if any). Reference to various embodiments does not limit the scope of the invention, which is limited only by the scope of the claims attached hereto. Furthermore, any examples set forth in this specification are not intended to be limiting and merely set forth some of the many possible embodiments for the claimed invention.

In embodiments, the disclosed compositions, articles, and methods of manufacture and use provide one or more advantageous features or aspects, including, for example, as described below. Features or aspects recited in any claims are generally applicable to all aspects of the invention. Any single or multiple features or aspects recited in any claim may be combined or combined with or substituted for any other features or aspects recited in any one or more other claims.

Definition of

"dentinal hypersensitivity" (DH) "dentinal sensitivity" (DS) or similar terms refer to transient stinging due to cold, heat, air, touch or chemical or osmotic stimuli such as sweet foods.

"occlusion," "blocking," "shielding," or similar terms refer to, for example, closing or blocking to an occlusion.

"glass" or similar terms may refer to glass or glass-ceramic.

"glass article" or similar terms may refer to any object made in whole or in part of glass or glass-ceramic.

"fragrance," "flavoring agent," or similar terms may refer to any natural or synthetic substance that provides an organoleptic property to the disclosed compositions when a user comes into contact with the compositions. The fragrance may be, for example, a single compound or a mixture of compounds. The perfume may be selected to impart a unique fragrance to the composition or product or to maintain fragrance consistency from product batch to product batch or after formulation changes. The fragrance may be any known or discovered compound, for example: diacetyl, levulinyl, acetoin, isoamyl acetate, benzaldehyde, cinnamaldehyde, ethyl propionate, methyl anthranilate, limonene, ethyl decadienoate (ethyl decadienoate), allyl caproate, ethyl maltol, ethyl vanillin, methyl salicylate, and the like or mixtures thereof.

Other typical composition components or formulation ingredients known to those skilled in the art such as abrasives, humectants, colorants, antimicrobials, surfactants, brighteners, binders, and similar components or ingredients are found in, for example, en.

"include," "includes," or similar terms are intended to include, but are not limited to, i.e., are inclusive and not exclusive.

"about" as used in the embodiments described herein to modify, for example, amounts, concentrations, volumes, processing temperatures, processing times, yields, flow rates, pressures, viscosities, and the like, and ranges thereof, or dimensions of components, and the like, and ranges thereof, of ingredients in a composition refers to changes in the amount of a value that may occur, for example, from conventional measurements and procedures used to prepare materials, compositions, composites, concentrates, component parts, articles of manufacture, or use the formulations; occasional errors from these processes; differences in the manufacture, source or purity of starting materials or ingredients used to carry out the method; and the like. The term "about" also includes amounts that differ due to aging of a composition or formulation having a particular initial concentration or mixture, as well as amounts that differ due to mixing or processing of a composition or formulation having a particular initial concentration or mixture.

"optional" or "optionally" means that the subsequently described event or circumstance may or may not occur, and that the description includes instances where the event or circumstance occurs and instances where it does not.

As used herein, the indefinite articles "a" or "an" and their corresponding definite articles "the" mean at least one, or one or more, unless otherwise indicated.

Abbreviations well known to those skilled in the art may be used (e.g., "h" or "hrs" for hours, "g" or "gm" for grams, "m L" for milliliters, "rt" for room temperature, "nm" for nanometers, and the like).

Specific and preferred values and ranges thereof disclosed in terms of components, ingredients, additives, dimensions, conditions, time, and the like are for illustration only; they do not exclude other defined values or other values within the defined range. The compositions and methods of the present disclosure can include any value or any combination of values, specific values, more specific values, and preferred values described herein, including explicit or implicit intermediate values and ranges.

Bioactive glasses have a widely recognized ability to promote bone cell growth and bind strongly to hard and soft tissues. Bioactive glass has also been reported to release ions that activate osteoblast gene expression and stimulate angiogenesis (see, e.g., Rahaman et al, "Bioactive glass in tissue engineering," Acta Biomater, 2011, 7: 2355-. Silicate glass based toothpaste (e.g. toothpasteAnd) Can react with saliva and release calcium, phosphate or fluoride ions, thereby on exposed dentin and on exposed dentinHydroxyapatite or fluorapatite is formed within the tubules of dentin (see Kulal, "An in-vitro composition of nano-hydro-xypatites, Novamin and Proargin sensing toothpastes, SEM study", J Clin Diagn Res, 2016, 10(10): ZC 51-ZC 54; L. J. L itkowski entitled "Compositions of Bioactive glass and use of Bioactive glass in treating tooth hypersensitivity)" US6338751 and Hitive glass composition entitled "Bioactive glass composition (US 9168272 for Bioactive glass composition").

Treatment with a toothpaste containing bioactive glass is a method that can provide long-term dentin protection (e.g., for months). Unlike other masking agents for dentinal tubules, the disclosed bioactive glass formulation can provide long-term treatment.

Interest in bioactive borate glasses is growing due to their novel properties (e.g., rapid breakdown and conversion to hydroxyapatite-like materials, support of angiogenesis, and regeneration of soft tissues) (see, e.g., Rahaman et al, supra). However, the rapid release of boron into solution can lead to reduced cell viability, particularly for in vitro cell culture. This cell viability problem can be solved by, for example, modifying the glass composition to include some silica or by culturing the cells in a dynamic environment (see Rahaman above). Certain aluminoborate glasses from corning incorporated have been demonstrated to have, for example, excellent biocompatibility, enhanced vascular production, and promotion of wound healing (see, e.g., the above-mentioned commonly owned USSN 62/342,384, 62/342,411 and (not yet assigned) _______ (r) (r)))). However, these compounds contain Al₂O₃In the bioactive glass of (2), the release of aluminum ions is a potential problem for neuro-cytotoxicity considerations. ZrO has been added to silicate glasses₂Glass durability is improved (seeSimhan，“Chemical durability of ZrO₂containing glasses (containing ZrO)₂Chemical durability of glass) "J Non-Crystal Solids, 1983, 54: 335-. However, ZrO is not clear₂Effect on biocompatibility based on silicate-free borate glasses.

In embodiments, the present disclosure provides a set of glass compositions based on borate glass, which have excellent biocompatibility. In addition, the disclosed glass compositions are capable of plugging dentinal tubules, suggesting use in the treatment of dentinal hypersensitivity.

In an embodiment, the present disclosure provides a material containing ZrO₂The borate glass composition of (1), which exhibits excellent biocompatibility and which can be used for the treatment of dentinal hypersensitivity.

In an embodiment, the glass comprises, in mole percent: 30 to 60% B₂O₃0.5 to 20% ZrO₂3 to 30% Na₂O, 0.1 to 15% K₂O, 0.1 to 15% MgO, 5 to 30% CaO, and 1 to 5% P₂O₅. Table 1 lists exemplary compositions and controls. These glasses can typically be melted at temperatures below, for example, 1300 c, and in some embodiments below 1200 c, which allows the composition to be melted in smaller commercial glass jars.

In embodiments, it has been unexpectedly found that the addition of ZrO to borate glasses₂The biocompatibility of the borate glass composition is improved. Compared with no ZrO₂In the disclosed glass compositions (e.g., disclosed example composition 1), a significantly greater number of viable cells was seen in the comparative borate glass (e.g., comparative control composition 2) (fig. 1) (see table 1). After 4 days, there were no viable cells on the comparative borate glass dishes, whereas the ZrO-containing glasses disclosed₂The composition of (4), wherein the cell count continues to increase. Continued cell growth in the disclosed compositions was confirmed using ATP assays (fig. 2). The excellent biocompatibility of the disclosed glass compositions is attributed to their lower boron ion release rate, which is believed to be due to the addition or presence of ZrO in the composition₂The result is.

In embodiments, the disclosed compositions can react with saliva and release calcium, phosphate, or fluoride ions, thereby forming hydroxycarbonate apatite (fig. 3) or fluoroapatite, exhibiting tubule shadowing by forming a smear layer within and at the surface of dentinal tubules, and reconstructing, strengthening, and protecting tooth structures. The fluoride ion may be in the form of a precursor (e.g., sodium fluoride (NaF), stannous fluoride (SnF)₂) Calcium fluoride (CaF)₂) Or mixtures thereof) is incorporated into the glass composition in an amount of, for example, 1 to 25 mole percent, based on the super addition of the composition.

In actual oral fluids, fluoride bound glass is expected to release fluoride and form fluorapatite, which is even more resistant to acid dissolution than hydroxycarbonate apatite (HCA).

In embodiments, the disclosed glasses may be processed into, for example, powders, staple fibers, beads, sheets, 3D scaffolds, and similar form factors by various known techniques. For example, glass powders can generally be prepared by jet milling or ball milling of glass frits. The staple fibers can be made by melt spinning or electrospinning. For example, beads can be made by flowing glass particles through a vertical furnace. For example, the sheet may be manufactured using a thin roll, float, or fusion draw process. For example, stents may be manufactured by rapid prototyping, polymer foam replication, and particle sintering and similar methods. For example, desirable glass forms can be used to support cell growth, soft and hard tissue regeneration, mimic gene expression, or angiogenesis.

The biocompatibility and the decomposition of the glass are influenced by the respective glass composition. In the disclosed glass composition, B₂O₃As the main glass-forming oxide. Borate glass is far less durable than silicate glass, which makes it attractive for rapid degradation. However, toxicity due to degradation and control of the rate of degradation remain a problem.

P₂O₅Also functions as a network former. In addition, phosphate ions are released to the living organismThe surface of the glass contributes to the formation of apatite. The provision of phosphate ions by the bioactive glass increases the rate of apatite formation and the binding capacity of the bone tissue. Furthermore, P₂O₅The viscosity of the glass is increased which in turn extends the operating temperature range and is thus advantageous for manufacturing and forming glass.

In addition to its role as a network former or intermediate in precursor glasses, ZrO₂Chemical durability in borate glass is improved without toxicity problems.

Basic oxide (i.e., L i)₂O、Na₂O、K₂O、Rb₂O and Cs₂O) acts as an adjuvant for achieving low melting and low liquidus temperatures. The addition of basic oxides is reported to improve biological activity (see, e.g., Rahaman et al, supra).

Divalent cation oxides (e.g., alkaline earth oxides) may also improve the melting behavior and bioactivity of the glass. In particular, CaO is found with P when immersed in Simulated Body Fluid (SBF) or in vivo₂O₅The reaction forms apatite. Ca released from the surface of the glass²⁺The ions contribute to the formation of a layer enriched in calcium phosphate.

In an embodiment, the present disclosure provides a bioactive borate glass composition comprising:

30 to 60% B₂O₃；

0.5 to 20% ZrO₂；

3 to 30% Na₂O；

0.1 to 15% K₂O；

0.1 to 15% MgO;

5 to 30% CaO; and

1 to 5% P₂O₅In mole%, based on 100 mole% of the total composition.

The mol% of the source has the following equivalent weight%: 30 to 60% B₂O₃0.5 to 20% ZrO₂3 to 30% Na₂O, 0.1 to 15% K₂O, 0.1 to 15% MgO, 5 to 30% CaOAnd 1 to 5% P₂O₅In% by weight, based on 100% by weight of the total composition.

In embodiments, the bioactive borate glass compositions described above are Al-free₂O₃Is free of SiO₂Or mixtures thereof may be absent.

In embodiments, the bioactive borate glass compositions described above may further comprise a fluoride ion source, for example selected from the group consisting of: sodium fluoride (NaF), stannous fluoride (SnF)₂) Calcium fluoride (CaF)₂) And similar fluoride ion sources, or mixtures thereof.

In an embodiment, the present disclosure provides a bioactive borate glass composition comprising:

30 to 60% B₂O₃；

0.5 to 20% ZrO₂；

3 to 30% Na₂O；

0.1 to 15% K₂O；

5 to 30% CaO; and

1 to 5% P₂O₅In mole%, based on 100 mole% of the total composition.

The mol% of the source has the following equivalent weight%: 30 to 60% B₂O₃0.5 to 20% ZrO₂3 to 30% Na₂O, 0.1 to 15% K₂O, 5 to 30% CaO, and 1 to 5% P₂O₅In% by weight, based on 100% by weight of the total composition.

In embodiments, the bioactive borate glass composition described above is MgO-free.

In embodiments, the bioactive borate glass compositions described above are Al-free₂O₃Is free of SiO₂MgO or a mixture thereof.

In embodiments, the bioactive borate glass composition described above may further comprise a fluoride ion source selected from the group consisting of: sodium fluoride (NaF), stannous fluoride (SnF)₂) Calcium fluoride (CaF)₂) To be provided withAnd similar fluoride ion sources, or mixtures thereof.

In an embodiment, the present disclosure provides a method of treating dentinal hypersensitivity comprising: contacting at least one surface of a tooth sample having at least one dentinal hypersensitivity phenomenon with a formulation comprising any of the disclosed compositions.

In an embodiment, the contacting may be done at a time zero of, for example, at least 1 day.

In embodiments, contacting may be accomplished 1 to 10 times per day, for example, for a period of 1 to 12 weeks.

The present disclosure has several advantages, including, for example:

it has been unexpectedly found that the disclosed ZrO-containing compounds₂The borate glass composition has excellent biocompatibility, and

the disclosed ZrO-containing glass compositions are comparable to known silicate glass compositions₂The borate glass compositions have unexpectedly faster rates of dentinal tubule plugging.

Referring to the drawings, fig. 1A to 1F show optical images of cell morphology from a live/dead cell assay over a seven day (7 day) cycle. Cell culture was done in 24-well culture plates on glass dishes (12.5mm diameter by 2.0mm thickness) of composition 1. In the initial color image (not provided), green image dots (depicted with solid dots) represent viable cells, and red dots (depicted with open dots) represent dead cells. The comparative composition (i.e., control 1(45S5)) (fig. 1A to 1C) and example composition 1 (fig. 1D to 1F) were used for cell morphology studies.

FIG. 2 shows an ATP assay of example composition 1. The ATP assay is used to determine cell proliferation and cytotoxicity of the disclosed compositions in mammalian cells. Cell culture was done in 24-well culture plates on glass dishes (12.5mm diameter by 2.0mm thickness) of composition 1. The higher the luminescence of the readings (measured at the end of day one, day 4 and day 7), the greater the number of cells.

Fig. 3A to 3D show SEM micrographs of test dentin disks with different treatments as follows: control dentin discs without any treatment (untreated, 3A); treatment of 1 week dentin disks (3B) with toothpaste base formulation (i.e., vehicle only); dentin disks (3C) were treated with toothpaste containing 45S5 (control 1) for 1 week; and a 1 week dentin disk (3D) treated with the disclosed toothpaste containing example composition 1. During the treatment, all samples were immersed in artificial saliva. For the toothpaste base formulation (3B), there was no occlusion of dentinal tubules. After treatment with the toothpaste containing 45S5, half of the dentinal tubules were masked by the crystalline precipitate (3C). After treatment with the toothpaste containing example composition 1, all dentinal tubules and dentinal surfaces were masked by crystalline deposits (3D).

Table 1 lists exemplary ZrO-containing materials₂Borate glass compositions and control compositions 1 and 2.

Table 1: containing ZrO₂Borate glass compositions and controls

For each dental formulation, the dentin disks made from human molars were evaluated for their ability to shield as shown in table 2.

Table 2: base toothpaste composition and toothpaste composition containing exemplary bioactive glass

The raw materials and/or equipment used to produce the glass compositions of the present invention may introduce certain impurities or components that are not intentionally added and which may be present in the final glass composition. Such materials may be present in small amounts in the glass composition and are referred to herein as "inclusions".

The disclosed glass compositions often contain impurities in trace amounts. Similarly, "iron-free", "sodium-free", "lithium-free", "zirconium-free", "alkaline earth metal-free", "heavy metal-free" or similar characterization means that the composition has no intentionally added impurities, but the composition may still contain iron, sodium, lithium, zirconium, alkaline earth metals or heavy metals, etc., but in approximate trace amounts or traces.

Unless otherwise indicated, all concentrations of components referred to herein are expressed in weight percent (wt%).

Although the transition term "comprising" may be used to describe various features, elements or steps of a particular embodiment, this includes, in alternate embodiments, those alternate embodiments that may be described using the transition term consisting of, or consisting essentially of.