Development of new drug delivery system for protein drugs using silicone (I)

Kajihara, Masako; Sugie, Toshihiko; Mizuno, Masayuki; Tamura, Nobuyuki; Sano, Akihiko; Fujioka, Keiji; Kashiwazaki, Yasuo; Yamaoka, Takashi; Sugawara, Shuichi; Urabe, Yosuke

doi:10.1016/s0168-3659(99)00257-6

Cited by 37 publications

(39 citation statements)

References 15 publications

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“…3,4) For example, double-layered formulation IFN/HSA-3 was prepared as follows. An aqueous solution (28.2 g) of IFN (114 MU/ml) was mixed with 2.5 g of gelatin and freeze-dried.…”

Section: Novel Drug Deliverymentioning

confidence: 99%

“…Silicone was originally investigated as carrier materials for lipophilic drugs, and several DDS products have been developed. Although silicone had been believed not to be suitable for delivering water-soluble macromolecules, Hsieh et al 1) and Fujioka et al [2][3][4] reported in the 1980s that proteins could be continuously released from silicone. As described above, a number of studies have been conducted on DDS using silicone.…”

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confidence: 99%

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Novel Drug Delivery Device Using Silicone: Controlled Release of Insoluble Drugs or Two Kinds of Water-Soluble Drugs.

Kajihara¹,

Sugie²,

Maeda³

et al. 2003

CHEMICAL & PHARMACEUTICAL BULLETIN

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Aiming at improving drug efficacy, minimizing side effects and promoting patient compliance, extensive studies on drug delivery system (DDS) have been conducted. For example, implantable DDS has been investigated in order to achieve prolonged effects and/or deliver water-soluble drugs which are poorly absorbed by the gastrointestinal tract. Since implantable DDS is administered inside a body, drug carrier materials should be biocompatible and resistant against sterilization. Silicone has been extensively used as a drug carrier material for implantable DDS, because it has appropriate features for such requirements.Drug release mechanism from silicone carrier differs depending on the physiochemical properties of the drugs as illustrated in Fig. 1. Silicone was originally investigated as carrier materials for lipophilic drugs, and several DDS products have been developed. Although silicone had been believed not to be suitable for delivering water-soluble macromolecules, Hsieh et al. 1) and Fujioka et al. [2][3][4] reported in the 1980s that proteins could be continuously released from silicone. As described above, a number of studies have been conducted on DDS using silicone. However, investigations have not been perfect to satisfy various medical requirements as pointed out subsequently. First, sustained release of insoluble drugs has been desired. On purpose to develop new vaccine formulations which are effective for a long period of time, sustained release of antigens from silicone carrier has been attempted 5) ; viruses or bacteria as antigens are insoluble either in water or in organic solvents. However, sustained release of insoluble drugs from silicone has not been reported so far. Second, simultaneous release of two kinds of watersoluble drugs is often required. For example, simultaneous release of two anti-cancer drugs would bring synergy effect without patients' burden by reducing administration frequency. Interferon (IFN) has anti-cancer and anti-viral effects, and its efficacy is reportedly enhanced by other drugs. 6) In other aspect of vaccine DDS, simultaneous release of antigens and ajuvants is expected to improve its efficacy. Since these drugs are often water-soluble, a method to release two kinds of water-soluble drugs with suitable release profile should be indispensable.In this study, we investigated technologies to control the release of drugs with different solubility from silicone carriers. This is the first report on the sustained release of insoluble drugs and the simultaneous release of two kinds of watersoluble drugs from silicone carrier. Drug release mechanism from silicone carrier differs depending on physicochemical properties of the drug. So far, there have been few reports on controlled release of insoluble drug and on simultaneous release of two kinds of water-soluble drugs. The purposes of this study are to establish methods for (1) continuous release of insoluble drug, and (2) release of two kinds of water-soluble drugs from silicone carrier. Polystyrene beads (PSTB) and proteins...

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“…3,4) For example, double-layered formulation IFN/HSA-3 was prepared as follows. An aqueous solution (28.2 g) of IFN (114 MU/ml) was mixed with 2.5 g of gelatin and freeze-dried.…”

Section: Novel Drug Deliverymentioning

confidence: 99%

mentioning

confidence: 99%

Novel Drug Delivery Device Using Silicone: Controlled Release of Insoluble Drugs or Two Kinds of Water-Soluble Drugs.

Kajihara¹,

Sugie²,

Maeda³

et al. 2003

CHEMICAL & PHARMACEUTICAL BULLETIN

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“…However, once HSA is released, VD 3 diffusion is no longer suppressed. On the contrary, since water-filled channels were formed inside the formulation, 9,10) remained VD 3 contacts with water easier than initial phase and the fact accelerates VD 3 release (Fig. 4a).…”

Section: Discussionmentioning

confidence: 99%

Novel Method to Control Release of Lipophilic Drugs with High Potency from Silicone.

Kajihara¹,

Sugie²,

Sano³

et al. 2003

CHEMICAL & PHARMACEUTICAL BULLETIN

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Silicone, which is mechanically flexible and biologically inert, has been extensively used for many biomedical applications. In the 1970s, much interest was focused on the use of silicone as a delivery system for lipophilic drugs. Norplant ®6) and Compudose ®7) are examples of commercialized silicone DDS and effective for long term with single administration, that is, five years and 100 d, respectively. In this way silicone was found to be suitable as DDS carrier material for lipophilic drugs. When a lipophilic drug which has high potency at low concentrations is applied for a silicone DDS, drug release rate should be strictly controlled. It has been reported that factors such as physicochemical properties of drugs, additives, membrane thickness and drug loading influence drug release rate from silicone matrix. [1][2][3][4][5] In this study, using vitamin D 3 (VD 3 ) as an example of lipophilic drugs which are highly potent at low concentrations, we investigated novel method to suppress initial burst and to modify drug release rate from silicone. This is the first report on continuous release of VD 3 from silicone. A.). The MDX4-4210 is cross-linked by hydrosilylation when a base and a curing agent are mixed in a mass ratio of 10 : 1. The base consists mainly of dimethylvinylsiloxy-terminated polydimethylsiloxane, and the curing agent consists of a platinum catalyst and a cross-linker. Q7-4750 is cross-linked by hydrosilylation when Part A and Part B are mixed in equal portions. Part A consists of dimethylvinylsiloxy-terminated poly(dimethylsiloxane-co-methylvinylsiloxane) and a platinum catalyst. Part B consists of the same siloxane as Part A and a cross-linker. RX-50 is a tube sample prepared using Q7-4750. The tensile strength of MDX4-4210 and Q7-4750 is higher than 550 and 1250 psi, respectively. Medical Adhesive Silicone Type A is a one-component silicone adhesive.1a,25-(OH) 2 VD 3 was purchased from Biomol Research Laboratories, Inc. (PA, U.S.A.). 2,6-Di-t-butyl-p-cresol (BHT), DL-a -tocopherol (TP) and sodium azide were purchased from Nacalai Tesque, Inc. (Kyoto, Japan). Sudan II, which is a dye modeling for lipophilic drugs, was purchased from Wako Pure Chemicals Industries, Ltd. (Osaka, Japan). Bovine serum albumin (BSA) and human serum albumin (HSA) Buminate ® were purchased from SIGMA CHEMICAL CO. (MO, U.S.A.) and Baxter Healthcare Corporation (IL, U.S.A.), respectively. Figure 1 shows the structure of the silicone formulations, and Table 1 lists their compositions. Preparation of VD 3 Silicone FormulationsMatrix Formulation (VD-1 and VD-2): The base and the curing agent of MDX4-4210 were mixed in a mass ratio of 10 : 1. TP and BHT (0.5% w/w each) were added to this mixture as anti-oxidants. Freeze-dried HSA powder (434.8 mg) was mixed with 1.00 g of MDX4-4210 to prepare VD-2. Each mixture was cast into a sheet, and 130 ml of VD 3 ethanol solution (concentration: 1.0 mg/ml) were placed on each film. Then, ethanol was removed under nitrogen flow and each mixture was kneaded to have VD 3 homogeneously...

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“…The excipient-modified silicone elastomer rods were based on implantable matrix and covered-rod formulations described previously in the literature [34][35][36][37][38]. The directly compressed tablets represent the most common and inexpensive drug dosage form, with widespread use for oral administration and occasionally used vaginally.…”

Section: Discussionmentioning

confidence: 99%

Sustained release of proteins from a modified vaginal ring device

Morrow

Woolfson

Donnelly

et al. 2011

European Journal of Pharmaceutics and Biopharmaceutics

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A new vaginal ring technology, the insert vaginal ring (InVR), is presented. The InVR overcomes the current shortfall of conventional vaginal rings (VRs) that are generally ineffectual for the delivery of hydrophilic and/or macromolecular actives, including peptides, proteins and antibodies, due to their poor permeation characteristics in the hydrophobic polymeric elastomers from which VRs are usually fabricated. Release of the model protein BSA from a variety of insert matrices for the InVR is demonstrated, including modified silicone rods, directly compressed tablets and lyophilised gels, which collectively provided controlled release profiles from several hours to beyond 4 weeks. Furthermore, the InVR was shown to deliver over 1 mg of the monoclonal antibody 2F5 from a single device, offering a potential means of protecting women against the transmission of HIV.

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Development of new drug delivery system for protein drugs using silicone (I)

Cited by 37 publications

References 15 publications

Novel Drug Delivery Device Using Silicone: Controlled Release of Insoluble Drugs or Two Kinds of Water-Soluble Drugs.

Novel Drug Delivery Device Using Silicone: Controlled Release of Insoluble Drugs or Two Kinds of Water-Soluble Drugs.

Novel Method to Control Release of Lipophilic Drugs with High Potency from Silicone.

Sustained release of proteins from a modified vaginal ring device

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