The related literatures at home and abroad in the preparation of pharmaceutical excipients hydroxypropyl methylcellulose (HPMC) in recent years were reviewed, analyzed and summarized, and its application in solid preparations, liquid preparations, sustained and controlled release preparations, capsule preparations, gelatin the latest applications in the field of new formulations such as adhesive formulations and bioadhesives. Due to the difference in relative molecular weight and viscosity of HPMC, it has the characteristics and uses of emulsification, adhesion, thickening, viscosity increasing, suspending, gelling and film-forming. It is widely used in pharmaceutical preparations and will play a greater role in the field of preparations. With the in-depth study of its properties and the improvement of formulation technology, HPMC will be more widely used in the research of new dosage forms and new drug delivery systems, thereby promoting the continuous development of formulations.

［Key words］ hydroxypropyl methylcellulose; pharmaceutical preparations; pharmaceutical excipients.

Pharmaceutical excipients are not only the material basis for the formation of raw drug preparations, but also related to the difficulty of the preparation process, drug quality, stability, safety, drug release rate, mode of action, clinical efficacy, and the development of new dosage forms and new routes of administration. closely related. The emergence of new pharmaceutical excipients often promotes the improvement of preparation quality and the development of new dosage forms. Hydroxypropyl methylcellulose (HPMC) is one of the most popular pharmaceutical excipients at home and abroad. Due to its different relative molecular weight and viscosity, it has the functions of emulsifying, binding, thickening, thickening, suspending, and glueing. Features and uses such as coagulation and film formation are widely used in pharmaceutical technology. This article mainly reviews the application of hydroxypropyl methylcellulose (HPMC) in formulations in recent years.

1. Basic properties of HPMC

Hydroxypropyl methyl cellulose (HPMC), the molecular formula is C8H15O8-(C10 H18O6) n- C8H15O8, and the relative molecular mass is about 86 000. This product is a semi-synthetic material, which is part of methyl and part of polyhydroxypropyl ether of cellulose. It can be produced in two ways: One is that methyl cellulose of a suitable grade is treated with NaOH and then reacted with propylene oxide under high temperature and high pressure. The reaction time must last long enough to allow the methyl and hydroxypropyl to form ether bonds It is connected to the anhydroglucose ring of cellulose in the form of cellulose, and can reach the desired degree; the other is to treat cotton linter or wood pulp fiber with caustic soda, and then react with chlorinated methane and propylene oxide successively, and then further refine it. , crushed into fine and uniform powder or granules.

The color of this product is white to milky white, odorless and tasteless, and the form is granular or fibrous easy-flowing powder. This product can be dissolved in water to form a clear to milky white colloidal solution with a certain viscosity. The sol-gel interconversion phenomenon can occur due to the temperature change of the solution with a certain concentration.

Due to the difference in the content of these two substituents in the structure of methoxy and hydroxypropyl, various types of products have appeared. In specific concentrations, various types of products have specific characteristics. Viscosity and thermal gelation temperature, therefore have different properties and can be used for different purposes. Pharmacopoeia of various countries has different regulations and representations on the model: The European Pharmacopoeia is based on the various grades of different viscosities and different degrees of substitution of products sold in the market, expressed by grades plus numbers, and the unit is "mPa s". In the US Pharmacopoeia, 4 digits are added after the generic name to indicate the content and type of each substituent of hydroxypropyl methylcellulose, such as hydroxypropyl methylcellulose 2208. The first two digits represent the approximate value of the methoxy group. Percentage, the last two digits represent the approximate percentage of hydroxypropyl.

Calocan's hydroxypropyl methylcellulose has 3 series, namely E series, F series and K series, each series has a variety of models to choose from. E series are mostly used as film coatings, used for tablet coating, closed tablet cores; E, F series are used as viscosifiers and release retarding agents for ophthalmic preparations, suspending agents, thickeners for liquid preparations, tablets and Binders of granules; K series are mostly used as release inhibitors and hydrophilic gel matrix materials for slow and controlled release preparations.

Domestic manufacturers mainly include Fuzhou No. 2 Chemical Factory, Huzhou Food and Chemical Co., Ltd., Sichuan Luzhou Pharmaceutical Accessories Factory, Hubei Jinxian Chemical Factory No. 1, Feicheng Ruitai Fine Chemical Co., Ltd., Shandong Liaocheng Ahua Pharmaceutical Co., Ltd., Xi'an Huian chemical plants, etc.

2. Advantages of HPMC

HPMC has become one of the most widely used pharmaceutical excipients at home and abroad, because HPMC has advantages that other excipients do not have.

2.1 Cold water solubility

Soluble in cold water below 40 ℃ or 70% ethanol, basically insoluble in hot water above 60 ℃, but can gel.

2.2 Chemically inert

HPMC is a kind of non-ionic cellulose ether, its solution has no ionic charge and does not interact with metal salts or ionic organic compounds, so other excipients do not react with it during the production process of preparations.

2.3 Stability

It is relatively stable to both acid and alkali, and can be stored for a long time between pH 3 and 11 without significant change in viscosity. The aqueous solution of HPMC has anti-mildew effect and maintains good viscosity stability during long-term storage. The pharmaceutical excipients using HPMC have better quality stability than those using traditional excipients (such as dextrin, starch, etc.).

2.4 Viscosity Adjustability

Different viscosity derivatives of HPMC can be mixed in different proportions, and its viscosity can be changed according to a certain law, and has a good linear relationship, so the proportion can be selected according to the needs.

2.5 Metabolic inertness

HPMC is not absorbed or metabolized in the body, and does not provide heat, so it is a safe pharmaceutical preparation excipient. 2.6 Safety It is generally considered that HPMC is a non-toxic and non-irritating material, the median lethal dose for mice is 5 g·kg - 1 , and the median lethal dose for rats is 5. 2 g · kg - 1 . The daily dose is harmless to the human body.

3. Application of HPMC in formulations

3.1 As film coating material and film-forming material

Using HPMC as a film-coated tablet material, the coated tablet has no obvious advantages in masking the taste and appearance compared with traditional coated tablets such as sugar-coated tablets, but its hardness, friability, moisture absorption, disintegration degree. , coating weight gain and other quality indicators are better. The low-viscosity grade of this product is used as a water-soluble film coating material for tablets and pills, and the high-viscosity grade is used as a film coating material for organic solvent systems, usually at a concentration of 2% to 20%.

Zhang Jixing et al. used the effect surface method to optimize the premix formulation with HPMC as the film coating. Taking the film-forming material HPMC, the amount of polyvinyl alcohol and plasticizer polyethylene glycol as the investigation factors, the tensile strength and permeability of the film and the The viscosity of the film coating solution is the inspection index, and the relationship between the inspection index and the inspection factors is described by a mathematical model, and the optimal formulation process is finally obtained. Its consumption is respectively film-forming agent hydroxypropyl methylcellulose (HPMCE5) 11.88 g, polyvinyl alcohol 24.12 g, plasticizer polyethylene glycol 13.00 g, and the coating suspension viscosity is 20 mPa·s, the permeability and tensile strength of the film reached the best effect. Zhang Yuan improved the preparation process, used HPMC as a binder to replace starch slurry, and changed Jiahua tablets to film-coated tablets to improve the quality of its preparations, improve its hygroscopicity, easy to fade, loose tablets, splintered and other problems, enhance the tablet stability. The optimal formulation process was determined by orthogonal experiments, namely, the slurry concentration was 2% HPMC in 70% ethanol solution during coating, and the stirring time during granulation was 15 min. Results The Jiahua film-coated tablets prepared by the new process and prescription were greatly improved in appearance, disintegration time and core hardness than those produced by the original prescription process, and the qualified rate of the film-coated tablets was greatly improved. reached more than 95%. Liang Meiyi, Lu Xiaohui, etc. also used hydroxypropyl methylcellulose as the film-forming material to prepare the patinae colon positioning tablet and the matrine colon positioning tablet, respectively. affect drug release. Huang Yunran prepared Dragon's Blood Colon Positioning Tablets, and applied HPMC to the coating solution of the swelling layer, and its mass fraction was 5%. It can be seen that HPMC can be widely used in colon-targeted drug delivery system.

Hydroxypropyl methylcellulose is not only an excellent film coating material, but also can be used as a film-forming material in film formulations. Wang Tongshun etc. are optimized to the prescription of compound zinc licorice and aminolexanol oral composite film, with the flexibility, uniformity, smoothness, transparency of film agent as investigation index, obtain optimal prescription is PVA 6.5 g, HPMC 0.1 g and 6.0 g of propylene glycol meet the requirements of slow-release and safety, and can be used as the preparation prescription of the composite film.

3.2 as binder and disintegrant

The low viscosity grade of this product can be used as a binder and disintegrant for tablets, pills and granules, and the high viscosity grade can only be used as a binder. The dosage varies with different models and requirements. Generally, the dosage of binder for dry granulation tablets is 5%, and the dosage of binder for wet granulation tablets is 2%.

Li Houtao et al screened the binder of tinidazole tablets. 8% polyvinylpyrrolidone (PVP-K30), 40% syrup, 10% starch slurry, 2.0% hydroxypropyl methylcellulose K4 (HPMCK4M), 50% ethanol were investigated as the adhesion of tinidazole tablets in turn. preparation of tinidazole tablets. The appearance changes of plain tablets and after coating were compared, and the friability, hardness, disintegration time limit and dissolution rate of different prescription tablets were measured. Results The tablets prepared by 2.0% hydroxypropyl methylcellulose were glossy, and the friability measurement found no edge chipping and cornering phenomenon, and after coating, the tablet shape was complete and the appearance was good. Therefore, tinidazole tablets prepared with 2.0% HPMC-K4 and 50% ethanol as binders were used. Guan Shihai studied the formulation process of Fuganning Tablets, screened the adhesives, and screened 50% ethanol, 15% starch paste, 10% PVP and 50% ethanol solutions with compressibility, smoothness, and friability as evaluation indicators. , 5% CMC-Na and 15% HPMC solution (5 mPa s). Results The sheets prepared by 50% ethanol, 15% starch paste, 10% PVP 50% ethanol solution and 5% CMC-Na had a smooth surface, but poor compressibility and low hardness, which could not meet the needs of coating; 15% HPMC solution ( 5 mPa·s), the surface of the tablet is smooth, the friability is qualified, and the compressibility is good, which can meet the needs of coating. Therefore, HPMC ( 5 mPa s) was chosen as the adhesive.

3.3 as suspending agent

The high-viscosity grade of this product is used as a suspending agent to prepare a suspension-type liquid preparation. It has good suspending effect, is easy to redisperse, does not stick to the wall, and has fine flocculation particles. The usual dosage is 0.5% to 1.5%. Song Tian et al. used commonly used polymer materials (hydroxypropyl methylcellulose, sodium carboxymethylcellulose, povidone, xanthan gum, methylcellulose, etc.) as suspending agents to prepare racecadotril. dry suspension. Through the sedimentation volume ratio of different suspensions, the redispersibility index, and the rheology, suspension viscosity and microscopic morphology were observed, and the stability of the drug particles under the accelerated experiment was also investigated. Results The dry suspension prepared with 2% HPMC as the suspending agent had a simple process and good stability.

Compared with methyl cellulose, hydroxypropyl methyl cellulose has the characteristics of forming a clearer solution, and only a very small amount of non-dispersed fibrous substances exist, so HPMC is also commonly used as a suspending agent in ophthalmic preparations. Liu Jie et al. used HPMC, hydroxypropyl cellulose (HPC), carbomer 940, polyethylene glycol (PEG), sodium hyaluronate (HA) and the combination of HA/HPMC as suspending agents to prepare different specifications For Ciclovir ophthalmic suspension, sedimentation volume ratio, particle size and redispersibility are selected as the inspection indicators to screen the best suspending agent. The results show that the acyclovir ophthalmic suspension prepared by 0.05% HA and 0.05% HPMC as the suspending agent, the sedimentation volume ratio is 0.998, the particle size is uniform, the redispersibility is good, and the preparation is stable Sex increases.

3.4 As a blocker, slow and controlled release agent and pore-forming agent

The high-viscosity grade of this product is used for the preparation of hydrophilic gel matrix sustained-release tablets, blockers and controlled-release agents of mixed-material matrix sustained-release tablets, and has the effect of delaying drug release. Its concentration is 10% to 80%. Low-viscosity grades are used as porogens for sustained-release or controlled-release preparations. The initial dose required for the therapeutic effect of such tablets can be quickly reached, and then the sustained-release or controlled-release effect is exerted, and the effective blood drug concentration is maintained in the body. . Hydroxypropyl methylcellulose is hydrated to form a gel layer when it meets water. The mechanism of drug release from the matrix tablet mainly includes the diffusion of the gel layer and the erosion of the gel layer. Jung Bo Shim et al prepared carvedilol sustained-release tablets with HPMC as sustained-release material.

Hydroxypropyl methylcellulose is also widely used in the sustained-release matrix tablets of traditional Chinese medicine, and most of the active ingredients, effective parts and single preparations of traditional Chinese medicine are used. Liu Wen et al. used 15% hydroxypropyl methylcellulose as the matrix material, 1% lactose and 5% microcrystalline cellulose as fillers, and prepared Jingfang Taohe Chengqi Decoction into oral matrix sustained-release tablets. The model is the Higuchi equation. The formula composition system is simple, the preparation is easy, and the release data is relatively stable, which meets the requirements of the Chinese Pharmacopoeia. Tang Guanguang et al. used total saponins of Astragalus as a model drug, prepared HPMC matrix tablets, and explored the factors affecting the drug release from the effective parts of traditional Chinese medicine in HPMC matrix tablets. Results As the dosage of HPMC increased, the release of astragaloside decreased, and the release percentage of the drug had a nearly linear relationship with the dissolution rate of the matrix. In the hypromellose HPMC matrix tablet, there is a certain relationship between the release of the effective part of the traditional Chinese medicine and the dosage and type of HPMC, and the release process of the hydrophilic chemical monomer is similar to it. Hydroxypropyl methylcellulose is not only suitable for hydrophilic compounds, but also for non-hydrophilic substances. Liu Guihua used 17% hydroxypropyl methylcellulose (HPMCK15M) as the sustained-release matrix material, and prepared Tianshan Xuelian sustained-release matrix tablets by wet granulation and tableting method. The sustained-release effect was obvious, and the preparation process was stable and feasible.

Hydroxypropyl methylcellulose is not only applied to the sustained-release matrix tablets of the active ingredients and effective parts of traditional Chinese medicine, but also more and more used in traditional Chinese medicine compound preparations. Wu Huichao et al. used 20% hydroxypropyl methyl cellulose (HPMCK4M) as the matrix material, and used the powder direct compression method to prepare the Yizhi hydrophilic gel matrix tablet that could release the drug continuously and stably for 12 hours. Saponin Rg1, ginsenoside Rb1 and Panax notoginseng saponin R1 were used as evaluation indicators to investigate the release in vitro, and the drug release equation was fitted to study the drug release mechanism. Results The drug release mechanism conformed to the zero-order kinetic equation and the Ritger-Peppas equation, in which the geniposide was released by non-Fick diffusion, and the three components in Panax notoginseng were released by skeletal erosion.

3.5 Protective glue as thickener and colloid

When this product is used as a thickener, the usual percentage concentration is 0.45% to 1.0%. It can also increase the stability of the hydrophobic glue, form a protective colloid, prevent particles from coalescing and agglomerating, thereby inhibiting the formation of sediments. Its common percentage concentration is 0.5% to 1.5%.

Wang Zhen et al. used the L9 orthogonal experimental design method to investigate the preparation process of medicinal activated carbon enema. The optimum process conditions for the final determination of medicinal activated carbon enema are to use 0.5% sodium carboxymethyl cellulose and 2.0% hydroxypropyl methylcellulose (HPMC contains 23.0% methoxyl group, hydroxypropoxyl Base 11.6%) as a thickener, the process conditions help to enhance the stability of medicinal activated carbon. Zhang Zhiqiang et al. developed a pH-sensitive levofloxacin hydrochloride ophthalmic ready-to-use gel with sustained-release effect, using carbopol as the gel matrix and hydroxypropyl methylcellulose as the thickening agent. Optimal prescription by experiment, finally obtains optimal prescription is levofloxacin hydrochloride 0.1 g, carbopol (9400) 3 g, hydroxypropyl methylcellulose (E50 LV) 20 g, disodium hydrogen phosphate 0.35 g, phosphoric acid 0.45 g of sodium dihydrogen, 0.50 g of sodium chloride, 0.03 g of ethyl paraben, and water were added to make 100 mL. In the test, the author screened the hydroxypropyl methylcellulose METHOCEL series of Colorcon Company with different specifications (K4M, E4M, E15 LV, E50LV) to prepare thickeners with different concentrations, and the result selected HPMC E50 LV as the thickener. Thickener for pH-sensitive levofloxacin hydrochloride instant gels.

3.6 as capsule material

Usually, the capsule shell material of capsules is mainly gelatin. The production process of the capsule shell is simple, but there are some problems and phenomena such as poor protection against moisture and oxygen-sensitive drugs, reduced drug dissolution, and delayed disintegration of the capsule shell during storage. Therefore, hydroxypropyl methylcellulose is used as a substitute for gelatin capsules for the preparation of capsules, which improves the capsule manufacturing formability and the use effect, and has been widely promoted at home and abroad.

Using theophylline as a control drug, Podczeck et al. found that the drug dissolution rate of capsules with hydroxypropyl methylcellulose shells was greater than that of gelatin capsules. The reason for the analysis is that the disintegration of HPMC is the disintegration of the entire capsule at the same time, while the disintegration of the gelatin capsule is the disintegration of the network structure first, and then the disintegration of the entire capsule, so the HPMC capsule is more suitable for Capsule shells for immediate release formulations. Chiwele et al. also obtained similar conclusions and compared the dissolution of gelatin, gelatin/polyethylene glycol and HPMC shells. The results showed that HPMC shells were rapidly dissolved under different pH conditions, while gelatin capsules It is greatly affected by different pH conditions. Tang Yue et al. screened a new type of capsule shell for low-dose drug blank dry powder inhaler carrier system. Compared with the capsule shell of hydroxypropyl methylcellulose and the capsule shell of gelatin, the stability of the capsule shell and the properties of the powder in the shell under different conditions were investigated, and the friability test was carried out. The results show that compared with gelatin capsules, HPMC capsule shells are better in stability and powder protection, have stronger moisture resistance, and have a lower friability than gelatin capsule shells, so HPMC capsule shells are more suitable for Capsules for dry powder inhalation.

3.7 as a bioadhesive

Bioadhesion technology uses excipients with bioadhesive polymers. By adhering to the biological mucosa, it enhances the continuity and tightness of the contact between the preparation and the mucosa, so that the drug is slowly released and absorbed by the mucosa to achieve the purpose of treatment. It is widely used at present. Treatment of diseases of the gastrointestinal tract, vagina, oral mucosa and other parts.

Gastrointestinal bioadhesion technology is a new drug delivery system developed in recent years. It not only prolongs the residence time of drug preparations in the gastrointestinal tract, but also improves the contact performance between the drug and the cell membrane at the absorption site, changes the fluidity of the cell membrane, and makes the The penetration of the drug into the small intestinal epithelial cells is enhanced, thereby improving the bioavailability of the drug. Wei Keda et al. screened the tablet core prescription with the dosage of HPMCK4M and Carbomer 940 as the investigation factors, and used a self-made bioadhesion device to measure the peeling force between the tablet and the simulated biofilm by the quality of the water in the plastic bag. , and finally selected the content of HPMCK40 and carbomer 940 to be 15 and 27.5 mg in the optimal prescription area of NCaEBT tablet cores, respectively, to prepare NCaEBT tablet cores, indicating that bioadhesive materials (such as hydroxypropyl methylcellulose) can significantly reduce the Improve the adhesion of the preparation to the tissue.

Oral bioadhesive preparations are also a new type of drug delivery system that has been studied more in recent years. Oral bioadhesive preparations can adhere the drug to the affected part of the oral cavity, which not only prolongs the residence time of the drug in the oral mucosa, but also protects the oral mucosa. Better therapeutic effect and improved drug bioavailability. Xue Xiaoyan et al. optimized the formulation of insulin oral adhesive tablets, using apple pectin, chitosan, carbomer 934P, hydroxypropyl methylcellulose (HPMC K392) and sodium alginate as bioadhesive materials, and freeze-drying to prepare oral insulin. Adhesive double layer sheet. The prepared insulin oral adhesive tablet has a porous sponge-like structure, which is favorable for insulin release, and has a hydrophobic protective layer, which can ensure the unidirectional release of the drug and avoid the loss of the drug. Hao Jifu et al. also prepared blue-yellow beads oral bioadhesive patches using Baiji glue, HPMC and carbomer as bioadhesive materials.

In vaginal drug delivery systems, bioadhesion technology has also been widely used. Zhu Yuting et al. used carbomer (CP) and HPMC as adhesive materials and sustained-release matrix to prepare clotrimazole bioadhesive vaginal tablets with different formulations and ratios, and measured their adhesion, adhesion time and swelling percentage in the environment of artificial vaginal fluid. , the suitable prescription was screened out as CP-HPMC1: 1, the prepared adhesive sheet had good adhesion performance, and the process was simple and feasible.

3.8 as topical gel

As an adhesive preparation, gel has a series of advantages such as safety, beauty, easy cleaning, low cost, simple preparation process, and good compatibility with drugs. Direction of development. For example, transdermal gel is a new dosage form that has been studied more in recent years. It can not only avoid the destruction of drugs in the gastrointestinal tract and reduce the peak-to-trough variation of blood drug concentration, but also has become one of the effective drug release systems to overcome drug side effects. .

Zhu Jingjie et al. studied the effect of different matrices on the release of scutellarin alcohol plastid gel in vitro, and screened with carbomer (980NF) and hydroxypropyl methylcellulose (HPMCK15M) as gel matrices, and obtained scutellarin suitable for scutellarin. Gel matrix of alcohol plastids. The experimental results show that 1. 0% carbomer, 1. 5% carbomer, 1. 0% carbomer + 1. 0% HPMC, 1. 5% carbomer + 1. 0% HPMC as gel matrix Both are suitable for scutellarin alcohol plastids. During the experiment, it was found that HPMC could change the drug release mode of carbomer gel matrix by fitting the kinetic equation of drug release, and 1.0% HPMC could improve 1.0% carbomer matrix and 1.5% carbomer matrix. The reason may be that HPMC expands faster, and the rapid expansion in the early stage of the experiment makes the molecular gap of the carbomer gel material larger, thereby accelerating its drug release rate. Zhao Wencui et al. used carbomer-934 and hydroxypropyl methylcellulose as carriers to prepare norfloxacin ophthalmic gel. The preparation process is simple and feasible, and the quality conforms to the ophthalmic gel of "Chinese Pharmacopoeia" (2010 edition) Quality requirements.

3.9 Precipitation inhibitor for self-microemulsifying system

Self-microemulsifying drug delivery system (SMEDDS) is a new type of oral drug delivery system, which is a homogeneous, stable and transparent mixture composed of drug, oil phase, emulsifier and co-emulsifier. The composition of the prescription is simple, and the safety and stability are good. For poorly soluble drugs, water-soluble fiber polymer materials, such as HPMC, polyvinylpyrrolidone (PVP), etc., are often added to make the free drugs and the drugs encapsulated in the microemulsion achieve supersaturated dissolution in the gastrointestinal tract, so as to increase the drug solubility and improve the bioavailability.

Peng Xuan et al. prepared a silibinin supersaturated self-emulsifying drug delivery system (S-SEDDS). Oxyethylene hydrogenated castor oil (Cremophor RH40), 12% caprylic capric acid polyethylene glycol glyceride (Labrasol) as co-emulsifier, and 50 mg·g-1 HPMC. Adding HPMC to SSEDDS can supersaturate free silibinin to dissolve in S-SEDDS and prevent silibinin from precipitating out. Compared with traditional self-microemulsion formulations, a larger amount of surfactant is usually added to prevent incomplete drug encapsulation. The addition of HPMC can keep the solubility of silibinin in the dissolution medium relatively constant, reducing the emulsification in self-microemulsion formulations. dosage of the agent.

4. Conclusion

It can be seen that HPMC has been widely used in preparations due to its physical, chemical and biological properties, but HPMC also has many shortcomings in preparations, such as the phenomenon of pre- and post-burst release. methyl methacrylate) to improve. At the same time, some researchers investigated the application of osmotic theory in HPMC by preparing carbamazepine sustained-release tablets and verapamil hydrochloride sustained-release tablets to further study its release mechanism. In a word, more and more researchers are doing a lot of work for the better application of HPMC in preparations, and with the in-depth study of its properties and the improvement of preparation technology, HPMC will be more widely used in new dosage forms and new dosage forms. In the research of pharmaceutical system, and then promote the continuous development of pharmacy.

original source: https://www.ihpmc.com/news/application-of-pharmaceutical-excipients-hydroxypropyl-methyl-cellulose-in-preparations/

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