Drinking type degradable guiding sheath as well as preparation method and application thereof

Abstract

The invention belongs to the technical field of biomedical materials, and provides a swallowed and degradable guide sheath as well as a preparation method and application thereof. The preparation method comprises the following steps: preparing a triggering solution by using an ionic crosslinking triggering agent and a viscosity agent, preparing a membrane solution by using a degradable high polymer material and a complexing slow-release agent, then applying the triggering solution in a pipeline, and waiting for 5-15 seconds to form a pipeline-shaped temporary retention liquid layer; and then a film forming solution is applied to the pipeline-shaped temporary retention solution layer, the film forming solution is applied within 30 s, the guiding sheath is formed, and the ionic crosslinking triggering agent is salt containing divalent metal cations and / or alkaline substances containing divalent metal cations. Furthermore, the guiding sheath can be used for achieving synchronous flow guiding, for example, liquid food, liquid nutrient solution or liquid medicine is infused after the guiding sheath is formed, mechanical stimulation and complication risks caused by intubation are remarkably reduced, patient compliance is improved, and the guiding sheath can be degraded after being used.

Description

Technical Field

[0001] This invention relates to the field of biomedical materials technology, and more specifically, to a swallowable and biodegradable guide sheath, its preparation method, and its application. Background Technology

[0002] For patients with swallowing difficulties, esophageal stricture, and those who require long-term oral administration of liquid nutrition or medication, nasogastric tubes or orogastric tubes are commonly used for assisted delivery of liquids. However, these methods are often accompanied by significant pain, a high complication rate, and require operation by professional medical staff, which limits their use in certain scenarios (such as making them difficult to use at home).

[0003] Therefore, there is an urgent need to develop an assisted feeding method that can alleviate patients' pain, is less likely to cause complications, and is easy to operate (can be done at home without the need for professional medical staff). Summary of the Invention

[0004] This invention aims to at least solve one of the technical problems existing in the prior art. To this end, this invention proposes a swallowable and biodegradable guide sheath, its preparation method, and its application. This invention prepares the guide sheath by sequentially applying a triggering liquid and a film-forming liquid. It can be further used for painless assisted feeding, such as as a guide sheath for liquid food intake, or for administering nutritional solutions or medications. Since both the triggering liquid and the film-forming liquid are liquids, a swallowing method can be used, enabling non-invasive feeding, greatly reducing patient pain, minimizing the risk of complications, and simplifying operation. It can be operated without professional medical personnel, has multiple application scenarios, and can be used by patients themselves or at home. Furthermore, the guide sheath is biodegradable, requiring no recycling after use and posing no risk of residue.

[0005] A first aspect of the present invention provides a method for preparing a swallowable and biodegradable guide sheath.

[0006] Specifically, a method for preparing a swallowable and biodegradable guiding sheath includes the following steps: (1) Dissolve the ionic crosslinking trigger in water, then mix it with a thickener and adjust the pH to 5.5-6.5 to obtain the trigger solution; The biodegradable polymer material is dispersed in water, then mixed with a complexing slow-release agent, and the pH value is adjusted to 5.5-6.5 to obtain a film-forming solution. (2) In the pipeline, first apply the triggering liquid and wait for 5-15 seconds to form a pipeline-shaped temporary stagnant liquid layer; then apply the film-forming liquid on the pipeline-shaped temporary stagnant liquid layer and complete the application of the film-forming liquid within 30 seconds to form the guiding sheath; In step (1), the ionic crosslinking trigger is a salt containing a divalent metal cation and / or an alkaline substance containing a divalent metal cation.

[0007] The guide sheath is prepared using triggering fluid and film-forming fluid as the main raw materials. Since both raw materials are liquids, they can be ingested via swallowing, avoiding the pain caused by insertion. The triggering fluid first forms a temporary, tubular retention layer within the channel. The film-forming fluid is then applied onto this layer. The ionic cross-linking trigger in the temporary retention layer triggers the biodegradable polymer material in the film-forming fluid to cross-link and form a film, thus creating the guide sheath in situ. The cross-linking process is very rapid, completing within seconds. A complexing sustained-release agent can complex with the ionic cross-linking trigger on the wall surface to temporarily "bind" the trigger, ensuring the formation of a hollow tubular structure.

[0008] Preferably, in step (2), both the application triggering liquid and the application film-forming liquid are administered orally or via the nose.

[0009] When both the triggering solution and the film-forming solution are ingested orally, the thickener in the triggering solution maintains a high viscosity at low shear rates, which facilitates the formation of a tubular, temporarily retained fluid layer on the esophageal wall. At high shear rates (such as during swallowing), it rapidly thins, preventing clumping. The ionic cross-linking trigger in the triggering solution can initiate cross-linking of the biodegradable polymeric materials in the tubular, temporarily retained fluid layer, thereby forming a guiding sheath in situ. Moreover, the cross-linking speed is very fast (it can be completed within seconds). Therefore, if ingested orally, a flexible, lubricating channel, i.e., a guiding sheath, can be formed on the entire esophageal wall before the triggering solution and film-forming solution have fully penetrated the stomach. Furthermore, after the film-forming solution is added, the complexing and sustained-release agent in it can complex with the ionic cross-linking trigger in the temporarily retained liquid layer in the tubular structure on the esophageal wall, temporarily "binding" the ionic cross-linking trigger and concentrating it in the esophageal wall region (where the concentration of the ionic cross-linking trigger is high and the diffusion distance is short). At this time, on the one hand, the concentration of the ionic cross-linking trigger on the esophageal wall reaches the cross-linking threshold, enabling cross-linking and film formation within seconds. On the other hand, due to the lack of ionic cross-linking trigger in the central region of the esophageal lumen, early cross-linking and gelation will not occur in the central region of the esophageal lumen for at least 20-40 seconds after the application of the film-forming solution, ensuring the unobstructed passage of the central esophageal lumen and forming a "hollow structure." This fundamentally avoids the blockage problem caused by "gelation in the lumen center first," facilitating the smooth entry of food or drugs into the gastrointestinal tract from the guiding sheath. In addition, the esophageal peristalsis (peristaltic wave) itself has a transit time of about 8-12 seconds, which also provides a window period for the cross-linking reaction.

[0010] Preferably, in step (2), the mass ratio of the triggering liquid to the film-forming liquid is 1:1.5 to 1:4. Mixing the triggering liquid and the film-forming liquid in a specific ratio ensures that the triggering liquid reacts uniformly and does not cause a deterioration in taste or a buildup of gastric acid due to excessive amounts.

[0011] More preferably, the mass ratio of the triggering liquid to the film-forming liquid is 1:2 to 1:3.

[0012] Preferably, in step (1), the raw material components of the triggering liquid, by mass percentage, include: 0.7-1.5 wt% ionic crosslinking triggering agent and 0.05-0.15 wt% thickener.

[0013] More preferably, in step (1), the raw material components of the triggering liquid, by mass percentage, include: 0.7-1.2 wt% ionic crosslinking triggering agent and 0.08-0.15 wt% thickener.

[0014] More preferably, in step (1), the raw material components of the triggering liquid, by mass percentage, include: 0.78-1.11 wt% of ionic crosslinking triggering agent and 0.08-0.12 wt% of thickener.

[0015] Preferably, in step (2), the volume of the applied triggering liquid is 40-60 mL.

[0016] More preferably, in step (2), the volume of the applied triggering liquid is 50-55 mL.

[0017] Preferably, in step (1), the pH value of the triggering solution is 5.5-6.2. A triggering solution with a suitable pH value is beneficial to both the patient's experience and the subsequent cross-linking kinetics.

[0018] More preferably, in step (1), the pH value of the triggering solution is 5.8-6.0.

[0019] Preferably, in step (2), the volume of the applied film-forming solution is 80-120 mL.

[0020] More preferably, in step (2), the volume of the applied film-forming solution is 100-110 mL.

[0021] Preferably, in step (1), the storage modulus (G') of the film-forming liquid at 1 Hz and 37 °C is 100-400 Pa, and / or the yield stress of the film-forming liquid is ≤10 Pa. Film-forming liquids that meet specific G' and yield stresses can avoid the formation of non-deformable "plugs" in the cavity.

[0022] Preferably, when the shear rate is 10s -1 Furthermore, at 37°C, the dynamic viscosity of the triggering fluid is 40-120 mPa. A triggering fluid of suitable viscosity can ensure the continuity of the film layer.

[0023] More preferably, when the shear rate is 10s -1 Furthermore, at 37°C, the dynamic viscosity of the triggering fluid is 80-120 mPa. s.

[0024] Preferably, the thickener is sodium carboxymethyl cellulose and / or xanthan gum.

[0025] Preferably, the salt containing divalent metal cations is CaCl2 and / or MgCl2.

[0026] Preferably, the alkaline substance containing divalent metal cations is Ca(OH)2 and / or Mg(OH)2.

[0027] Preferably, the triggering liquid further contains a temperature-sensitive triggering agent and / or a surfactant.

[0028] Preferably, the triggering liquid further contains 0.05-0.5 wt% thermosensitive triggering agent and 0.001-0.02 wt% surfactant by mass percentage.

[0029] Preferably, the thermosensitive trigger is at least one of the following: poly(N-isopropylacrylamide) copolymer (which undergoes a phase transition at 32-34°C), methylcellulose (MC), hydroxypropyl methylcellulose (HPMC) (methylcellulose and hydroxypropyl methylcellulose gel at around 37°C), poloxamer 188, and poloxamer 407 (or Pluronic F127) (both poloxamer 188 and poloxamer 407 can form temperature-sensitive gels). The thermosensitive trigger can initiate a phase transition to enhance esophageal wall adhesion and film stability.

[0030] Preferably, the surfactant is at least one of Tween 80, Tween 20, and soy lecithin. The surfactant helps the triggering solution spread evenly on the esophageal wall.

[0031] Preferably, the triggering fluid also contains a calcium source.

[0032] Preferably, the calcium source is a microencapsulated slow-release calcium source and / or calcium salt microparticles. Microencapsulated slow-release calcium sources and calcium salt microparticles easily adhere to the wall surface and release calcium ions slowly, further ensuring "wall-first film formation".

[0033] Preferably, the microencapsulated sustained-release calcium source is microencapsulated calcium lactate (such as wall material gelatin / gum arabic; Dv50=10-50µm; encapsulation rate≥80%, model CaLac-ME50).

[0034] Preferably, the calcium salt particles are CaCl2 particles. The CaCl2 particles are in the form of Ca... 2+ The concentration is calculated to be 5-20 mmol / L; the total concentration with free CaCl2 does not exceed 0.12 mol / L.

[0035] Preferably, the average particle size of the calcium source is 10-50 μm.

[0036] Preferably, the triggering solution also contains a pH adjuster.

[0037] Preferably, the pH adjuster is citric acid.

[0038] Preferably, in step (1), the film-forming liquid contains 0.2-1 wt% of degradable polymeric material and 0.15-0.30 wt% of complexing sustained-release agent by mass percentage.

[0039] Preferably, the biodegradable polymer material is at least one of sodium alginate, sodium hyaluronate, gelatin, and gellan gum.

[0040] More preferably, the biodegradable polymer material is sodium alginate and sodium hyaluronate. Using sodium alginate as the main substrate for film formation, it can undergo a cross-linking reaction with the divalent metal cations in the ionic cross-linking trigger to form a hydrogel network. Sodium hyaluronate also plays a role in lubrication and improving patient comfort.

[0041] Preferably, the complexing sustained-release agent is at least one selected from citrate, gluconate, lactate, tartrate, phytate, and pyrophosphate.

[0042] More preferably, the complexing sustained-release agent is at least one selected from sodium citrate, sodium gluconate, sodium lactate, sodium tartrate, sodium phytate, and sodium pyrophosphate.

[0043] More preferably, the biodegradable polymer material is sodium alginate and sodium hyaluronate, and the film-forming solution contains 0.25-0.5 wt% sodium alginate, 0.05-0.2 wt% sodium hyaluronate, and 0.1-0.20 wt% complexing sustained-release agent by mass percentage.

[0044] More preferably, the film-forming solution contains, by mass percentage, 0.25-0.45 wt% sodium alginate, 0.05-0.1 wt% sodium hyaluronate, and 0.15-0.30 wt% complexing sustained-release agent.

[0045] More preferably, the film-forming solution contains, by mass percentage, 0.35-0.45 wt% sodium alginate, 0.08-0.1 wt% sodium hyaluronate, and 0.15-0.20 wt% complexing sustained-release agent.

[0046] Preferably, the film-forming liquid further contains at least one of a plasticizer, a temperature-sensitive coagulating agent, a superhydrophobic outer layer component, and a locally soothing component.

[0047] More preferably, the film-forming liquid contains, by mass percentage, 0.5-2.0 wt% plasticizer, 2-4 wt% temperature-sensitive coagulating agent, 0.1-0.3 wt% superhydrophobic outer layer agent, and 0.06-0.5% local soothing agent.

[0048] More preferably, the film-forming liquid contains, by mass percentage, 0.8-1.5 wt% plasticizer, 2-3 wt% thermosensitive coagulating agent, 0.1-0.25 wt% superhydrophobic outer layer agent, and 0.065-0.45% local soothing agent.

[0049] Preferably, the plasticizer is glycerin. The plasticizer can improve the flexibility of the film layer, preventing it from becoming too brittle or too hard, while also improving the swallowing experience and providing moisturizing properties.

[0050] Preferably, the temperature-sensitive coagulant is Pluronic F127. The temperature-sensitive coagulant slightly thickens above 37°C, improving the stability of the wall coating.

[0051] Preferably, the superhydrophobic outer layer component is nanocellulose and / or plant wax emulsion. During the cross-linking process, the superhydrophobic outer layer component segregates to the outer surface of the membrane, forming a low surface energy rough outer layer to reduce inter-wall friction and prevent outer layer adhesion and thickening.

[0052] More preferably, the superhydrophobic outer layer is composed of nanocellulose and plant wax emulsion.

[0053] Preferably, the plant wax emulsion is a carnauba wax emulsion.

[0054] More preferably, the film-forming solution contains 0.05-0.10 wt% nanocellulose and 0.05-0.15 wt% plant wax emulsion by mass percentage.

[0055] More preferably, the film-forming solution contains 0.08-0.10 wt% nanocellulose and 0.1-0.15 wt% plant wax emulsion by mass percentage.

[0056] Preferably, the local soothing ingredient is at least one selected from L-menthol microcapsules, aloe vera extract, dipotassium glycyrrhizate, and chamomile extract. The local soothing ingredient provides a cooling and lubricating sensation, reduces the feeling of a foreign body in the throat and esophagus during drinking, improves compliance, and also has mild anti-inflammatory and mucosal protective effects.

[0057] More preferably, the film-forming solution contains the following locally soothing ingredients by mass percentage: 0.005-0.05 wt% L-menthol microcapsules, 0.02-0.2 wt% aloe vera extract, 0.02-0.1 wt% dipotassium glycyrrhizate, and 0.02-0.1 wt% chamomile extract.

[0058] Preferably, in step (2), after the film-forming solution is applied, 5-10 mL of water is applied. Water is continued to be applied to rinse away the ungelatinized liquid; if taken orally, additional water can be drunk to push the ungelatinized liquid in the center into the stomach.

[0059] Preferably, the total volume of the triggering solution and the film-forming solution applied in a single application is ≤200mL.

[0060] Preferably, the application of the triggering solution once, followed by the application of the film-forming solution once, constitutes one round of operation. Performing at least one round of operation, with a time interval of at least 15 minutes between each round, allows for the formation of a thicker film to accommodate more food or medication intake.

[0061] A second aspect of the invention provides a swallowable and biodegradable guide sheath.

[0062] A swallowable and biodegradable guide sheath, the guide sheath being a hollow tubular structure comprising a tube wall and a central cavity, the tube wall having a thickness of 0.1-0.5 mm and the central cavity having a diameter of 5-10 mm.

[0063] A third aspect of the invention provides an application of a swallowable and biodegradable guide sheath.

[0064] Application of a swallowable and biodegradable guiding sheath in assisting feeding or drug delivery.

[0065] Preferably, the assisted feeding is the delivery of liquid food, liquid nutrient solution, or liquid medicine.

[0066] More preferably, the assisted feeding involves delivering liquid food, liquid nutrient solution, or liquid medicine through a tube or cup.

[0067] Compared with the prior art, the beneficial effects of the present invention are as follows: The present invention provides a drinkable and biodegradable guiding sheath. First, a triggering solution is prepared using an ionic crosslinking trigger and a thickener. Then, a film-forming solution is prepared using a biodegradable polymer and a complexing sustained-release agent. Next, the triggering solution is applied to a channel, and after 5-15 seconds, a channel-shaped temporary retention liquid layer is formed. Then, a film-forming solution is applied onto the channel-shaped temporary retention liquid layer, and the application of the film-forming solution is completed within 30 seconds, forming the guiding sheath. The ionic crosslinking trigger is a salt containing a divalent metal cation and / or an alkaline substance containing a divalent metal cation. The biodegradable polymer in the film-forming solution is the main substrate for film formation, capable of reacting with the ionic crosslinking trigger in the triggering solution and crosslinking to form a hydrogel network. Furthermore, the guiding sheath of the present invention can be used to achieve synchronous drainage. For example, after the guiding sheath is formed, it can be used as a liquid feeding guiding sheath to infuse liquid food, liquid nutrition solution or medicine through a catheter or cup. This method of assisting feeding significantly reduces the risk of mechanical stimulation and complications caused by intubation, improves patient compliance, is suitable for long-term use in homes and nursing homes, and the guiding sheath is biodegradable after use, requiring no recycling and posing no risk of residue. Attached Figure Description

[0068] Figure 1 This is a schematic diagram of the formation process of the guide sheath in Application Example 1; Figure 2 This is a schematic diagram of the structure of the device for simulating the formation of the esophageal guiding sheath in vitro and the device for measuring the friction coefficient. Figure 3 A schematic diagram of the cross-sectional structure of the guiding sheath formed in the esophagus in Application Example 1; Figure 4 This is a schematic diagram of the application of Example 1, where oral ingestion forms a guiding sheath. Detailed Implementation

[0069] To enable those skilled in the art to more clearly understand the technical solutions described in this invention, the following embodiments are provided for illustration. It should be noted that the following embodiments do not constitute a limitation on the scope of protection claimed by this invention.

[0070] Unless otherwise specified, the raw materials, reagents or devices used in the following examples are available from conventional commercial sources or can be obtained by existing known methods.

[0071] The main raw material components used in this invention are sourced from the following sources: Pluronic F127: Manufactured by BASF in Germany.

[0072] Nanocellulose: 10±2% solids content, manufactured by Borregaard, model Exilva® F10.

[0073] Plant wax emulsion: solid content 30±5%, specifically carnauba wax emulsion, manufactured by Koster Keunen, model Carnauba Wax Emulsion30.

[0074] All raw materials used in this invention must meet food-grade or medical device-grade standards to ensure safety.

[0075] Example 1 A swallowable and biodegradable guiding sheath, the raw materials for which are prepared include a triggering liquid and a film-forming liquid in a mass ratio of 1:2; Trigger solution: 50 mL, pH=5.8 (adjusted with edible citric acid), composed of the following components by mass percentage: CaCl2 0.78 wt%, sodium carboxymethyl cellulose 0.12 wt%, Tween 80 0.02 wt%, balance water.

[0076] Film-forming solution: 100 mL in volume, composed of the following components by mass percentage: sodium alginate 0.35 wt%, sodium hyaluronate 0.10 wt%, glycerin 1.0 wt%, sodium citrate 0.20 wt%, Pluronic F127 3.0 wt%, nanocellulose 0.08 wt%, plant wax emulsion 0.10 wt%, and the balance being water.

[0077] The method for preparing the above-mentioned swallowable and biodegradable guide sheath includes the following steps: (1) Preparation of triggering solution and film-forming solution: Triggering solution: Dissolve CaCl2 in water, add sodium carboxymethyl cellulose and Tween 80, and adjust the pH to 5.8 (adjusted with edible citric acid).

[0078] Film-forming solution: Disperse sodium alginate and sodium hyaluronate in water, stir at 7000 rpm for 3-5 min, and let stand to remove bubbles; add nanocellulose and plant wax emulsion, shear at 10000 rpm for 3-5 min, then remove bubbles at -0.08 MPa for 3-5 min, and then add sodium citrate, glycerol, and Pluronic F127 to adjust the pH to 5.5-6.5.

[0079] (2) Preparation of the guiding sheath: Take a transparent silicone esophageal model (such as...) Figure 2 As shown, the tube has an inner diameter of 20 mm and a length of 250 mm. First, a triggering fluid is injected into one end of the tube, and wait for 10 seconds. Then, a film-forming fluid is injected from the same position. The film-forming fluid is applied within 30 seconds to form a guide sheath.

[0080] Example 1 shows that using 50 mL of triggering solution with 100 mL of film-forming solution can form a stable film layer in the adult esophagus.

[0081] Example 2 A swallowable and biodegradable guiding sheath, the raw material components of which include a triggering liquid and a film-forming liquid in a mass ratio of 1:3; Trigger solution: 40 mL, pH = 6.0 (adjusted with edible citric acid), consisting of the following components by mass percentage: CaCl2 0.55 wt%, xanthan gum 0.10 wt%, Tween 80 0.02 wt%, balance water.

[0082] Film-forming solution: 80 mL in volume, which consists of the following components by mass percentage: sodium alginate 0.45 wt%, sodium hyaluronate 0.10 wt%, glycerin 1.0 wt%, sodium citrate 0.20 wt%, Pluronic F127 3.0 wt%, nanocellulose 0.08 wt%, plant wax emulsion 0.10 wt%, and the balance being water.

[0083] The preparation method is the same as in Example 1.

[0084] Example 3 A swallowable and biodegradable guiding sheath, the raw material components of which include a triggering liquid and a film-forming liquid in a mass ratio of 1:2; Trigger solution: 50 mL, pH = 6.2 (adjusted with edible citric acid), consisting of the following components by mass percentage: 0.78 wt% CaCl2, 0.12 wt% sodium carboxymethyl cellulose, and the balance being water.

[0085] Film-forming solution: 100 mL in volume, which consists of the following components by mass percentage: sodium alginate 0.35 wt%, sodium hyaluronate 0.10 wt%, sodium citrate 0.20 wt%, and the balance being water.

[0086] The preparation method is the same as in Example 1.

[0087] Example 4 A swallowable and biodegradable guiding sheath differs from Example 1 in that the triggering fluid also contains 0.1 wt% of the thermosensitive triggering agent hydroxypropyl methylcellulose. The thermosensitive triggering agent is added together with sodium carboxymethyl cellulose to obtain the triggering fluid; other steps are the same as in Example 1.

[0088] Example 5 A swallowable and biodegradable guide sheath differs from Example 1 in that the film-forming solution further contains the following components: 0.05 wt% L-menthol microcapsules, 0.2 wt% aloe vera extract, 0.1 wt% dipotassium glycyrrhizate, and 0.1 wt% chamomile extract (the above components are locally soothing ingredients). The preparation method of the guide sheath in Example 5 differs from that in Example 1 in that the preparation method of the film-forming solution is different, specifically: Sodium alginate and sodium hyaluronate were dispersed in water and stirred at 7000 rpm for 3-5 minutes, then allowed to stand to remove bubbles. Nanocellulose and plant wax emulsion were added, and the mixture was sheared at 6000-10000 rpm for 3-5 minutes, followed by degassing at -0.08 MPa for 3-5 minutes. Then, sodium citrate, glycerin, and Pluronic F127 were added. After cooling to ≤25°C, the locally soothing ingredients were slowly added at 400 rpm under low shear, and stirred for 2-3 minutes to ensure uniform dispersion. The pH was adjusted to 5.5-6.5. Other steps were the same as in Example 1.

[0089] Comparative Example 1 A guide sheath, which differs from Example 1 in that the triggering fluid does not contain the thickener sodium carboxymethyl cellulose.

[0090] Comparative Example 2 A guiding sheath differs from that of Example 1 in that its raw material components are no longer divided into two liquids, a film-forming liquid and a triggering liquid, but are instead a single liquid component with a volume of 150 mL, containing: 0.78 wt% CaCl2, 0.12 wt% sodium carboxymethyl cellulose, 0.02 wt% Tween 80, 0.35 wt% sodium alginate, 0.10 wt% sodium hyaluronate, 1.0 wt% glycerol, 0.20 wt% sodium citrate, 3.0 wt% Pluronic F127, 0.08 wt% nanocellulose, 0.10 wt% plant wax emulsion, with the balance being water, for a total weight percentage of 100%.

[0091] Comparative Example 3 A swallowable and biodegradable guiding sheath, which differs from Example 1 in that the film-forming solution does not contain the complexing sustained-release agent sodium citrate.

[0092] Application Example 1 Assisted feeding is achieved using a swallowable and biodegradable liquid feeding guide sheath. Figure 1 ), including the following steps: (1) The patient should be in a semi-sitting position (60-80°). When swallowing, the chin can be slightly tucked in. This position can reduce the risk of liquid entering the airway and prolong the contact time between the esophagus and the liquid, which is conducive to film formation.

[0093] (2) Take the triggering solution and film-forming solution from Example 1. The patient should first drink 50 mL of the triggering solution orally, swallowing it in one or two mouthfuls. Wait 10 seconds to allow time for the triggering solution to spread and form a uniform triggering solution retention layer on the esophageal wall.

[0094] (3) Then, the patient orally drinks 100mL of the film-forming solution, completing the drinking in 2-3 sips within 30 seconds to avoid prolonged retention of the liquid in the mouth, which could lead to premature reaction. After drinking, the patient drinks another 5-10mL of warm water to push the non-gelatinized liquid portion into the stomach, forming a liquid feeding guide sheath in situ. Figure 4 Subsequently, continuous infusion was initiated ≤30s after the film-forming solution was applied, and 200mL of isotonic nutrient solution (37℃) was administered orally within 5 minutes to ensure that the center was not static. Throughout the process, due to continuous flow and dilution, the center of the esophageal lumen was not static and no overall gelation was formed in the esophageal lumen (if interrupted for ≥40s, rinse with 5-10mL of warm water before continuing).

[0095] OCT (Optical Coherence Tomography) verification results showed that the central cavity diameter of the liquid feeding guide sheath was ≥6mm, and the nutrient solution throughput was ≥95wt% (n≥10), indicating that the nutrient solution could indeed pass through the guide sheath smoothly. After the nutrient solution was consumed, the guide sheath was subsequently degraded (the guide sheath was considered degraded if the mass loss rate was ≥95% within 30 minutes under the action of gastric acid and digestive enzymes).

[0096] The liquid feeding guide sheath formed in Application Example 1 has the following structure: Figure 3 As shown, after the triggering liquid is ingested, a temporary stagnant layer of the triggering liquid is formed on the esophageal wall. Subsequently, the film-forming liquid is ingested, and a film-forming reaction occurs, forming a guiding sheath with a wall thickness of 0.2-0.4 mm. Its central channel (central cavity) with an inner diameter of 6-8 mm allows other substances to pass through. The outer wall of the guiding sheath is a superhydrophobic layer, which can reduce the friction between the membrane layer and the esophageal wall.

[0097] Application Example 2-5 The usage method of Application Examples 2-5 is the same as that of Application Example 1, except that the triggering liquid and film-forming liquid of Example 1 are replaced with the triggering liquid and film-forming liquid of Example 2-5 respectively.

[0098] Comparative Application Example 1 A method of using a swallowable and biodegradable guide sheath differs from Application Example 1 in that the triggering liquid and film-forming liquid of Example 1 are replaced with the triggering liquid and film-forming liquid of Comparative Example 1.

[0099] Comparative Application Example 2 A method of using a swallowable and biodegradable guide sheath differs from Application Example 1 in that the triggering liquid and film-forming liquid of Example 1 are replaced with the liquid of Comparative Example 2.

[0100] Comparative Application Example 3 A method of using a swallowable and biodegradable guide sheath differs from Application Example 1 in that the triggering liquid and film-forming liquid of Example 1 are replaced with the triggering liquid and film-forming liquid of Comparative Example 3.

[0101] Comparative Application Example 4 The method of using a swallowable and biodegradable guiding sheath differs from that in Application Example 1 in that the order of steps (2) and (3) is reversed. The patient first drinks 100 mL of film-forming fluid orally, swallowing it in one or two gulps and waiting for 10 seconds. Then the patient drinks 50 mL of triggering fluid orally, completing the drinking in 2-3 gulps within 30 seconds. After drinking, the patient drinks 5-10 mL of warm water.

[0102] Product effectiveness test 1. Gelation time and rheological properties The gelation time and rheological properties of the guide sheaths in the above embodiments and comparative examples were tested: (1) Test method ① Esophageal wall gelation time (t1) and overall intraluminal gelation time (t2): Test model as follows Figure 2 As shown, a transparent silicone esophagus (20 mm inner diameter, 250 mm length) was used as a model (simulating esophageal peristalsis, 8-12 s transit time). It was rinsed with artificial saliva at a flow rate of 5 mL / s for 30 s at 37℃, allowed to stand for 60 s, and then drained to allow a stable water film to form on the inner wall. The artificial saliva (pH 6.8, enzyme-free) was used to simulate the esophageal environment. Next, the triggering solution and film-forming solution were injected at a constant rate of 2 mL / s. During this time, a high frame rate camera was used to determine and record the time when a continuous ring-shaped gel appeared on the wall as t1 (wall gelation time; at this time, the image processing software identified a continuous ring-shaped "light and dark band / translucent band" closing along 360° and lasting for ≥1.0s, and the first time the condition was met was recorded as t1). Then, the model was left to stand, and every 2s, the model was quickly tilted to 60° and held for 3s. It was observed whether the central liquid was flowable (displacement ≥10mm). If the central liquid showed no visible displacement (<10mm) within 3s for the first time, and the subsequent two tilting repetitions also showed no flow, this was recorded as the transition time t2 (overall gelation time in the cavity) from flowable to non-flowable within the in vitro standing cavity. The entire test was conducted in a constant temperature chamber at 37±0.5℃; the ambient humidity was ≥60%RH to reduce evaporation deviation.

[0103] The raw materials and their target concentrations for the aforementioned artificial saliva (pH 6.8, enzyme-free) are as follows: NaCl 0.400 g / L, KCl 1.200 g / L, CaCl2·2H2O 0.146 g / L, KH2PO4 0.340 g / L, NaHCO3 1.500 g / L, with purified water added to a final volume of 1L.

[0104] ② Storage modulus (G'), yield stress (τy), and viscosity (η, 37℃): G' of the film-forming liquid was measured using a rotational rheometer (1Hz, γ=1% small amplitude oscillation), and τy was obtained by stress scanning. Steady-state shear was measured at 10 s. -1 50 s-1 150s -1 η (37℃) was obtained.

[0105] If G' > 400 Pa or τy > 10 Pa, then it is abnormal thickening.

[0106] (2) Test results Table 1. Gel formation time and rheological properties of each guide sheath

[0107] As shown in the table above, during the formation of the guiding sheath in Embodiments 1-5 of the present invention, after the film-forming liquid is applied, the gelation time (t1) of the esophageal wall is about 1-3 seconds, which can ensure that the liquid forms a film on the esophageal wall quickly before entering the stomach; and from the perspective of the overall gelation time (t2) in the lumen, gelation will not occur in the lumen for 22-38 seconds, and t2 / t1≈13.7 (that is, t2 / t1≥7 is satisfied), which can ensure that the center of the lumen has enough time to remain unobstructed and avoid blockage, so that subsequent liquid food can pass smoothly.

[0108] Furthermore, the rheological properties of the guiding sheaths in Embodiments 1-5 of the present invention are as follows: at 37°C, they exhibit shear-thinning rheology (n≈0.4-0.7), and at low shear (10s... -1 The viscosity can reach as high as 240-530 mPa. s@10s -1 (Does not sag, facilitates continuous film formation), high shear (50-150s) -1 When the viscosity decreases to 45-130 mPa s (e.g., when swallowed, it quickly thins out, does not form a "clump", passes easily, and does not accumulate). At the same time, the low frequency G' (1Hz, 37℃) of the film-forming fluid is controlled in the range of 150-330Pa, and the yield stress is ≤9Pa to avoid the formation of an indeformable "plug" in the cavity.

[0109] Compared with Example 1, since no thickener was added in Comparative Example 1, the gelation time of the wall surface was prolonged, and the overall gelation of the cavity occurred earlier.

[0110] Compared with Example 1, although the raw material composition of Comparative Example 2 was unchanged, the triggering liquid and film-forming liquid were not distinguished, which caused the entire cavity to gel rapidly, making it difficult to use for subsequent liquid food feeding.

[0111] Compared with Example 1, Comparative Example 3 does not contain a complexing sustained-release agent, which causes the entire cavity to gel rapidly, making it difficult to use for subsequent liquid food intake.

[0112] 2. Membrane and channel parameters (1) Test method Film thickness and channel diameter: The guide sheaths prepared in each embodiment and comparative example were cryosectioned and tested by OCT (Optical Coherence Tomography).

[0113] Coefficient of friction μ: The friction stage using a material mimicking the esophageal mucosa (e.g., a friction platform). Figure 2 As shown, the simulated esophageal mucosa friction stage is a specialized device for testing the frictional performance of lubricating films. It forms a lubricating film within the surface, simulating the environment inside the esophagus. It is specifically designed to determine the coefficient of friction (μ≤0.06) of the lubricating film to verify its lubrication effect. The transparent silicone esophageal model is used to simulate the overall process of food / medication transport within the esophagus. The friction stage focuses on testing the performance of the lubricating film, while the esophageal model focuses on simulating the overall transport scenario. The coefficient of friction is measured under conditions of 1-2 N, 5-20 mm / s, and 37℃, following the ASTM G99 "Standard Test Method for Wear Testing with a Pin-on-Disk Apparatus" / equivalent SOP. A coefficient of friction μ (37℃) > 0.055 is considered abnormal.

[0114] (2) Test results Table 2. Membrane and channel parameters of each guide sheath

[0115] The guide sheaths prepared in Examples 1-4 of this invention have a membrane thickness (wall thickness) of 0.20-0.34 mm, which is uniform and can effectively protect the esophageal wall without affecting the central channel; the inner diameter of the central channel (diameter of the central cavity) is maintained at 6-7.5 mm, which can provide sufficient space for the subsequent delivery of liquid nutrition solutions or medicines; the coefficient of friction (37°C) of the guide sheath is 0.032-0.055, which can reduce the friction between the membrane layer and the esophageal wall and reduce the feeling of foreign body.

[0116] Because nanocellulose and plant wax emulsion were added to the film-forming solution in Example 1 as superhydrophobic outer layer components, the superhydrophobic outer layer components were deposited together with the gelation process to form a rough surface through in-situ self-assembly, thereby forming a superhydrophobic coating on the side surface of the liquid feeding guide sheath. This coating covers the outer surface of the liquid feeding guide sheath facing the central channel. Figure 3 It can reduce friction and adhesion between nutrient solution and the inner wall of the liquid feeding guide sheath, reduce infusion resistance and foreign body sensation; it can also prevent nutrient solution from leaking out, improve delivery efficiency, and reduce residue through the "self-cleaning effect".

[0117] Compared to Example 1, Comparative Example 1 did not add a thickener, resulting in a thinner film, a smaller channel diameter, and a larger coefficient of friction.

[0118] Compared with Example 1, Comparative Example 2, although the raw material composition remained unchanged, failed to distinguish between the triggering liquid and the film-forming liquid, resulting in channel blockage and a high coefficient of friction.

[0119] Compared with Example 1, Comparative Example 3 does not contain a complexing sustained-release agent, resulting in a narrower inner diameter of the central channel and a larger coefficient of friction.

[0120] 3. Degradation performance The guide sheaths of each embodiment and comparative example were placed in standard artificial gastric fluid (pH=1.2, containing 0.32% (w / v) pepsin, 37°C), with a solid-liquid ratio of 1:20 (g:mL) between the guide sheath and the standard artificial gastric fluid. The mass loss rate of each guide sheath within 30 min was tested.

[0121] Table 3. Mass loss rate (%) of each guiding sheath in standard simulated gastric fluid over 30 min.

[0122] As shown in the table above, the guide sheaths of Examples 1-5 of the present invention have a mass loss rate of ≥93% in standard artificial gastric fluid within 30 minutes, and there are no intact fragments. This indicates that the guide sheaths of the present invention have degradable properties and can be completely degraded and emptied under the action of gastric acid and digestive enzymes, with no risk of residue.

[0123] The guide sheaths of Comparative Examples 1-3 showed a decrease in mass loss rate within 30 minutes in standard artificial gastric fluid, with Comparative Example 2 even showing a risk of fragmentation.

[0124] 4. Quality Control and Release Standards The guide sheaths obtained in Examples 1-5 of this invention all meet the following requirements: (1) Sterility / microbial limits: Meet the sterility and microbial limits requirements of relevant medical devices or food in GB 15979-2024 Hygiene requirements for disposable sanitary products and ISO 11737-1-2018 Microbiological methods for sterilization of medical devices - Part 1 Determination of microbial communities on products, to prevent microbial contamination.

[0125] (2) Limits for heavy metals and impurities: Strictly control the content of heavy metals and impurities in raw materials and finished products, in accordance with the relevant safety standards of GB 2762—2022 National Food Safety Standard Limits for Contaminants in Food / Chinese Pharmacopoeia General Rules Limits.

[0126] (3) Sensory and thermophilic stability tests: The samples were stored at 5±3℃ (refrigerated), 25±2℃ / 60±10%RH (room temperature), and 40±2℃ / 75±5%RH (accelerated aging) conditions, respectively. The following performance parameters were tested at 0, 2, 4, 8, and 12 weeks. The changes that met the judgment criteria were considered to be without significant changes: Appearance, color, and odor: No layering, flocculation, or visible sediment; color difference ΔE* ≤ 2.0; Sensory evaluation methods and criteria: Sensory evaluation uses a 5-point pleasure scale, where 1 point = obviously unacceptable, 2 points = slightly poor, 3 points = generally acceptable, 4 points = good, and 5 points = very good. At least 10 simply trained evaluators will comprehensively score the appearance, color, odor, and overall taste of the samples under standard light and constant temperature conditions. The arithmetic mean of all evaluators' scores for each sample will be used as the sensory score, with an average score ≥ 4.0, and no individual samples should have a score ≤ 2. This score is used to determine whether the sensory quality of the finished product remains good under specified storage conditions.

[0127] The results showed that the sensory score was ≥4.

[0128] pH (25℃): ΔpH≤0.20 in the range of 5.5-6.5; Rheology and yield (37℃, 1Hz, γ=1%): G' change ≤15% and G'≤400Pa; τy change ≤2Pa and τy≤10Pa; Viscosity (37℃, steady-state shear 10, 50, 150s) -1 ): Δη≤20% for each grade; Film formation time sequence (37℃, artificial saliva pH 6.8): t1 is maintained for 1-3s with a variation of ≤0.3s; t2 (defined as in vitro static setting) is maintained for 20-40s with a relative variation of ≤15%. Friction coefficient μ (37℃): absolute value ≤ 0.055, and Δμ ≤ 0.005; Degradation rate at 30 min (artificial gastric fluid pH 1.2, pepsin 0.32% (w / v), 37℃): ≥95%; Microbial limits: Compliant with the relevant limits of GB 15979-2024 Hygienic requirements for disposable sanitary products and ISO 11737-1-2018 Microbiological methods for sterilization of medical devices - Part 1 Determination of microbial communities on the product.

[0129] Stress assessment: After three freeze-thaw cycles (two-phase cycles at -5±2℃ and 40±2℃, 12h per phase), the above indicators still meet the same judgment criteria.

[0130] The results showed that the guide sheaths of Examples 1-5 had good sensory characteristics, with no off-odor, discoloration, layering or obvious precipitation; they had good stability when stored at different temperatures of 5±3℃ (refrigerated), 25±2℃ / 60±10%RH (room temperature), and 40±2℃ / 75±5%RH (accelerated aging), and no significant changes in various performance parameters.

[0131] In summary, this invention utilizes two liquids as the main raw material components of the guiding sheath, namely the triggering liquid and the film-forming liquid. The liquids are easily taken orally, and after oral ingestion, they can form a guiding sheath. It has the following characteristics: (1) Film-forming properties: Two oral liquids (trigger liquid and film-forming liquid) are the main raw materials, and the order of "trigger liquid first, then film-forming liquid" must be strictly followed. After the trigger liquid is ingested first, a tubular temporary retention liquid layer will be formed on the esophageal wall (containing weak gel components: ionic cross-linking trigger agent and thickener, which can temporarily retain the liquid; the addition of thickener ensures that the viscosity of the trigger liquid meets the requirements of 240-530 mPa at low shear). s@10s -1 It can form a 50-120 μm retention fluid layer on the esophageal wall, which rapidly thins under high shear (such as during swallowing) and does not clump together. This retention fluid layer contains ionic cross-linking triggers, providing an ionic basis for subsequent film formation. When the film-forming fluid is subsequently ingested, it comes into contact with the ionic cross-linking triggers in the tubular temporary retention fluid layer, immediately triggering rapid cross-linking (if it contains a temperature-sensitive trigger, contact with the ionic cross-linking triggers will also trigger a phase transition, enhancing esophageal wall adhesion and film stability). Because this cross-linking reaction can be completed in seconds (1-3 seconds), a continuous and complete flexible lubricating channel, i.e., a guiding sheath, can be formed in situ on the esophageal wall before the liquid has completely entered the stomach. In addition, esophageal peristalsis (peristaltic waves) itself has a transit time of approximately 8-12 seconds, which also provides a window period for the reaction. Furthermore, this invention employs a rheological design that utilizes ion gradient-directed film formation (i.e., using a complexing sustained-release agent to ensure the concentration of the ion crosslinking trigger in the wall region reaches the crosslinking threshold first, resulting in film formation on the wall first (within seconds); the central cavity does not gel because the effective concentration of the ion crosslinking trigger is complexed and therefore falls below the gelation threshold) and shear thinning (the center thins during high shear conditions such as swallowing, becoming more like water than "glue") to ensure a "wall-first film formation, center-maintained patency" mechanism. This avoids blockage in the center of the cavity and maintains its patency, thus achieving the effect of "esophageal wall-first film formation, esophageal center passage maintained patency." The guiding sheath can then be used for the assisted delivery of food or medication that needs to be administered orally or nasally, suitable for patients with swallowing difficulties, esophageal stricture, or those requiring long-term oral administration of liquid nutrition or medication (however, it is not recommended for those with severe unassessed esophageal stricture or active gastroesophageal bleeding).

[0132] If the application order is reversed, for example, in Comparative Application Example 4, the film-forming solution first, when orally ingested, will slide directly into the stomach and hardly remain in the esophagus, thus failing to form a film. The subsequent triggering solution, although containing an ionic cross-linking trigger, lacks a film-forming matrix, ultimately only forming a slight localized gel and failing to form a continuous guiding sheath. Furthermore, after applying the triggering solution, a 5-15 second waiting period is required to establish a continuous temporary retention layer on the wall and the effective activity threshold of the ionic cross-linking trigger. If the waiting time is insufficient, the effective concentration of the localized ionic cross-linking trigger will not reach the cross-linking threshold, resulting in discontinuous film formation.

[0133] Sodium citrate added to the film-forming solution acts as a complexing and sustained-release agent. It can undergo a complexation reaction with the ionic crosslinking trigger to temporarily "bind" the ionic crosslinking trigger, so that the ionic crosslinking trigger is concentrated only in the wall area (where the calcium ion concentration is high and the diffusion distance is short). This causes the concentration of the ionic crosslinking trigger in the wall area to exceed the complexation inhibition threshold, achieving second-level crosslinking film formation in the wall area. Meanwhile, the ionic crosslinking trigger in the cavity center is lacking and has a low concentration. Premature gelation will not occur within 20-40 seconds, ensuring the unobstructed flow of the central channel and avoiding the blockage problem caused by "gelation in the cavity first" from the root.

[0134] (2) Degradable properties: The biodegradable polymer material used in this invention is the main film-forming material. After use, the guiding sheath can be completely degraded and emptied within 10-30 minutes, and will not remain in the body. There is no need to use other special methods to remove the guiding sheath, which would increase the patient's pain.

Claims

1. A method for preparing a guide sheath, characterized in that, Includes the following steps: (1) Dissolve the ionic crosslinking trigger in water, then mix it with a thickener and adjust the pH to 5.5-6.5 to obtain the trigger solution; The biodegradable polymer material is dispersed in water, then mixed with a complexing slow-release agent, and the pH value is adjusted to 5.5-6.5 to obtain a film-forming solution. (2) In the pipeline, first apply the triggering liquid and wait for 5-15 seconds to form a pipeline-shaped temporary stagnant liquid layer; then apply the film-forming liquid on the pipeline-shaped temporary stagnant liquid layer and complete the application of the film-forming liquid within 30 seconds to form the guiding sheath; In step (1), the ionic crosslinking trigger is a salt containing a divalent metal cation and / or an alkaline substance containing a divalent metal cation.

2. The preparation method according to claim 1, characterized in that, In step (2), both the application triggering liquid and the application film-forming liquid are administered orally or via the nose.

3. The preparation method according to claim 1, characterized in that, In step (1), the raw material components of the triggering liquid, by mass percentage, include: 0.7-1.5 wt% ionic crosslinking triggering agent and 0.05-0.15 wt% thickener.

4. The preparation method according to claim 1, characterized in that, In step (1), the film-forming liquid contains 0.2-1 wt% of degradable polymeric material and 0.15-0.30 wt% of complexing sustained-release agent by mass percentage.

5. The preparation method according to claim 1, characterized in that, In step (1), the biodegradable polymer material is at least one of sodium alginate, sodium hyaluronate, gelatin, and gellan gum.

6. The preparation method according to claim 1, characterized in that, In step (1), the thickener is sodium carboxymethyl cellulose and / or xanthan gum.

7. The preparation method according to claim 1, characterized in that, In step (1), the complexing sustained-release agent is at least one of citrate, gluconate, lactate, tartrate, phytate, and pyrophosphate.

8. The preparation method according to claim 1, characterized in that, In step (1), the triggering liquid also contains a temperature-sensitive triggering agent and / or a surfactant.

9. The guide sheath prepared by the method according to any one of claims 1-8, characterized in that, The guide sheath is a hollow tubular structure, including a tube wall and a central cavity. The thickness of the tube wall is 0.1-0.5 mm, and the diameter of the central cavity is 5-10 mm.

10. The use of the guiding sheath of claim 9 in assisting feeding or drug delivery.

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