Combined osmotic hydrogel cervical dilator and preparation method thereof

Abstract

A cervical dilator comprises a stem comprising a partially or completely dehydrated hydrogel comprising a water-insoluble synthetic hydrophilic polymer capable of radial expansion due to absorption of water from bodily fluids. The cervical dilator softens and matures cervical tissue and dilates the cervical canal through a combination of radial hydrogel stem expansion and osmotic absorption of water from the tissue. The osmotic absorption is caused by at least one osmotically active compound, such as a water-soluble salt, polyelectrolyte, or mixtures thereof, dispersed within the hydrogel. The cervical dilator may also include a non-toxic plasticizer for the hydrogel, such as water.

Description

[0001] CROSS-REFERENCE TO RELATED APPLICATIONS

[0002] This application claims priority to U.S. Provisional Patent Application No. 62 / 404,997, filed on October 6, 2016. The disclosure of which is incorporated herein by reference. Technical Field

[0003] The present invention relates to a cervical dilator, and a method for preparing a cervical dilator. Background Art

[0004] Tissue expansion is used in various surgical procedures. Tissue expansion can be temporary or permanent. A well-known example of temporary expansion is the expansion of the cervical canal in gynecology. It is achieved naturally during childbirth, but it can also be achieved artificially in various ways, such as by administering prostaglandins (see MJ Keirse, Prostaglandins in preinduction cervical ripening. Meta-analysis of worldwide clinical experience, The Journal of reproductive medicine (1993) 38: 89-100). Using a mechanical dilator, the cervical canal can also be temporarily expanded in response to short-term radial stress. Mechanical dilators are typically a collection of plastic or metal rods of various designs (e.g., Hegar dilators, Hank dilators), whose diameters gradually increase and are forced to enter the cervical canal in sequence. Newer mechanical dilators are described in, for example, U.S. Patent 7,105,007 (named Cervical medical device, system and method). The mechanical pressure generated by these devices partially and reversibly dehydrates the tissue, thereby becoming softer and more deformable. However, the maximum rate of partial dehydration produced by mechanical pressure is controlled by the water permeability of the cell wall, and it takes some time for water to be expelled from the tissue. Therefore, mechanical expanders force the tissue to expand faster than the dehydration rate allows, which can lead to cell membrane rupture and subsequent tissue damage, or even scarring.

[0005] Therefore, various designs of inflatable dilation catheters have been developed (see, for example, U.S. Patent Publication No. US2004 / 0116955 and U.S. Patent No. 4,664,114) to allow safer, slower, and more controlled cervical dilation. However, the dilation rate is still not easy to control, and thus the safety limit of the rate of fluid drainage from the tissue can be easily exceeded.

[0006] An alternative to mechanical dehydration of cervical tissue is osmotic dehydration, which exploits the expulsion of water from the tissue in response to local osmotic imbalances. Osmotic dilators are used that dehydrate cervical tissue using magnesium sulfate salts dispersed in the pores of a synthetic sponge carrier (see U.S. Patent 4,467,806). This tissue softening and dilation is reversible with minimal changes in hormone levels or permanent changes in cervical tissue. These devices operate on a purely osmotic principle because the hydrogel sponge used as a salt carrier is inherently soft and cannot exert any significant mechanical pressure on the tissue.

[0007] More effective are osmotic hydrogel cervical dilators, which combine local osmotic tissue dehydration with mechanical dilation due to device expansion. This approach employs the insertion of a dehydrated hydrogel (or "xerogel") stem into the cervical canal. The xerogel is hypertonic relative to the contacting tissue and therefore draws water from the tissue. As osmotic pressure increases in the tissue and decreases in the hydrogel stem, the osmotic gradient gradually decreases until equilibrium is reached. As the xerogel hydrates into a hydrogel, the volume of the stem expands. This expansion creates controlled mechanical pressure on the cervical tissue, aiding in its dehydration. Furthermore, this expansion helps maintain close contact between the tissue and the device required for osmotic transport of water. Thus, the hydrogel cervical dilator combines the modalities of a mechanical dilator and an osmotic dilator for optimal results.

[0008] Hydrogels have been used for tissue dilation for some time. For a "natural" means of cervical dilation, the dried stems of seaweed (Laminaria japonica, "LJ") have been used for cervical dilation for centuries (see, e.g., U.S. Pat. No. 4,624,258, and MH Goldrath, Vaginal removal of the pedunculated submucous myoma: the use of laminaria, Obstetrics and gynecology (1987) 70:670-2). The stems of LJ contain a natural polysaccharide hydrogel that enables the dried stem to swell upon rehydration, resulting in osmotic transport of water and mechanical expansion upon hydration with water in body fluids. However, dilators from LJ have various disadvantages: hydration is relatively slow and rather irregular, the morphology and geometry of the dried stem are rather irregular, the osmotic pressure is relatively low, mechanical dilation against the pressure of stiff cervical tissue (e.g., internal os) may be limited, the mechanical strength in the maximally hydrated state may be too low to prevent disintegration, the sterilization of the product may be uncertain, and there are no design features or properties to prevent multiple use to reduce the risk of infection.

[0009] These shortcomings have led to the search for improved synthetic hydrogel expanders. For example, A. Michaels proposed a composite hydrogel expander in U.S. Patent No. 4,237,893, while V. Stoy et al. used synthetic acrylic hydrogel to anisotropically swell synthetic hydrogel expanders in U.S. Patent No. 4,480,642. Thus, for example, DILAPAN Products such as cervical dilators are now available as alternatives to dry LJ stems and penetrative dilators (see, e.g., DA Grimes et al., Lamicel versus laminaria for cervical dilation before early second-trimesterabortion: a randomized clinical trial, Obstetrics and gynecology (1987) 69:887-90; and EC Wells et al., Cervical dilation: A comparison of Lamicel and Dilapan, American journal of obstetrics and gynecology(1989)161:1124-6). Summary of the Invention

[0010] The present invention relates to a cervical dilator comprising a stem comprising a partially or completely dehydrated hydrogel comprising a water-insoluble synthetic hydrophilic polymer capable of radial expansion due to absorption of water from body fluids. The cervical dilator further comprises at least one osmotically active compound dispersed within the hydrogel.

[0011] Additionally, the present invention describes a method for making the cervical dilator. The method comprises providing a hydrogel in a partially or completely dehydrated state, and axially stretching the hydrogel at a temperature above the glass transition temperature of a water-insoluble synthetic hydrophilic polymer, thereby producing a stem comprising the partially or completely dehydrated hydrogel and achieving radial expansion. The stem comprising the partially or completely dehydrated hydrogel is then cooled to ambient temperature under axial stress.

[0012] In addition, the present invention describes another method for making the cervical dilator, which includes providing a hydrogel in a hydrated state, and axially stretching the hydrogel and maintaining the hydrogel at a predetermined length while drying the hydrogel, thereby producing a stem comprising a partially or completely dehydrated hydrogel and achieving radial expansion capability. BRIEF DESCRIPTION OF THE DRAWINGS

[0014] Figure 1Graph showing the NaCl concentration in the hydrogel in equilibrium with NaCl solution and in the final xerogel stem according to Example 1.

[0015] Figure 2 Perspective views of a cervical dilator are shown in a dehydrated state (in the top figure) and in a hydrated state (in the bottom figure). Detailed Description of the Invention

[0017] The present invention combines more than one means of osmotic dehydration of cervical tissue into a single device by dispersing at least one osmotically active compound within a partially or completely dehydrated synthetic hydrogel stem, thereby resulting in a more effective hydrogel cervical dilator. The osmotically active compound is an ionic, water-soluble substance capable of absorbing water and, if not embedded in a hydrogel, forming an aqueous solution. The osmotically active compound is dispersed within the hydrogel material (i.e., the hydrogel matrix) of the stem.

[0018] In one embodiment of the cervical dilator, a low molecular weight or polymeric salt is dispersed in an anisotropically swellable dehydrated hydrogel. Although both salts and dehydrated hydrogels can be used to generate an osmotic gradient to draw some water from surrounding tissue, there are some differences between the two. Specifically, for salts, the osmotic pressure and the volume of water drawn from the tissue will be higher than for a corresponding partially dehydrated hydrogel (xerogel). As used herein, the term "xerogel" refers to a hydrogel that has been dehydrated to its hard state, i.e., a state having a residual water concentration at which the glass transition temperature (T g ) is above ambient temperature or body temperature (whichever is higher). As used herein, the term "partially dehydrated hydrogel" refers to a hydrogel in its plasticized (i.e., reversibly deformable) or rubbery (i.e., elastic) state, wherein the water content is sufficient to g The temperature of the hydrogel is lowered to below ambient temperature, but the water content is lower than the liquid content in equilibrium with an isotonic aqueous solution. Since these terms refer to hydrogel components with different levels of dehydration, unless there is a specific reason to distinguish between "xerogel" and "partially dehydrated hydrogel", the two terms are used interchangeably in the present invention. In addition, although salts can migrate away from the dilation site by diffusion or by flowing away when dissolved, salts, on the other hand, remain in place until removed. Moreover, salts cannot generate mechanical pressure on cervical tissue like hydrogels. Finally, some multivalent ions from salts (e.g., Ca 2+ , Al 3+ , Zn 2+ or Mg 2+ ) can generate high osmotic pressure, but can also interact with tissue components (such as proteins) and cause adverse reactions. In contrast, hydrogels are generally inert with respect to tissue components and are highly biocompatible.

[0019] In another embodiment of the cervical dilator, the at least one osmotically active compound is a polyelectrolyte, preferably a polyelectrolyte salt having a fixed negative charge, which contains negatively charged side chain units, such as carboxylate units, sulfate units, sulfonic acid units or phosphate units. Examples of such polyelectrolytes are polymers and copolymers of acrylic acid and methacrylic acid; poly(ethylene sulfonic acid); poly(phosphoric acid); poly(styrene sulfonic acid); poly(vinyl sulfuric acid); poly(vinyl phosphonic acid); poly(maleic acid); poly(2-methacryloyloxyethane-1-sulfonic acid); poly(3-methacryloyloxypropane-1-sulfonic acid); poly(3-(vinyloxy)propane-1-sulfonic acid); poly(4-vinylphenyl sulfate); and their respective salts, in particular salts with monovalent countercations such as sodium, potassium, lithium, ammonium or organic bases such as NR4 + or NR3H + (wherein R represents an alkyl or hydroxyalkyl substituent having 1 to 4 carbon atoms), pyridine, etc. We note that many organic bases have biological activity and can also be used to inhibit pain, infection, etc. In addition, the water-soluble polyelectrolyte used as an osmotic active compound can also be formed from other water-soluble ionic polymers and copolymers known to those skilled in the art.

[0020] Advantageously, the polyelectrolyte is entrapped within the hydrogel network. Preferably, at least 50% by weight, more preferably at least 90% by weight of the entrapped polyelectrolyte remains entrapped within the hydrogel during cervical dilation. The polyelectrolyte can be formed within the hydrogel network, for example, by polymerizing water-soluble monomers that form the polyelectrolyte within the hydrogel network. This approach results in one type of interpenetrating network. Conversely, the hydrogel network can be formed around polyelectrolyte chains or particles by polymerization of monomer molecules, or by coagulation of chains that form a hydrogel in the presence of a polyelectrolyte, or by other polymer formation techniques known to those skilled in the art. This results in different types of interpenetrating networks, or in structures with discrete permeable compartments dispersed within a continuous hydrogel material.

[0021] Preferably, the polyelectrolyte is present in the cervical dilator at a concentration of about 1 wt % to about 60 wt %, more preferably about 1 wt % to about 50 wt %, still more preferably about 5 wt % to about 40 wt %, and still more preferably about 5 wt % to about 20 wt %, based on the weight of the dehydrated hydrogel stem.

[0022] Polyelectrolytes can be advantageously combined with positively charged monovalent countercations, such as Na + , K + , Li + , NH4 + , NR4 + or NR3H +(wherein R represents an alkyl or hydroxyalkyl substituent having 1 to 4 carbon atoms) or mixtures thereof to form another embodiment of the osmotically active compound.

[0023] In another embodiment of the cervical dilator, the at least one osmotically active compound is a low molecular weight, non-toxic, water-soluble salt that is capable of diffusing out of the hydrogel at least in its fully hydrated state and is formed by combining a monovalent cation and a monovalent, divalent, trivalent or even multivalent anion. Preferably, the monovalent cation is Na + , K + , Li + , NH4 + , NR4 + or NR3H + (wherein R represents an alkyl or hydroxyalkyl substituent having 1 to 4 carbon atoms), or any mixture thereof.

[0024] In another embodiment, these monovalent cations are combined with water-soluble negatively charged counterions, such as Cl - 、F - Br - 、SO4 2- 、CNS - PO3 3- PO3H 2- PO3H2 - 、CO2 2- 、CO2H - HCOO - 、CH3COO - 、HO(CH2) n COO - (wherein n is an integer from 1 to 6), or in combination with an anion derived from an organic hydroxy acid or amino acid, or a combination thereof. One of the preferred salts is sodium chloride because it occurs naturally in body fluids and its solubility is relatively independent of temperature.

[0025] The cation-anion combination can be dispersed within the hydrogel as a solid salt, as a highly concentrated saline solution, or in a combination thereof. For example, the salts can be uniformly dispersed within a continuous hydrogel matrix, or they can form a concentration gradient where more salt is located on the surface of the hydrogel than within its bulk. In one embodiment, the salts can form crystals that are fully or partially embedded within the dehydrated hydrogel matrix. Preferably, the hydrogel forms a continuous polymer matrix rather than a sponge that is unable to generate significant external pressure through its expansion.

[0026] Preferably, salt is incorporated into the hydrogel in two basic steps. First, the hydrogel is contacted with an excess of an aqueous solution of the selected salt, and the salt ions (cations and anions) are allowed to diffuse into the hydrogel. When the ratio of the concentration inside and outside the hydrogel corresponds to the corresponding partition coefficient, the salt concentration inside the hydrogel gradually approaches the equilibrium value. Diffusion of ions into the hydrogel can be accelerated by increasing the temperature.

[0027] Next, after a predetermined amount of time or when the ion concentration reaches a predetermined value based on the desired final salt concentration, the hydrogel is removed from the aqueous solution and placed on a suitable drying rack. The hydrogel is stretched to a predetermined ratio, which is calculated to achieve the desired axial and radial changes in size between the dehydrated and hydrated states of the hydrogel. It has been determined that the change in length of a dehydrated hydrogel stem in either direction through maximum swelling under physiological conditions is preferably no more than about one-quarter (+ or - 25%). Even more preferably, the axial change in stem length through hydration should be -20% to +10%. The axial length change can be controlled by hydration and the degree of stretching at the beginning of this drying step. If the hydrogel is stretched more before drying, it will expand less, or even shrink due to hydration.

[0028] For example, the stretch ratio can be determined as follows. First, the volume expansion coefficient or VEXF can be calculated. VEXF is the ratio of the volume of the final hydrogel state 1 to the volume of the initial xerogel state 0. It should be understood that states 1 and 0 can be in vivo or in vitro, and the required parameters are determined under simulated experimental conditions.

[0029] In state 0, from g 10 grams of solvent, water-soluble salt or plasticizer (including residual water) and g 20 Starting with a xerogel of mass G0 consisting of grams of polymer, the weight fraction of solvent will be w 10 =g 10 / G0, the weight fraction of the polymer is w 20 =g 20 / G0, and w 10 +w 20 = 1. The density of the polymer is d p , the density of the solvent is d s , and assuming that the fractional volumes of polymer and solvent are additive (i.e., approximating the mixing as an “ideal solution”), the density of the expander in its initial state will be d e0 =d 10 *(1-w 20 )+d 20 *w 20 , and its volume will be V0=G0 / d e0 .

[0030] In state 1, the hydrogel weight reaches G1 as the solvent is exchanged with the external isotonic medium which swells the polymer. The expander is now composed of the same amount of polymer g 20 (the natural assumption is that the polymer is insoluble in the isotonic medium), but composed of different amounts of isotonic medium g m1 Therefore, G1=g 20 +g m1 , the weight fractions of the isotonic medium and polymer are w m1 =g m1 / G1 and w 21 =g 20 / G1, and w m1 +w 21 = 1. The density of the expander in state 1 is d e1 =d m1 *(1-w 21 )+d 20 *w 21 , this is under the same assumption as used in the initial state, namely that the fractional volumes will be additive. The volume of the expander is now V1 = G1 / d e1 , and VEXF=V1 / V0.

[0031] It can also be observed that the volume fraction of the polymer v 20 =(g 20 *d 20 ) / (G0*d e0 ) and v 21 =(g 20 *d 20 ) / (G1*d e1 ), so that

[0032] v 20 *G0*d e0 =v 21 *G1*d e1 And therefore v 20 *V0=v 21 *V1, so that VEXF = v 20 / v 21 .

[0033] In other words, the volume expansion coefficient (VEXF) of a hydrogel between two different states with two different liquid contents is equal to the inverse ratio of the volume fraction of the polymer in the two states. Alternatively, VEXF can be calculated from the relative weight change as VEXF = (G1 / G0)*(d e1 / d e0 ).

[0034] Once the VEXF value of a given xerogel-hydrogel system is known, the linear expansion coefficient or LINEXF can be calculated in three different directions. In the case of isotropic expansion, LINEXF = VEXF^ (1 / 3) For anisotropic expansion, the linear expansion coefficients must be defined in three independent dimensions, e.g. LINEXF x LINEXF y and LINEXF z , then it maintains VEXF = LINEXF x *LINEXF y *LINEXF z .

[0035] For example, let us consider a cylindrical xerogel stem from a multi-block acrylic copolymer that reaches a final VEXF = 8 and where the diameter needs to be tripled (e.g., from about 4 mm + / - 0.2 mm in the xerogel state to about 12 mm in the fully hydrated state). If the xerogel expands isotropically, then LINEXF = VEXF^ in each direction. (1 / 3) = 2, resulting in a final diameter of only 8 mm. Simultaneously, the stem length would have to double, for example, from 65 mm to 130 mm. To achieve the desired 12 mm diameter through isotropic expansion, the length would have to increase to 195 mm—too long given the anatomy of the cervix. Furthermore, VEXF would have to have a value of 27, a 27-fold increase in volume, so that the final hydrogel would contain a very low concentration of polymer. This would result in very low mechanical strength and very low expansion pressure on cervical tissue.

[0036] Now, if we start with a hydrogel rod in its final hydrated state and with the final desired dimensions (e.g., 12 mm hydrated diameter and 55 mm hydrated length), and take into account the length in the Z-axis, then LINEXF z x=55 / 65=0.85. If the hydrogel is stretched (LINEXF z )^ (-1) = 1.18 times the length and fixed at this length until it dries to the xerogel state. The diameter reduction from the hydrogel to the xerogel state will be 1 / LINEXF d =1 / ((VEXF / LINEXF z )^ (1 / 2) ) = 1 / (8*1.18)^2 = a factor of 0.325. Therefore, the xerogel stem will be 3.9 mm in diameter and 65 mm in length, which in the fully hydrated state will change to the desired dimensions of 12 mm in diameter and 55 mm in length.

[0037] The stretched hydrogel rod can be dried to a predetermined water content. A predetermined amount of water is removed by evaporation while subjecting the hydrogel to axial tension. Drying to a fixed length creates stress that orients the polymer chains in a preferred axial direction. When the hydrogel is rehydrated with water from body fluids, the randomization of the oriented chains reduces axial expansion and increases radial expansion, which facilitates cervical dilation.

[0038] Air drying under axial stress can be carried out under various conditions (temperature, air flow, air humidity, etc.) to produce a smooth surface and uniform xerogel rod diameter. The optimal drying conditions are related to the required drying time, the required xerogel surface quality and the acceptable variability of the xerogel stem diameter. In one embodiment, the preferred drying process is first carried out at ambient temperature in air with a relative humidity of less than 50% until more than 50% by weight of the water is removed, and then the drying is completed at an elevated temperature of more than 70°C. The stems are still fixed on the drying rack. Another drying method uses a high drying temperature of more than about 105°C, at which temperature even completely dehydrated polymers are in their rubbery state.

[0039] Generally speaking, drying conditions are selected so that water evaporating from the surface can be replaced by diffusion from the interior to an extent sufficient to keep the outer skin partially hydrated and deformable. If evaporation is too rapid and / or the temperature is too low, a deformed "skin" may form on the outer surface.

[0040] The resulting xerogel rod contains a predetermined concentration of salt, which depends on parameters such as diffusion time, diffusion rate, partition coefficient, hydration of the polymer at a given salt concentration, as is well known to those skilled in the art. For example, the xerogel may contain from about 3% to 50% by weight of a salt or a mixture of different salts. Higher salt concentrations provide higher osmotic dehydration, but this is generally more difficult to achieve due to the limited solubility of certain salts and due to the osmotic dehydration of the hydrogel. Therefore, a preferred salt concentration range is from 7% to 25% by weight, and a more preferred salt concentration range is from 9% to 19% by weight, based on the mass of the xerogel.

[0041] By varying the salt concentration and drying conditions, various distributions of salt concentration within the xerogel can be achieved. For example, one embodiment includes conditions that result in increasing salt concentration from the center of the xerogel toward the periphery, wherein the salt is present on the xerogel surface in the form of fine crystals embedded in the surface layer of the xerogel. This salt distribution can lead to faster tissue dehydration and improved cervical ripening and dilation. The salt distribution is controlled by its concentration and the drying process conditions. Higher salt concentrations (e.g., typically above 10% to 15% by weight, depending on the salt type and hydrogel composition) produce steeper concentration gradients, or even a "skin" of fine salt crystals embedded in the xerogel. Slower drying regimes (lower drying temperatures, higher relative humidity of the drying air) tend to further favor this salt separation and the formation of larger salt crystals. Preferably, the salt concentration in the xerogel is 5-15% by weight, but salt concentrations up to 50% by weight can be achieved and used.

[0042] In another embodiment of the cervical dilator, the hydrogel in the dilator is plasticized with a suitable non-toxic polar liquid that is capable of lowering the glass transition temperature of the water-insoluble synthetic hydrophilic polymer that forms the hydrogel. This plasticizer will make the xerogel less brittle and less prone to breaking, especially at lower temperatures. In addition, it will accelerate the diffusion of water into the hydrogel, thereby increasing the swelling of the amorphous phase in the hydrogel. The plasticized xerogel will be more deformable, making it easier to bend or form a specific geometry that fits the cervical canal. Finally, it can make the xerogel stem more flexible, which will reduce the risk of tissue damage during insertion. The most preferred plasticizers are glycerol, glycerol monoacetate, glycerol diacetate, glycerol formate, glycolic acid, 1,2-propylene glycol, dimethyl sulfoxide (DMSO), water, or any mixture thereof.

[0043] Preferably, the plasticizer is present in a concentration of about 3% to 25% by weight, based on the weight of the xerogel. More preferably, the plasticizer is water, present in a concentration range of about 5% to 22% by weight, based on the weight of the xerogel. A particularly preferred plasticizer is water, which can be absorbed into the sterile xerogel through a semipermeable membrane, such as a permeable sterilization bag designed for autoclaving or gas sterilization. Once the desired water concentration in the xerogel is achieved, the device can be sealed in a secondary bag that is impermeable to water or water vapor.

[0044] Another advantage of water as a plasticizer is that it facilitates sterilization of xerogels by ionizing radiation (e.g., gamma or beta radiation). In particular, sterilization in the presence of an aqueous plasticizer reduces discoloration of the xerogel and improves the mechanical properties of the hydrogel after complete hydration. The recommended radiation dose for sterilization by gamma or beta radiation is 20 kGy to 50 kGy, preferably 25 kGy to 45 kGy.

[0045] One aspect of the disclosed cervical dilator is the anisotropic swelling of a partially to completely dehydrated xerogel into a hydrogel that hydrates by absorbing water from tissue and body fluids. For example, a xerogel stem can expand radially to at least two times, or even at least three times, its original diameter, while its axial expansion is much smaller and can even be negative (i.e., the stem shrinks in length). In practice, the axial change should be less than one-quarter (i.e., + or - 25%) of the xerogel stem's original length. The anisotropy of stem expansion is important for cervical dilation. For example, if radial expansion from a 4 mm diameter to a 12 mm diameter is desired, isotropic expansion would increase the stem length from an original, say, 65 mm, to an excessively long 195 mm. More importantly, a threefold expansion, equal in all directions, would translate into a 27-fold increase in stem volume. This would require a hydrogel with a very low volume fraction of the polymer component (approximately 3.7% by volume if the original xerogel contained only polymer). Such a low concentration of polymer network would be unlikely to provide sufficient mechanical strength or sufficient expansion pressure.

[0046] The cervical dilator disclosed in the present invention also includes a stem comprising a partially or completely dehydrated hydrogel. The mechanical and physicochemical properties of the hydrogel are important for the function of the cervical dilator. For example, the physico-chemical properties include the maximum hydration rate (expressed as, for example, equilibrium liquid content) and the expansion pressure generated at a specific hydration rate, while the mechanical properties in the fully hydrated state include tensile strength, relative extension at break, and resistance to crack propagation. Preferably, the hydration rate of the hydrogel corresponds to a liquid content of 75% to 95% by weight in equilibrium (relative to an isotonic solution with a pH of 7-7.5 at 35°C), more preferably 85% to 93% by weight. In addition, the hydrogel should not contain any toxic or irritating extractables, be sufficiently stable and sterilizable.

[0047] Suitable hydrogels for use in cervical dilators include hydrogels having a network based at least in part on physical interactions rather than covalent bonding. Examples of such hydrogels are polyvinyl alcohol (PVA)-based hydrogels, as described, for example, in the following U.S. Patents: U.S. Patent 4,734,097, U.S. Patent 4,663,358, U.S. Patent 5,981,826, U.S. Patent 6,231,605, and U.S. Patent 7,332,117, each of which is incorporated herein by reference in its entirety.

[0048] Another class of suitable hydrogels for use in cervical dilators is hydrophilic polyurethanes and polyureas (HPU). Examples of such hydrophilic polyurethanes and polyureas can be found in US Pat. No. 5,688,855, which is incorporated herein by reference in its entirety.

[0049] Although both PVA and HPU hydrogels have good mechanical properties in the hydrated state, they may lack ionic groups, such as sulfonyl, sulfate, or carboxyl groups, which provide the hydrogel with a fixed negative charge density (FNCD), which improves the swelling pressure.

[0050] Thus, the most preferred polymers for the hydrogels of cervical dilators are physically cross-linked acrylic hydrogels based on multi-block copolymers (MBCs). For example, these "thermoplastic" hydrogels are based on hydrolyzed or aminolyzed polyacrylonitrile (PAN) and are described in several U.S. patents, such as U.S. Patent 4,943,618, U.S. Patent 5,252,692, U.S. Patent 6,593,451, U.S. Patent 6,451,922, U.S. Patent 6,232,406, U.S. Patent 5,252,692, U.S. Patent 4,420,589, U.S. Patent 4,379,874, U.S. Patent 4,369,294, U.S. Patent 4,370,451, U.S. Patent 4,337,327, U.S. Patent 4,331,783, U.S. Patent 4,107,121, and U.S. Patent 3,948,870, each of which is incorporated herein by reference in its entirety.

[0051] These hydrogels based on hydrolyzed or amino-decomposed PAN are known for their high mechanical strength (and their high resistance to fracture propagation and fatigue) even at high water contents. Their side chain nitrile groups are organized into sequences (or "blocks") alternating with sequences of hydrophilic acrylic acid groups selected from acrylamide, N-substituted acrylamides, acrylamidine, N-substituted acrylamidine, and acrylic acid and its salts. The sequences of monomer units with side chain nitrile groups separate themselves from the rest of the polymer structure into crystalline domains with a typical crystallinity of PAN, which can be detected, for example, by X-ray diffraction or by solid-state NMR. The crystalline domains form a 3D network that provides high mechanical strength to the hydrogel even at high water contents. The hydrophilic acrylate monomer units form a hydrophilic amorphous phase that absorbs aqueous liquids and swells due to hydration. Particularly preferred are hydrogels with a high content of negatively charged side groups in the amorphous domains, such as sulfonic or carboxylate groups in N-substituted amides and amidines, or carboxyl groups in acrylic acid units. The concentration of negatively charged side groups in a polymer is often expressed as fixed charge density (FCD), expressed as the number of moles of charged groups per mole of monomeric unit. A high FCD facilitates the generation of osmotic and swelling pressures, particularly at high water contents. The FCD in the MBC chains can be supplemented by the charge of polyelectrolytes incorporated into the hydrogel structure in the form of polymer blends or interpenetrating networks (IPNs). For example, a blend can be prepared by forming a dispersion of a polyelectrolyte in an MBC solution or its melt prior to hydrogel formation. This polyelectrolyte can be incorporated in its dry powder form. Examples of suitable polyelectrolytes are polymers and copolymers of acrylic acid and methacrylic acid; poly(ethylene sulfonic acid); poly(phosphoric acid); poly(styrene sulfonic acid); poly(vinyl sulfuric acid); poly(vinyl phosphonic acid); poly(maleic acid); poly(2-methacryloyloxyethane-1-sulfonic acid); poly(3-methacryloyloxypropane-1-sulfonic acid); poly(3-(vinyloxy)propane-1-sulfonic acid); poly(4-vinylphenyl sulfate); and their respective salts, which can be formed by their neutralization before or after blending. Preferred salts are those with monovalent countercations, such as sodium, potassium, lithium, ammonium or organic bases such as NR4 + or NR3H + (wherein R represents an alkyl or hydroxyalkyl substituent having 1 to 4 carbon atoms), pyridine, and the like.

[0052] The xerogel stem in the form of a rod containing the osmotically active compound and, optionally, a plasticizer, is then cut to the appropriate size, trimmed, and fitted with a suitable handle and guide wire, as understood in the art. Preferably, the final cervical dilator product is then sealed in a sterilization container and sterilized. Sterilization can be performed, for example, by a gas such as ethylene oxide, by ozone, by vapors of peracetic acid, or by other means known to those of ordinary skill in the art. A preferred sterilization method is by ionizing radiation, such as gamma radiation, beta radiation, or an accelerated electron beam. Irradiation is preferably performed on a partially dehydrated xerogel containing water in a concentration ranging from 3% to 25% by weight, more preferably from 5% to 19% by weight. Example

[0053] Example 1 :

[0054] A hydrogel for a cervical dilator was prepared according to U.S. Patent 6,232,406, which is incorporated herein by reference in its entirety. PAN having a weight-average molecular weight of 200,000 g / mol was dissolved in a 55% by weight aqueous solution of NaSCN to form a 10% by weight polymer solution. NaOH dissolved in a 55% by weight aqueous solution of NaSCN was added at ambient temperature in an amount such that the PAN / NaOH mass ratio was 1:10. The solution was then transferred to a jacketed tubular reactor, where it was heated to 70°C for 60 hours. The resulting multi-block acrylic copolymer solution was cooled to 40°C and transferred to a pressure vessel, which was then fed to a metering pump with a progressing cavity rotor by pressurized gas. The solution was extruded through a cooling nozzle into a coagulation bath filled with an aqueous solution of NaSCN having a NaSCN concentration of 1 to 5% by weight. The condensed hydrogel rods were washed until substantially all of the NaSCN was removed. The hydrogels were then immersed in excess aqueous solutions containing different concentrations of NaCl (approximately 1%, 7.5%, 10%, 12.5%, and 20% by weight) for a total of 48 h, wherein the solution was replaced twice with fresh saline solution after 24 h intervals to obtain a balanced NaCl distribution between the hydrogel and the liquid phase.

[0055] Sections of hydrogel rods with varying NaCl concentrations were stretched into a drying rack with a relative length extension of 25% and secured with clips. The rack was placed in a drying oven with airflow and dried at 125°C for 24 hours. The xerogel rods were then cut into approximately 75 mm long sections, each fitted with a glued plastic handle on one side and ground into a rounded shape on the other. The xerogels were then stored in humid air to absorb approximately 15% by weight of moisture.

[0056] The NaCl concentration in the hydrogel in equilibrium with the NaCl solution and in the final xerogel was determined by extracting NaCl into distilled water and titrating the chloride ions with argyrometry. The NaCl concentration in the hydrogel and the final xerogel stem was as follows: Figure 1 shown.

[0057] Cervical dilators with water-plasticized and NaCl-loaded compartments are sealed in sterilization bags and sterilized by gamma irradiation at a dose of 25 to 50 kGy. Compared to completely dry cervical dilators sterilized under the same conditions, products sterilized in the water-plasticized state exhibit significantly less discoloration and improved mechanical strength after swelling in a buffered isotonic solution. Water-plasticized xerogels also exhibit faster initial swelling and are resistant to fracture. The recommended water content of the cervical dilator is 4 to 20% by weight, preferably 8 to 15% by weight, based on the weight of the stem.

[0058] The sterilized product combining the xerogel and salt of Example 1 provides accelerated cervical tissue ripening and dilation compared to a similar hydrogel dilator without the water-soluble salt.

[0059] Example 2 :

[0060] The hydrogel prepared according to Example 1 was soaked with 10 wt % aqueous solution of the following monomers:

[0061] 1. Sodium acrylate

[0062] 2. Methacryloyloxypropane-1-sulfonic acid

[0063] 3.4-Vinylphenyl sulfate

[0064] 4. Vinylphosphonic acid.

[0065] After each solution reached equilibrium, the monomer-soaked hydrogel rods were stretched on a drying rack similar to Example 1 and dried at 80°C for 18 hours. Although no initiator was used and drying was performed in the presence of air, all monomers polymerized and formed an interpenetrating network of polyelectrolytes within the multi-block copolymer hydrogel. When swollen in an isotonic solution, no elution of the polyelectrolyte was observed, as it was clearly firmly anchored within the hydrogel structure.

[0066] The xerogel stems can then be fitted with glued plastic handles and sterilized by radiation or gas. Figure 2 Shown is a cervical dilator in its dehydrated (top) and hydrated (bottom) states. Figure 2 Chinese: "1 x " means an anisotropic swellable xerogel stem in its original sterile state, completely or partially dehydrated; "1 H"" indicates a hydrated hydrogel stem, fully hydrated in an isotonic solution with a pH of 7.0-7.5 at 35°C; "2" indicates a plastic handle glued to the stem; "3" indicates a locator ring. Reference Figure 2 , xerogel stem length L X and diameter D X The length L of the hydrated hydrogel stem H and diameter D H Due to anisotropic expansion, (D H / D X )>>(L H / L X ). Preferably, (D H / D X ) is 2 to 5, more preferably 3 to 4. Preferably, (L H / L X ) is 0.7 to 1.5, more preferably 0.85 to 1.15. Moreover, the locator ring 3 can be a wire made of, for example, polyamide, polyolefin, polyester, polyurethane or cellulose.

[0067] Compared to the device according to Example 1 without the saline gel stick, the cervical dilator product of Example 2 exhibited increased anisotropic radial expansion, with increased radial expansion pressure and expansion rate, and faster maturation of cervical tissue due to greater osmotic dehydration.

[0068] Example 3 :

[0069] The hydrogel interpenetrating network of Example 2 having poly(methacryloyloxypropane-1-sulfonic acid) monomers was soaked with an excess of an aqueous solution containing 5 wt% sodium sulfate, 3 wt% 1,2-propylene glycol, and 1 wt% triethanolamine. It was then dried under radial tension at 70°C until the residual water content reached approximately 18 wt%. The product was then cut to size, trimmed, equipped with handles, and sealed in sterilization bags, as in the previous examples. The cervical dilator device was sterilized by electron beam at 40 kGy. The cervical dilator device provided rapid cervical ripening, had strong radial expansion, and could be shaped to fit any specific cervical canal geometry prior to insertion.

[0070] The foregoing embodiments and description should be considered as illustrative and not limiting of the present invention as defined by the claims. As will be readily appreciated, many variations and combinations of the features described above may be utilized without departing from the present invention as set forth in the claims. Such variations are not to be considered as departing from the spirit and scope of the present invention, and all such variations are intended to be included within the scope of the appended claims.

[0071] All articles, references, and patents cited herein are hereby incorporated by reference in their entirety.

Claims

1. A cervical dilator comprising: a stem comprising a partially or completely dehydrated hydrogel comprising a water-insoluble osmotically active synthetic hydrophilic polymer capable of radially expanding due to absorption of water from body fluids, resulting in a first osmotic dehydration; and at least one second osmotically active compound dispersed in the hydrogel, causing a second osmotic dehydration; wherein the cervical dilator is configured to osmotically extract water from the tissue using the first and second osmotic dehydrations; wherein the water-insoluble osmotically active synthetic hydrophilic polymer is selected from the group consisting of polyvinyl alcohol, polyurethane, polyurea, and acrylic copolymers containing pendant nitrile and carboxylate groups; and wherein the at least one second osmotically active compound is selected from: A water-soluble polymer electrolyte which is a polymer having side chain substituents selected from the group consisting of carboxylate groups, salts of carboxylate groups, sulfate groups, salts of sulfate groups, phosphate groups, salts of phosphate groups, sulfonate groups, and salts of sulfonate groups; or A non-toxic water-soluble salt comprising a monovalent cation selected from the group consisting of sodium, potassium, lithium, ammonium, and organic amine cations, and an anion selected from the group consisting of chloride, bromide, sulfate, phosphate, thiocyanate, and acetate anions; or a mixture thereof.

2. The cervical dilator of claim 1, wherein at least one of the at least one second osmotically active compound is a water-soluble polymer electrolyte at a concentration of 1% to 60% by weight based on the weight of the hydrogel.

3. The cervical dilator of claim 2, wherein the water-soluble polymer electrolyte forms an interpenetrating network with the water-insoluble osmotically active synthetic hydrophilic polymer forming the hydrogel.

4. The cervical dilator of claim 2, wherein the polymer electrolyte is present in the form of discrete domains dispersed within the hydrogel.

5. The cervical dilator according to claim 1, wherein the at least one second osmotically active compound comprises a non-toxic water-soluble salt or a mixture of non-toxic water-soluble salts.

6. The cervical dilator of claim 5, wherein the non-toxic water-soluble salt comprises anions selected from the group consisting of chloride, sulfate, phosphate, thiocyanate, and acetate anions.

7. The cervical dilator according to claim 6, wherein the anion is a chloride anion.

8. The cervical dilator according to claim 5, wherein the one or more salts are present in a concentration range of 3% to 60% by weight based on the weight of the hydrogel.

9. The cervical dilator according to claim 5, wherein the one or more salts are present in a concentration range of 7% to 45% by weight.

10. The cervical dilator according to claim 5, wherein the one or more salts are present in a concentration range of 9% to 35% by weight.

11. The cervical dilator of claim 5, wherein the one or more salts are dispersed within the stem in a concentration gradient such that the one or more salts are present in a higher concentration on the surface of the stem than in the center of the stem.

12. The cervical dilator of claim 1, wherein the hydrogel comprises 3% to 25% by weight of a non-toxic plasticizer, based on the weight of the hydrogel.

13. The cervical dilator according to claim 12, wherein the plasticizer comprises at least one compound selected from the group consisting of glycerol, glycerol monoacetate, glycerol diacetate, glycerol formate, glycolic acid, 1,2 propylene glycol, dimethyl sulfoxide (DMSO), and water.

14. The cervical dilator according to claim 13, wherein the hydrogel comprises 5% to 22% water by weight.

15. The cervical dilator of claim 1, wherein the stem comprising a partially or fully dehydrated hydrogel is capable of radial expansion to more than 200% of its dehydrated diameter while its axial dimension changes by + 25% to - 25% of its dehydrated length under the same conditions.

16. The cervical dilator of claim 1, wherein the hydrogel comprises an acrylic copolymer comprising pendant nitrile and carboxylate groups.

17. The cervical dilator of claim 16, wherein the pendant nitrile groups are organized into crystalline domains detectable by X-ray diffraction.

18. The cervical dilator according to claim 16 or 17, wherein the copolymer is a partial hydrolysis or aminolysis product of polyacrylonitrile (PAN).

19. The cervical dilator of claim 1, wherein the cervical dilator is a sterile device enclosed in a water and water vapor impermeable container.

20. A method of preparing a cervical dilator according to claim 1, the method comprising: Providing a hydrogel in a partially or completely dehydrated state having at least one second osmotically active compound dispersed therein; Axially stretching the hydrogel at a temperature above the glass transition temperature of the water-insoluble osmotically active synthetic hydrophilic polymer, thereby producing a stem comprising a partially or completely dehydrated hydrogel and achieving the ability to expand radially; and The stem comprising the partially or completely dehydrated hydrogel is then cooled to ambient temperature under axial stress.

21. A method of preparing a cervical dilator according to claim 1, the method comprising: Providing a hydrogel in a hydrated state having at least one second osmotically active compound dispersed therein; The hydrogel is axially stretched while drying and maintaining a predetermined length of the hydrogel, thereby producing a stem comprising a partially or completely dehydrated hydrogel and achieving the ability to expand radially.

22. The method of claim 20 or 21, wherein the hydrogel comprises an acrylic copolymer comprising pendant nitrile and carboxylate groups, wherein the copolymer is a partial hydrolysis or aminolysis product of polyacrylonitrile (PAN), and wherein the partial hydrolysis or aminolysis is achieved by reacting PAN dissolved in a concentrated sodium thiocyanate solution in the presence of an alkali metal hydroxide to produce a viscous solution of the partially hydrolyzed or aminolyzed polyacrylonitrile copolymer.

23. The process according to claim 22, wherein the partial hydrolysis or aminolysis is carried out at a temperature of 30°C to 100°C.

24. A process according to claim 23, wherein the viscous solution of partially hydrolysed or aminolysed polyacrylonitrile copolymer is converted into a hydrogel by coagulating the solution with an aqueous liquid, followed by a full or partial thiocyanate solvent extraction and a subsequent drying step.

25. The method according to claim 20 or 21, wherein the at least one second osmotically active compound comprises a non-toxic water-soluble salt or a mixture of non-toxic water-soluble salts, wherein the hydrogel contains 3% to 25% by weight of a non-toxic plasticizer, and wherein the hydrogel is kept in contact with an aqueous solution of at least one second osmotically active compound and / or at least one precursor of a second osmotically active compound and / or plasticizer prior to the drying step, the precursor being a water-soluble monomer having negatively charged functional groups selected from the group consisting of carboxylate groups, sulfate groups, phosphate groups, sulfonate groups, and salts thereof.

26. The method according to claim 25, wherein the at least one second osmotically active compound permeates into the hydrogel to a concentration that is at least half of the equilibrium concentration.

27. The method of claim 20 or 21, comprising sterilizing the cervical dilator within a water and water vapor impermeable container by exposing the cervical dilator to ionizing radiation.

28. The method of claim 27, wherein the ionizing radiation is gamma radiation.

29. The method of claim 27, wherein the ionizing radiation is electron beam radiation.

30. The method of claim 27, wherein the at least one second osmotically active compound comprises a non-toxic water-soluble salt or a mixture of non-toxic water-soluble salts, wherein the hydrogel contains 3% to 25% by weight of a non-toxic plasticizer, and wherein the radiation is applied while the one or more salts and the plasticizer are dispersed in the partially or completely dehydrated hydrogel.

31. The cervical dilator of claim 2, wherein the polymer electrolyte is present in a concentration of 5% to 40% by weight based on the dehydrated hydrogel stem.

32. The method of claim 22, wherein the alkali metal hydroxide is sodium hydroxide.

33. The method of claim 22, wherein the partial hydrolysis or aminolysis is carried out at a temperature of 50°C to 85°C.

34. The method of claim 27, wherein the ionizing radiation is beta radiation.

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