TWI856229B - Method for stiffening soft tissue, and the composition thereof - Google Patents

Abstract

The present application provides a use of riboflavin for preparing a composition for stiffening soft tissue, wherein the composition is smear agent, injection, or microneedles containing riboflavin, and the soft tissue is a soft palate and/or a tongue, which can treat snoring and/or sleep apnea. In addition, the present application also provides microneedles for stiffening soft tissue, comprising a base, a microneedle array disposed on the base, and above 40 μg of riboflavin.

Description

Method and composition for curing soft tissue

The present application relates to the use of riboflavin for soft tissue solidification, in particular for solidifying soft palate and/or tongue soft tissue to treat snoring and/or sleep apnea.

Snoring and obstructive sleep apnea syndrome (OSAS) are directly related to the narrowing or collapse of the upper airway space during sleep. The space behind the tongue and the larynx is narrower when lying down than when standing up due to gravity. In addition, after falling asleep, the tension of the throat muscles and tongue muscles decreases, causing the airway space to collapse and narrower than when awake, which in turn causes breathing problems during sleep. Usually, the soft tissues of the oropharynx (soft palate, spondylosis, tonsils, tongue root) or nasal cavity of patients are also enlarged than those of ordinary people, so it is easier to aggravate the obstruction symptoms.

The goal of treatment for obstructive sleep apnea is to improve the inadequate breathing or pause caused by narrowing or collapse of the upper airway. The use of nasal positive pressure respirator is currently the recommended first-line treatment, but sometimes patients are reluctant to accept and have low compliance. Therefore, surgery provides another treatment option for many patients. Common procedures include laser suspended soft palatoplasty (LAUP), which uses laser to remove the suspensory palate and part of the soft palate, and unsuspensory soft palatopharyngoplasty (UPPP), which removes the tonsils and excessive suspensory palate, and improves the problem of loose oropharyngeal cavity by suturing. In recent years, there have been some surgical methods developed, such as using wireless radio frequency technology (RF) or laser to reduce the soft palate or tongue root, implanting a pillar implant in the soft palate to increase mechanical strength to prevent collapse, and electrocauterizing the soft palate tissue to harden it and prevent tissue collapse.

Rivoflavin can crosslink with collagen in tissues through UVA irradiation, thereby increasing the mechanical strength of the tissues. This mechanism has been widely used to treat a number of corneal diseases, called corneal collagen crosslinking, or CXL for short. It is most effective in treating keratoconus by hardening the cornea and stabilizing the corneal tissue. The treatment process involves scraping off the patient's corneal epidermis, then dripping riboflavin, and then irradiating with ultraviolet light (UVA). There is also a technology that uses microneedles to penetrate corneal tissue to deliver riboflavin to the corneal tissue, such as the content disclosed in US Patent Publication No. US20120238938A1.

Currently available microneedle patches can be divided into four types: solid microneedle, coated microneedle, hollow microneedle, and dissolvable microneedle. Solid microneedles are made of materials such as metal, ceramic, or silicon. They are strong and easy to manufacture, but if they break and remain in the skin, they may have adverse effects and are currently rarely used.

Coating type microneedles can be made of metal or biomedical polymer materials, and the drug is coated on the surface of the microneedle. Although the processing is divided into two steps, it is still a simpler method. However, the total amount of drug coated on the surface of the microneedle is difficult to estimate, and the drug may be scattered at the bottom of the microneedle instead of staying at the tip of the needle, or the drug may form a ring in the microneedle body due to surface tension, so it is more difficult to control the amount of the coating; in use, if the amount of drug entering the body does not need to be too precise (such as some painkillers), it is still an effective way to administer the drug.

Hollow microneedles are similar to current injection syringes, but with micronized needles. Each needle is significantly reduced in size to a few hundred microns long, and stores the drug in a liquid storage tank, which is then injected into the skin under pressure. This type of needle is usually made of metal, glass, or silicon. Although it allows the drug to be injected into the skin in liquid form and has the advantages of a larger amount of drug, it also has problems such as the concern of needle breakage and easy blockage of the needle port.

The most common soluble microneedles are made of medical-grade polymer materials and some low-molecular sugar additives. The effective drug ingredients are contained in the microneedles. After the microneedles pierce the stratum corneum, the polymer microneedles swell or dissolve in the skin, and the drugs are gradually released, which then diffuse into the human blood vessels to achieve the desired effect.

The present application provides a use of riboflavin for preparing a soft tissue solidification composition.

In one embodiment, the soft tissue is the soft palate and/or tongue.

In one embodiment, the soft tissue solidifying composition is used to treat respiratory obstruction during sleep. Preferably, the respiratory obstruction during sleep refers to snoring and/or sleep apnea.

In one embodiment, the composition is a riboflavin-containing ointment, injection or microneedle.

In addition, the present application provides a microneedle for soft tissue solidification, comprising a substrate; a microneedle array located on the substrate; and more than 40 micrograms of riboflavin.

In one embodiment, the microneedles are coated microneedles, hollow microneedles or dissolvable microneedles.

In one embodiment, the microneedles are soluble microneedles, and the microneedle array is formed by a water-soluble polymer and riboflavin. Preferably, the water-soluble polymer is polyvinylpyrrolidone (PVP).

In one embodiment, the microneedle array is a riboflavin/polyvinyl pyrrolidone mixture with a weight ratio of 1:25, the substrate is a polyvinyl alcohol (PVA)/polyvinyl pyrrolidone mixture with a weight ratio of 1:4, and the microneedles contain 60 micrograms of riboflavin phosphate.

In one embodiment, the riboflavin content is 40-200 μg, 40-100 μg, 50-80 μg or 60 μg.

When riboflavin is irradiated and excited by ultraviolet light (UV) with a wavelength of 100nm~400nm or ultraviolet light A (UVA) with a wavelength of 320nm~400nm, riboflavin will generate free radicals that cause the collagen fibers in the tissue to physically cross-link, thereby hardening the gradually thinning and weakened soft tissue. Snoring is caused by excessive relaxation and paralysis of the throat muscles, which blocks the upper airway and causes sleep apnea. Therefore, applying the microneedles of this application to the soft palate or tongue tissue can solidify the soft tissue and eliminate the collapse of the airway during sleep.

The advantages and features of the present invention and the methods for achieving the same will be described in more detail with reference to the exemplary embodiments and drawings so as to be more easily understood. However, the present invention can be implemented in different forms and should not be understood to be limited to the embodiments described herein. On the contrary, for those having ordinary knowledge in the art, the embodiments provided will make the disclosure more thorough and comprehensive and fully convey the scope of the present invention, and the present invention will be defined only by the scope of the attached patent application. As used herein, the term "and/or" includes any and all combinations of one or more of the relevant listed items.

Unless otherwise defined, all terms used herein (including technical and scientific terms) have the same meaning as generally understood by those skilled in the art to which the present invention belongs. It will be further understood that, for example, those terms defined in commonly used dictionaries should be understood to have a meaning consistent with the content of the relevant field, and unless clearly defined herein, will not be understood in an overly idealized or overly formal sense. As recorded in this specification, range values are used as a shorthand representation of each and every value within the range, and any value within the range can be selected as the end value of the range.

The present application provides a use of riboflavin for preparing a soft tissue solidification composition.

In one embodiment, the soft tissue is the soft palate and/or tongue.

In one embodiment, the soft tissue solidifying composition is used to treat respiratory obstruction during sleep. Preferably, the respiratory obstruction during sleep refers to snoring and/or sleep apnea.

In one embodiment, the composition is a riboflavin-containing ointment, injection or microneedle.

In addition, the present application provides a microneedle for soft tissue solidification, comprising a substrate; a microneedle array located on the substrate; and more than 40 micrograms of riboflavin.

In one embodiment, the microneedles are coated microneedles, hollow microneedles or dissolvable microneedles.

In one embodiment, the microneedles are soluble microneedles, and the microneedle array is formed by a water-soluble polymer and riboflavin. Preferably, the water-soluble polymer is polyvinylpyrrolidone (PVP).

In one embodiment, the microneedle array is a riboflavin/polyvinyl pyrrolidone mixture with a weight ratio of 1:25, the substrate is a polyvinyl alcohol (PVA)/polyvinyl pyrrolidone mixture with a weight ratio of 1:4, and the microneedles contain 60 micrograms of riboflavin phosphate.

In one embodiment, the riboflavin content is 40-200 μg, 40-100 μg, 50-80 μg or 60 μg.

The following are several soft tissue solidified microneedle states as examples to illustrate the implementation of this application; those familiar with this art can easily understand the advantages and effects that can be achieved by this creation through the content of this manual, and make various modifications and changes without deviating from the spirit of this creation to implement or apply the content of this creation. For example, Figure 1 discloses the state of the soluble microneedle of this application; Figure 2 discloses the state of the coated microneedle of this application; Figure 3 discloses the hollow microneedle of this application. The following will use the state and preparation method of the soluble microneedle as an example, but it is not limited to it.

The soluble microneedle disclosed in FIG1 is a microneedle array (120) formed by mixing riboflavin (130) in a water-soluble polymer. After the microneedles penetrate into the soft tissue, the microneedle array (120) can be separated from the substrate (110) and remain in the soft tissue to release riboflavin.

The water-soluble polymer may be selected from maltose, sucrose, trehalose, lactose, dextrin, maltodextrin, b-cyclodextrin, 2-hydroxypropyl-b-cyclodextrin, dextran, amylopectin, starch, sodium hyaluronate, poly(methyl vinyl ether-alt-maleic anhydride, PMVE/MA), sodium carboxymethyl cellulose, carboxymethylcellulose (CMC), methylcellulose (MC), hydroxypropylmethylcellulose (HPMC), hydroxypropyl cellulose (HPC), gelatin, polyvinyl alcohol (PVA), polyvinylpyrrolidone (PVP), polyethylene glycol (PEG), polylactic acid (PLA), polyglycolic acid (PGA), polylactic acid-hydroxyacetic acid copolymer (PLGA), chitosan or a combination thereof. In this embodiment, 50% polyvinylpyrrolidone (PVP) is used, but the present invention is not limited thereto.

The size and material of the substrate (110) are not limited and can be adjusted according to actual needs. In this embodiment, 16% polyvinylpyrrolidone (PVP) is mixed with 4% polyvinyl alcohol (PVA), but it is not limited to this.

The preparation method of the soluble microneedles of this application is to first cast the silicone on a commercially available metal male needle mold, place it in a 60 ^o C oven overnight to allow the silicone to crosslink and then demold to obtain a silicone master mold. Next, mix 50% PVP and different concentrations of Riboflavin, cast it on the aforementioned silicone master mold, and place it in a room temperature fume hood for one day. Next, mix 16% PVP and 4% PVA, cast it on the top of the silicone master mold, and place it in a room temperature fume hood for 48 hours. Finally, remove the silicone master mold to obtain a complete soluble microneedle.

Using the above preparation method, soluble microneedles prepared with 0.5%, 1%, 1.5% and 2% Riboflavin contained 15 μg, 30 μg, 45 μg and 60 μg Riboflavin, respectively. The microneedles containing different amounts of Riboflavin were applied to the soft palate tissue of pigs, and the application area was irradiated with UVA 375nm for 15 minutes. Tensile modulus test was then performed. The results are shown in Figure 4.

As can be seen from Figure 4, in the groups using 2% and 1.5% Riboflavin, the mechanical properties after application to the pig soft palate tissue were better, indicating that the microneedles containing 45 micrograms and 60 micrograms of Riboflavin were better in solidifying the soft palate tissue, and the standard error of the group using 2% Riboflavin was smaller than that of the group using 1.5% Riboflavin.

In addition, this study compared the effects of different Riboflavin delivery methods on the curing of soft palate tissue. At the same Riboflavin dose (60 micrograms), soft palate tissue was treated by application, injection, and microneedle. In the application group, the Riboflavin solution was applied to the soft palate tissue of the pig, and after 30 minutes, the application site was irradiated with UVA 375nm for 15 minutes; in the injection group, the Riboflavin solution was injected into multiple sites of the soft palate tissue of the pig, and the application site was irradiated with UVA 375nm for 15 minutes; in the microneedle group, the operation method was the same as above. The soft palate tissue treated by the three methods was also tested for tensile modulus, and the results are shown in Figure 5.

As can be seen from Figure 5, the soft palate tissues treated by the three methods are comprehensively compared. Whether it is the soft palate tissue treated by applying, injection, or microneedle, the results of the tensile modulus test are better than those of the control group. Among them, the mechanical properties of the soft palate tissue treated by microneedle are the most prominent. Therefore, this embodiment proves that the three application methods of applying, injection, and microneedle can solidify the soft palate tissue, and the method of delivering Riboflavin by microneedle is the most efficient method.

In addition, the soft palate tissues treated in the three ways were also subjected to frequency sweep tests. The results are shown in Figures 6 and 7.

As can be seen from Figure 6, the storage modulus of the soft tissue after microneedle treatment is smaller than that of other groups. This is because its mechanical properties are improved, which reduces the number of vibrations with frequency. As can be seen from Figure 7, the tan δ of the soft tissue after microneedle treatment is the largest, and its tissue damping is greater, so the number of vibrations decreases, which can alleviate snoring.

The soft tissue solidifying microneedles of the present application can be placed at the front end of a long strip-shaped device and injected into the patient's soft palate by pressing.

100: Soluble microneedles 110: Base 120: Microneedle array 130: Riboflavin 200: Coated microneedles 210: Base 220: Microneedle array 230: Riboflavin 300: Hollow microneedles 310: Base 320: Microneedle array 330: Riboflavin

FIG1 is a schematic diagram of the soluble microneedle of the present application.

FIG2 is a schematic diagram of the coated microneedle of the present application.

FIG3 is a schematic diagram of the hollow microneedle in this application.

Figure 4 shows the tensile modulus test results of microneedles prepared with different riboflavin concentrations and applied to soft palate tissue.

Figure 5 shows the results of tensile modulus testing of soft palate tissue treated in different ways.

Figure 6 shows the results of the frequency sweep test of soft palate tissue treated in different ways.

Figure 7 shows the results of the frequency sweep test of soft palate tissue treated in different ways.

100: Soluble microneedles

110: Base

120: Microneedle array

130:Riboflavin

Claims (5)

A use of riboflavin for preparing a soft tissue solidification composition, wherein the soft tissue is a soft palate and/or a tongue, wherein the soft palate and/or the tongue is irradiated with ultraviolet light A (UVA) after applying a composition of 40-200 micrograms of riboflavin at least once. For the purpose of claim 1, it is used to treat respiratory obstruction, snoring and/or sleep apnea during sleep. For use as claimed in claim 1, wherein the composition is a riboflavin-containing ointment, injection or microneedle. A microneedle for soft tissue solidification, comprising a substrate; a microneedle array located on the substrate; and 40-200 micrograms of riboflavin; wherein the microneedle is a soluble microneedle; wherein the microneedle array is a riboflavin/polyvinyl pyrrolidone mixture with a weight ratio of 1:25, and/or the substrate is a polyvinyl alcohol (PVA)/polyvinyl pyrrolidone mixture with a weight ratio of 1:4. The microneedle of claim 4, wherein the microneedle contains 60 micrograms of riboflavin phosphate.